WO2021097288A1 - Compositions and methods for treating neurodegenerative diseases - Google Patents

Abstract

The present disclosure relates to compositions and methods for treating a neurodegenerative disease such as Alzheimer's Disease. Provided herein are pharmaceutical compositions and formulations comprising a bacterial mixture and/or an oligomannurarate polymer (or derivative thereof). The bacterial mixture can include a bacterial isolate, a preparation of uncultured fecal bacteria, or a combination thereof.

Description

COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE

DISEASES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Application 62/935,940 filed November 15, 2019, which is herein incorporated by reference in its entirety.

BACKGROUND

[0002] Mammals harbor diverse microbial taxa in their gastrointestinal (GI) tracts. Interactions between gut microbes and between gut microbes and the host, e.g. the host immune system, shape a microbiota. A healthy microbiota provides the host with multiple benefits, including colonization resistance to a broad spectrum of pathogens, essential nutrient biosynthesis and absorption, and immune stimulation that maintains a healthy gut epithelium and an appropriately controlled systemic immunity. An unbalanced microbiota (also called ‘dysbiosis’ or disrupted symbiosis) may lose its beneficial function and result in increased susceptibility to pathogens, altered metabolic profiles, or induction of proinflammatory signals that can lead to local or systemic inflammation or autoimmunity. Additionally, such a disrupted microbiota may be infected by incoming pathogens, which can cause pain, diarrhea, gas, and constipation among other symptoms. Hence, the intestinal microbiota plays a significant role in the pathogenesis of many disorders such as pathogenic infections of the gut.

[0003] Implantation or administration of human colonic microbiota into the bowel of a sick patient is called Fecal Microbiota Transplantation (FMT), also commonly known as fecal bacteriotherapy. FMT is believed to repopulate the gut with a diverse array of microbes that control key pathogens by creating an ecological environment inimical to their proliferation and survival. It represents a therapeutic protocol that allows a fast reconstitution of a normal compositional and functional gut microbial community.

[0004] FMT has been used to treat Clostridium difficile infection (CDI). FMT has also been suggested in treating other gut infective agents such as E. coli and Vancomycin resistant Enterococci (VRE). It entails infusions through a colonoscope, an enema or via a nasojejunal tube of human microbiota either in the form of homogenized stool, or cultured stool components such as Clostridia, to implant in the colon and thereby displace or eradicate pathogenic bacteria, e.g., C. difficile. Fecal bacteriotherapy has also been successful in treating conditions having a neurological component, such as autism spectrum disorder (ASD), Multiple Sclerosis and Chronic Fatigue Syndrome.

[0005] A typical donor fecal microbiota administered to a patient during fecal bacteriotherapy can contain hundreds of bacterial strains, and the identity of the strains necessary for the treatment of the disorder, as well as the mechanisms by which such introduced strains interact with each other, the patient’s endogenous microbiome, and host cells, is largely unknown. Further, potential variation in (i) the identity and relative abundance of particular bacterial strains across different donor samples introduced into the guts of FMT recipients; and (ii) the extent to which a particular bacterial strain engrafts in the intestine of an FMT recipient, can lead to variable efficacy of fecal bacteriotherapy across a patient group afflicted with or susceptible to a disorder.

SUMMARY

[0006] In an aspect, this disclosure provides a pharmaceutical composition comprising an oligomannurarate (or a derivative thereof) and/or a bacterial mixture comprising a preparation of uncultured fecal bacteria derived from a stool of a healthy human donor.

[0007] In another aspect, this disclosure provides a method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject (i) an oligomannurarate or derivative thereof; and (ii) a bacterial mixture comprising a preparation of uncultured fecal bacteria derived from a stool of a healthy human donor. [0008] In a further aspect, this disclosure provides a method of manufacturing a pharmaceutical composition comprising a community of fecal bacteria, the method comprising: receiving a stool from a healthy human donor following ingestion by the donor of an oligomannurarate or derivative thereof; extracting the community of fecal bacteria from the stool; and formulating the community of fecal bacteria as the pharmaceutical composition, wherein the fecal bacteria are not cultured.

DETAILED DESCRIPTION

[0009] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0011] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. By way of example, “an element” means at least one element and can include more than one element.

[0012] As used herein, the term “substantially”, when used to modify a quality, generally allows certain degree of variation without that quality being lost. For example, in certain aspects such degree of variation can be less than 0.1%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, between 1-2%, between 2-3%, between 3-4%, between 4-5%, or greater than 5% or 10%.

[0013] Where a range of values is provided, it is understood that each intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the disclosure.

[0014] To avoid any doubt, used herein, terms or phrases such as “about”, “at least”, “at least about”, “at most”, “less than”, “greater than”, “within” or alike, when followed by a series of list of numbers of percentages, such terms or phrases are deemed to modify each and every number of percentage in the series or list, regardless whether the adverb, preposition, or other modifier phrase is reproduced prior to each and every member.

[0015] As used herein, the term “relative abundance” refers to relative representation of an organism of a particular kind (e.g., abacterial strain, species, or genus) relative to all organisms of similar nature in a certain community (e.g., a preparation of uncultured fecal bacteria or a bacterial mixture). Relative abundance is calculated by dividing the number of an organism of a particular kind by the total number of all organisms of similar nature in a certain community. In an aspect, relative abundance is measured by qPCR comparing PCR products generated with 16S primers targeting specific bacterial strains of interest against PCR products generated with universal primers targeting all 16S sequences. See e.g., Chu, N., et al. , “Profiling living bacteria informs preparation of fecal microbiota transplantations.” PLoS One 12(1): 1-16 (2017). In another aspect, the relative abundance is measured based on the number of sequence reads detected via high-throughput sequencing. Unless specified otherwise, a bacterial relative abundance mentioned herein is measured via high-throughput sequencing. In a further aspect, propidium monoazide (PMA) is used to differentiate between viable and dead fecal microbes as shown in Chu et al, PLoS One 12(1): 1-16 (2017).

[0016] As used herein, the term “treating” refers to (i) completely or partially inhibiting a disease, disorder or condition, for example, arresting its development; (ii) completely or partially relieving a disease, disorder or condition, for example, causing regression of the disease, disorder and/or condition; or (iii) completely or partially preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder and/or condition, but has not yet been diagnosed as having it. Similarly, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures.

[0017] As used herein, a “subject” refers to any animal subject including humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs, turkeys, chickens), and household pets (e.g., dogs, cats, rodents, etc.). Preferred subjects are human subjects. The human subject may be a pediatric, adult or a geriatric subject. In some aspects, the terms “patient” and “subject” are used interchangeably. As used herein, a “healthy subject” refers to a subject who has no history of gastrointestinal disease or condition. Exemplary healthy subjects include the screened donors described in paragraph [0235] below.

[0018] As used herein, a stool refers to a piece of solid matter or part thereof that is released by a mammal (e.g., human) from a bowel movement.

[0019] As used herein, a “microbiota” and “flora” refer to a community of microbes that live in or on a subject’s body, both sustainably and transiently, including eukaryotes, archaea, bacteria, and viruses (including bacterial viruses (i.e., phage)). A “fecal microbiota” or “fecal microbiota preparation” refers to a community of microbes present in or prepared from a subject’s feces. Typically a pharmaceutical composition described herein is prepared by incorporating such a fecal microbiota into the composition without culturing the fecal microbiota after its purification from a stool. Herein “uncultured fecal bacteria” or a “preparation of uncultured fecal bacteria” refer to a preparation comprising multiple non- pathogenic viable bacterial strains that have been harvested, extracted or purified from one or more stool samples, without culturing the strains (e.g. in culturing medium). Such a preparation of uncultured fecal bacteria can also be referred to as a collection of uncultured fecal bacteria or a population of uncultured fecal bacteria.

[0020] In some aspects, a preparation of uncultured fecal bacteria comprises non-selected fecal bacteria. Herein “non-selected fecal bacteria” refers to a collection of viable fecal bacterial strains (e.g., present in a fecal microbiota) extracted from one or more stool samples without subjecting the extracted bacteria to environmental conditions that intentionally select for a particular type, state or taxonomic category of bacteria (e.g., by deliberate removal of certain strains of bacteria, treatment of the bacteria with an agent such as ethanol or chloroform, or culturing). Such non-selected fecal bacteria can comprise bacterial strains in proportional content to corresponding bacterial strains in a fecal or intestinal microbiota of a normal healthy human. Steps taken to non-selectively extract fecal bacteria from a stool sample can include, for example, homogenization and filtering of the stool sample to separate the fecal bacterial strains from non-cellular stool material such as fiber and rough particulate matter, as well as, for example, eukaryotic host cells and viruses. Herein typically a non-selected fecal bacterial preparation can be prepared in either aerobic or anaerobic conditions, or a combination thereof. In certain aspects, a preparation of non-selected fecal bacteria comprises all or substantially all of the bacteria of a fecal microbiota of a stool sample. In certain aspects, a preparation of non- selected fecal bacteria comprises all or substantially all of the strains of a fecal microbiota of a stool sample. In certain aspects, a preparation of non-selected fecal bacteria comprises all or substantially all of the species of a fecal microbiota of a stool sample. In certain aspects, a preparation of non-selected fecal bacteria comprises all or substantially all of the genera of a fecal microbiota of a stool sample. In certain aspects, a preparation of non-selected fecal bacteria comprises all or substantially all of the phyla of a fecal microbiota of a stool sample. Therefore, such non-selective fecal microbiota can substantially resemble microbial constituents and the bacterial population structure found in such fecal sample.

[0021] In an aspect, a preparation of uncultured fecal bacteria comprises at least 2, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, or 600 bacterial species or strains. In another aspect, a preparation of uncultured fecal bacteria comprises between 2 and 5, 5 and 10, 10 and 20, 20 and 30, 30 and 40, 40 and 50, 50 and 60, 60 and 100, 100 and 200, 200 and 300, 300 and 400, 400 and 500, or 500 and 600 bacterial species or strains.

[0022] In an aspect, a preparation of uncultured fecal bacteria and/or non-selected fecal bacteria does not comprise an antibiotic resistant population of bacteria. [0023] In another aspect, the preparation of a composition comprising uncultured fecal bacteria can involve steps that select for a particular, type, state, or taxonomic category of bacteria (e.g., by deliberate removal of certain strains of bacteria, treatment of the population with a selective agent such as ethanol or chloroform, and/or screening of the bacteria for the ability to produce a metabolite at or above a threshold level).

[0024] Herein uncultured fecal bacteria are distinguished from a single, purified strain of bacteria such as a bacterial isolate. As used herein, “bacterial isolate” refers to an isolated group of substantially genetically identical bacterial cells generated by proliferation via binary fission from a single predecessor bacterial cell (e.g., by culturing the bacteria). Typically, a bacterial isolate is originally isolated as a single cell or genetically pure group of cells, for example, as a single colony on solid culture media or via serial dilutions in liquid culture, and thereafter archived (e.g. as a frozen stock) to provide a consistent and stable source for the isolate. Once isolated, in some aspects, a bacterial isolate can be grown as a pure culture of cells; in other aspects, multiple bacterial isolates can be grown simultaneously in the same vessel as a mixed culture. The term “substantially genetically identical” refers to the very high (e.g. >99.9%) genetic identity shared by different cells in uncontaminated pure compositions of bacterial isolates, owing to their proliferation from a common predecessor, but accounts for minor genetic dissimilarity between cells due to accumulations of relatively rare mutations. Generally, a bacterial isolate is synonymous with a pure culture of bacterial cells. Typically, herein a bacterial isolate consists of non-pathogenic bacteria. In an aspect, a bacterial isolate can be a probiotic, or an ingredient in a probiotic.

[0025] As used herein, the term “bacterial cocktail”, sometimes called a “bacterial consortium” or “synthetic bacterial mixture”, refers to an engineered mixture of bacteria comprising a defined consortium of multiple bacterial isolates. The term “defined consortium of multiple bacterial isolates” means that the bacterial cocktail contains two or more bacterial isolates, and that the identity of each bacterial isolate in the cocktail is known, and thus the cocktail can be consistently produced (e.g. by combining isolated bacterial strains) to have a stable composition and properties across separate batches. Herein “identity” of a bacterial isolate can refer to any characteristic of the isolate that uniquely identifies the isolate as different from one or more other bacterial isolates or bacterial strains. Examples of identifying characteristics of a bacterial isolate include nucleotide sequences such as a 16S rRNA sequence, the sequence of one or more coding or non-coding regions of a nucleic acid, and entire genome sequences, levels of gene expression, physiological or metabolic traits, or anatomical traits such as staining pattern or cell wall characteristics.

[0026] As used herein, “bacterial mixture” refers to an engineered composition comprising viable bacterial cells. In some aspects, a bacterial mixture comprises one or more non- pathogenic bacterial isolates. In some aspects, a bacterial mixture comprises a preparation of uncultured fecal bacteria. In some aspects, a bacterial mixture comprises both of one or more non-pathogenic bacterial isolates and a preparation of uncultured fecal bacteria.

[0027] As used herein, “therapeutically effective amount,” “effective amount” or “pharmaceutically active dose” refers to an amount of a composition which is effective in treating the named disease, disorder, condition, or symptom.

[0028] As used herein, “oligomannurarate”, also referred to as “oligomannate”, refers to an alginate oligosaccharide composed of at least two b-D-mannuronic acid subunits linked by 1,4 glycosidic bonds. Oligomannurarate is a heparanase inhibitor. In an aspect, the oligomannurarate oligosaccharide is a polymer comprising a degree of polymerization ranging from 2 to 22. In an aspect, the structural formula of an oligomannurarate is:

wherein, n represents an integer of 0 or any from 1-19.

[0029] In another aspect, the structural formula of an oligomannurarate is:

wherein, n represents an integer of 0 or any from 1-19.

[0030] As used herein, “oligomannurarate derivative” refers to a chemical derivative of oligomannurarate. Non-limiting examples of derivatives include salts, for example sodium, potassium, calcium, magnesium, and the like. Another example of an oligomannurarate derivative is an oligomannurarate sulfate, wherein one or more of the hydroxyl groups in the oligomannurarate is sulfated. Other derivatives include, but are not limited to, metabolites, salts, esters, hydrates, solvates, isomers, enantiomers, crystalline forms, co-crystalline forms, amorphous forms, free acid forms, free base forms, pro-drug (including any ester pro-drug) forms, racemates, polymorphs, chelates, stereoisomers, and tautomers. [0031] As used herein, “isolated” or “purified” refers to a bacterium or other entity or substance that has been (1) separated from at least some of the components with which it was associated when initially produced (whether it was initially produced in nature or in an experimental setting), and/or (2) produced, prepared, purified, and/or manufactured by the hand of man. Isolated or purified bacteria can be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated.

[0032] As used herein, the terms “non-pathogenic” in reference to a bacterium or any other organism or entity includes any such organism or entity that is not capable of causing or affecting a disease, disorder or condition of a host organism containing the organism or entity.

[0033] As used herein, “spore” or a population of “spores” includes bacteria (or other single- celled organisms) that are generally viable, more resistant to environmental influences such as heat and bacteriocidal agents than vegetative forms of the same bacteria, and typically capable of germination and out-growth. “Spore-formers” or bacteria “capable of forming spores” are those bacteria containing the genes and other necessary abilities to produce spores under suitable environmental conditions.

[0034] As used herein, “colony forming units” (CFUs) refers to an estimate of the number of viable microorganism cells in a given sample. The number of CFUs can be assessed by counting the number of colonies on an agar plate as in standard methods for determining the number of viable bacterial cells in a sample.

[0035] As used herein, “viable” means possessing the ability to multiply. The viability of bacterial populations can be monitored as a function of the membrane integrity of the cell. Cells with a compromised membrane are considered to be dead or dying, whereas cells with an intact membrane are considered live. For example, SYTO 9 and propidium iodide are used to stain and differentiate live and dead bacteria. See Stocks, Cytometry A. 2004 Oct;61 (2): 189-95. Cell viability can also be evaluated via molecular viability analyses, e.g., a PCR-based approach, which can differentiate nucleic acids associated with viable cells from those associated with inactivated cells. See Cangelosi and Mescheke, Appl Environ Microbiol. 2014 Oct; 80(19): 5884—5891.

[0036] As used herein, “Shannon Diversity Index” refers to a diversity index that accounts for abundance and evenness of species present in a given community using the formula H = -

where H is Shannon Diversity Index, R is the total number of species in the community, and pi is the proportion of R made up of the z^'th species. Higher values indicate diverse and equally distributed communities, and a value of 0 indicates only one species is present in a given community. For further reference, see Shannon and Weaver, (1949) The mathematical theory of communication. The University of Illinois Press, Urbana. 117pp.

[0037] As used herein, “antibiotic” refers to a substance that is used to treat and/or prevent bacterial infection by killing bacteria, inhibiting the growth of bacteria, or reducing the viability of bacteria.

[0038] As used herein, “adverse events (AEs)” refers to any dose that results in procedure- or microbiota-related signs or symptoms. As used herein, “serious adverse events (SAEs)” refers to any medical occurrence that at any dose: results in death or is life-threatening. As used herein "life-threatening" refers to an event in which the patient is at risk of death at the time of the event. Adverse events are graded according to a scale used by one of ordinary skill in the art (e.g., National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)).

[0039] Described herein are pharmaceutical compositions comprising at least one of (i) a bacterial mixture; and (ii) an oligomannurarate or derivative thereof for the treatment of a neurodegenerative disease. In an aspect, a composition comprises a bacterial mixture, for example comprising a preparation of uncultured fecal bacteria and/or a bacterial isolate. In an aspect, a composition comprises at least one oligomannurarate or derivative thereof. In an aspect, a composition comprises a combination of a bacterial mixture (e.g., a preparation of uncultured fecal bacteria) and at least one oligomannurarate or derivative thereof.

[0040] Without wishing to be bound by theory, administration of oligomannurarate or derivative thereof to a subject may facilitate the alleviation of intestinal microbial dysbiosis in the subject by changing the relative abundance of bacterial strains in the gut. For example, oligomannurarate or derivative thereof may selectively promote the proliferation of certain beneficial bacterial strains in a patient’s intestine by providing a carbohydrate-based nutrient source for those strains. Such changes in bacterial relative abundances in a patient’s gut microbiota may lead to a reduction in the concentration of certain potentially harmful metabolites (e.g., amino acids such as phenylalanine and isoleucine) secreted by the microbiota into the intestine and absorbed into the blood. In certain aspects, such metabolites can cross the blood-brain barrier to deleteriously influence neural function (e.g., by inducing or contributing to synaptic degeneration, amyloid deposition, and/or cognitive impairment). In an aspect, administration of oligomannurarate or derivative thereof increases the relative abundance of facultative or obligate anaerobic bacteria (e.g., by selectively promoting the proliferation of the bacteria). In an aspect, administration of oligomannurarate or derivative thereof increases the relative abundance of at least one member of the bacterial phylum Firmicutes (e.g., by selectively promoting the proliferation of the bacteria). In an aspect, administration of oligomannurarate or derivative thereof increases the relative abundance of at least one member of the bacterial phylum Bacteroidetes (e.g., by selectively promoting the proliferation of the bacteria). In an aspect, administration of oligomannurarate or derivative thereof increases the relative abundance of at least one member of the bacterial phylum Verrucomicrobia (e.g., by selectively promoting the proliferation of the bacteria).

[0041] The impact of oligomannurarate administration on the microbial composition of the intestinal microbiota of a patient is limited to modifying relative abundances of bacterial strains pre-existing in the intestine prior to the administration. Oligomannurarate administration alone cannot introduce new strains of bacteria into a patient’s intestine, and as such may not be sufficient on its own to alleviate gut dysbiosis or a neurodegenerative disease related thereto, e.g., if the dysbiosis or neurodegenerative disease is related at least in part to the absence of one or more bacterial strains from the patient’s gut microbiota. In an aspect, co-administration to a patient of a bacterial mixture described herein (e.g., comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria derived from a fecal microbiota of a healthy human donor who does not have the gut dysbiosis or a neurodegenerative disease associated with the dysbiosis) with oligomannurarate or derivative thereof advantageously introduces beneficial bacterial strains into the intestine of the subject. In certain aspects, once such bacterial strains are introduced into the patient’s intestine via administration of the bacterial mixture, co-administered oligomannurarate or derivative thereof can act on the strains to further increase their relative abundance. In another aspect, a bacterial mixture introduces into a patient’s intestine comprises one or more beneficial bacterial strains that are present at a low relative abundance prior to the administration of the bacterial mixture (e.g., compared to the relative abundance of the one or more bacterial strains in a healthy patient not having the dysbiosis). In certain aspects, once a bacterial strain’s relative abundance is increased by administering the bacterial mixture, co-administered oligomannurarate or derivative thereof can act on the bacterial isolate to further increase its relative abundance.

[0042] Accordingly, it will be understood that a bacterial mixture and oligomannurarate or derivative thereof can act in concert when co-administered to a patient in order to promote an increase in the relative abundance of beneficial bacterial strains to rectify a gut dysbiosis and/or treat a neurodegenerative disease. In an aspect, oligomannurarate or derivative thereof and a bacterial mixture act synergistically to increase the relative abundance of a bacterial strain, for example because the function of oligomannurarate or derivative thereof in promoting the relative abundance of the strain depends on the delivery of the bacterial strain into the patient’s intestine by administration of the bacterial mixture. In other aspects, oligomannurarate or derivative thereof and the bacterial mixture may act in parallel to treat a gut dysbiosis and/or neurodegenerative disease by increasing the relative abundance of different beneficial bacterial strains, thereby collectively generating a healthier gut flora than either is capable of promoting individually. For example, a bacterial mixture containing a preparation of uncultured fecal bacteria may lack a beneficial bacterial strain that oligomannurarate is capable of acting on to increase its relative abundance. If such bacterial strain is present in the patient’s gut, then administration of the oligomannurarate can increase its relative abundance, despite that the strain is not present in the bacterial mixture. Conversely, oligomannurarate may be incapable of acting on certain beneficial bacterial strains to increase their relative abundance in a patient’s gut. If such bacterial strains are present in the bacterial mixture (e.g., containing a preparation of uncultured fecal bacteria), then administration of the bacterial mixture can increase the relative abundance of the strain, despite that the strain is not affected by oligomannurarate.

[0043] In another aspect, administration of oligomannurarate or derivative thereof reduces the relative abundance of one or more bacterial strains (e.g., one or more non-beneficial bacterial strains) in the microbiota of a patient, for example by selectively promoting the proliferation of other bacterial strains in the microbiota.

[0044] In an aspect, a composition comprises only one species of oligomannurarate or a derivative thereof. In an aspect, all or substantially all of the oligomannurarate in a composition described herein can be of the same polymer chain length or the same degree of polymerization. For example, all or substantially all of the oligomannurarate can be a dimer of oligomannurarate or a derivative thereof, a trimer of oligomannurarate or a derivative thereof, a tetramer of oligomannurarate or a derivative thereof, a 5-mer of oligomannurarate or a derivative thereof, a 6-mer of oligomannurarate or a derivative thereof, a 7-mer of oligomannurarate or a derivative thereof, an 8-mer of oligomannurarate or a derivative thereof, a 9-mer of oligomannurarate or a derivative thereof, a 10-mer of oligomannurarate or a derivative thereof, an 11-mer of oligomannurarate or a derivative thereof, a 12-mer of oligomannurarate or a derivative thereof, a 13-mer of oligomannurarate or a derivative thereof, a 14-mer of oligomannurarate or a derivative thereof, a 15-mer of oligomannurarate or a derivative thereof, a 16-mer of oligomannurarate or a derivative thereof, a 17-mer of oligomannurarate or a derivative thereof, an 18-mer of oligomannurarate or a derivative thereof, a 19-mer of oligomannurarate or a derivative thereof, a 20-mer of oligomannurarate or a derivative thereof, a 21-mer of oligomannurarate or a derivative thereof, or a 22-mer of oligomannurarate or a derivative thereof.

[0045] In another aspect, a composition comprises a mixture of multiple different species of an oligomannurarate or derivative thereof, i.e., with each species having a different polymer chain length or degree of polymerization. For example, a composition comprising an oligomannurarate can comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or greater than 22 different polymer species of an oligomannurarate or derivative thereof.

[0046] In an aspect, a composition comprises a mixture of sodium oligomannurarate polymers having degrees of polymerization ranging from dimers to decamers, with each polymer having an average molecular weight of approximately 1 kDa. Such a mixture of oligomannurarate polymers is referred to herein as “GV-971” and is described in Wang et al., “Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression” Cell Research (2019) 29:787-803, the contents of which are hereby incorporated by reference herein in their entirety. Each sodium oligomannurarate polymer in GV-971 can be depicted by the following molecular structure:

n=1-9; =Q,1 or 2; m -0 or 1

[0047] In an aspect, an oligomannurarate or a derivative thereof is manufactured as described in U.S. Patent No. 9,493,496, U.S. Patent No. 8,835,403, U.S. Patent No. 10,213,456, or U.S.

Pat. App. Pub. 2019/0255092, the contents of which are hereby incorporated by reference herein in their entirety. In another aspect, an oligomannurarate or a derivative thereof is extracted from a brown seaweed.

[0048] In an aspect, an oligomannurarate or derivative thereof described here is in a single composition with a bacterial culture or mixture or a preparation of uncultured fecal bacteria described here. In a further aspect, an oligomannurarate or derivative thereof described here is in a single kit or prescribed medication with, but separate compositions from, a bacterial culture or mixture or a preparation of uncultured fecal bacteria described here.

[0049] In aspects of the present disclosure, a pharmaceutical composition comprises a bacterial mixture comprising a preparation of uncultured fecal bacteria, for example non-selected fecal bacteria. In an aspect, a bacterial mixture comprises a single bacterial isolate or multiple bacterial isolates (e.g., in the form of a bacterial cocktail). In an aspect, a pharmaceutical composition comprises a bacterial mixture comprising (i) a preparation of uncultured fecal bacteria; and (ii) at least one bacterial isolate. Such a bacterial mixture can be referred to as a preparation of uncultured fecal bacteria enriched, supplemented or “spiked” with one or more bacterial isolates. By enriching or spiking a population of uncultured bacteria derived from a stool sample (e.g., a fecal microbiota) of a healthy donor with one or more non-pathogenic bacterial isolates, a composition can be produced in which the amount of a particular bacterial strain or strains (i.e. the spiked-in bacterial isolate(s)) can be accounted for and precisely controlled. Without being bound by theory, this is advantageous, for example, where the at least one bacterial isolate spiked into the preparation of uncultured fecal bacteria is important for or involved in the treatment of a subject (e.g., having or susceptible to acquiring one or more symptoms of a neurodegenerative disease), but insufficient on its own to generate an enhanced or optimal treatment response in the subject. Administration of one or more bacterial isolates together with a “backbone” preparation of uncultured fecal bacteria (i.e., derived from a healthy donor) provides a patient with the advantage of the administered bacterial isolate combined with multi-factorial benefits conferred by the additional fecal bacterial strains present in the preparation of uncultured fecal bacteria. These additional fecal bacterial strains may combine to, for example, provide for the necessary context or interactions (e.g. via one or more released factors) to enable the bacterial isolate to induce an optimal response in the subject, or may directly induce a response in the subject that combines and/or synergizes with a response induced by the bacterial isolate to treat the subject. Accordingly, in certain aspects, a pharmaceutical composition comprising a mixture of one or more bacterial isolates and a preparation of uncultured fecal bacteria can be more effective in treating a subject (e.g., having or susceptible to acquiring one or more symptoms of a neurodegenerative disease) than a composition comprising the bacterial isolate alone. In an aspect, a spike-in bacterial isolate (or a bacterial isolate used to enrich or supplement a preparation of uncultured fecal bacteria) comprises, or is from, one or more bacteria or other microbes capable of producing an oligomannurarate or a derivative thereof. Exemplary oligomannurarate-producing bacteria include, for example, Pseudomonas and Azotobacter. In an aspect, a spike-in bacterial isolate (or a bacterial isolate used to enrich or supplement a preparation of uncultured fecal bacteria) comprises, or is from, one or more fecal bacterial genera that change their level (e.g., increasing their relative abundance) in response to oligomannurarate intake. Exemplary bacteria that respond to oligomannurarate can be found in Figure 4 of Wang et al., “Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression” Cell Research (2019) 29:787- 803.

[0050] In an aspect, a pharmaceutical composition comprises a bacterial mixture comprising at least one non-pathogenic bacterial isolate and/or a bacterial isolate having attenuated pathogenicity. A bacterial isolate can be isolated from any non-living (e.g., soil) or living source (e.g., animal), including a mammal such as a sheep, swine, bovine, primate, or human. If isolated from an animal, a bacterial isolate can be derived or isolated from any part of the animal, such as an organ, fluid or secretion, including an intestine, oral cavity, milk, saliva, or feces. In another aspect, a bacterial isolate is derived from a human. In another aspect, a bacterial isolate is derived from the fecal microbiota or intestinal microbiota of a human. In an aspect, a pharmaceutical composition administered herein comprises fecal bacteria. In another aspect, a pharmaceutical composition administered herein comprises one or more bacterial isolates extracted, isolated and/or cultured from a stool sample of a healthy human donor.

[0051] In some aspects, a bacterial isolate incorporated into a pharmaceutical composition described herein comprises live, vegetative cells. In some aspects, the bacterial isolate comprises bacteria capable of forming spores. In some aspects, the bacterial isolate comprises bacteria in the form of spores, e.g. viable spores. In some aspects, the bacterial isolate comprises bacteria in the form of live, vegetative cells and spores. In some aspects, a bacterial isolate is substantially free of live, vegetative cells. In some aspects, an entire bacterial cocktail is substantially free of live vegetative cells. In some aspects, a bacterial isolate is substantially free of spores. In some aspects, an entire bacterial cocktail is substantially free of spores.

[0052] In an aspect, a pharmaceutical composition can include a bacterial isolate (e.g., in combination with or spiked into a preparation of uncultured fecal bacteria) comprising, for example, a species of Lactobacillus, Bifidobacterium, Streptococcus, Clostridium, Collinsella, Dorea, Ruminococcus, Coprococcus, Prevotella, Veillonella, Bacteroides, Baccillus, or a combination thereof. In another aspect, a pharmaceutical composition can include a bacterial isolate comprising a species of Veillonellaceae, Firmicutes, Gammaproteobacteria, Bacteroidetes, or a combination thereof. In another aspect, a pharmaceutical composition can comprise a bacterial isolate comprising bacterial spores. In one aspect, fecal bacterial spores are Clostridium spores, Bacillus spores, or a combination thereof. In another aspect, a pharmaceutical composition can comprises a preparation of cultured fecal bacteria comprising one or more, two or more, three or more, four or more, or five or more viable fecal microorganisms that increase their relative abundance in response to an oligomannurarate intake (e.g., from bacterial genera listed in top half of Figure 4b of Wang et al., Cell Research (2019) 29:787-803). In another aspect, a preparation of cultured fecal bacteria do not contain more than three, more than two, more than one, or any bacteria that decrease their relative abundance in response to an oligomannurarate intake (e.g., from bacterial genera listed in bottom half of Figure 4b of Wang et al., Cell Research (2019) 29:787-803).

[0053] In an aspect, a bacterial isolate incorporated into a pharmaceutical composition described herein is a probiotic, or an ingredient in a probiotic. In an aspect, multiple bacterial isolates incorporated into a pharmaceutical composition described herein are probiotics, or ingredients in a probiotic. In an aspect, one or more bacterial isolates are in the form of a probiotic when incorporated into a pharmaceutical composition.

[0054] In aspects of the present disclosure, a pharmaceutical composition can comprise a bacterial mixture comprising multiple bacterial isolates (e.g. as a bacterial cocktail). In aspects of the present disclosure, the bacterial mixture can comprise at least two bacterial isolates, at least three bacterial isolates, at least four bacterial isolates, at least five bacterial isolates, at least six bacterial isolates, at least seven bacterial isolates, at least eight bacterial isolates, at least nine bacterial isolates, at least ten bacterial isolates, or a greater number of bacterial isolates, e.g., fifteen, twenty, twenty-five, thirty, or more bacterial isolates.

[0055] In various aspects, a pharmaceutical composition comprises a bacterial mixture comprising one or more bacterial isolates capable of engrafting in a subject’s GI tract following administration of the composition to the subject. Herein “engrafting” or “engraftment” refers to the stable presence over time of cells of a bacterial strain or bacterial isolate in the intestinal tract of a subject (e.g., after introducing the bacterial strain or isolate into the subject’s intestinal tract by administering a composition described herein, for example, orally or rectally). Typically, engraftment of a bacterial isolate introduced into the intestine of a subject (e.g. by oral and/or rectal administration) is measured longitudinally, or over time, by comparing the abundance of the bacterial isolate in fecal samples of the subject before and after administration of the bacterial isolate to the subject. In an aspect, the bacterial isolate introduced into the intestine of the subject was absent prior to the administration. In another aspect, the bacterial isolate introduced into the intestine of the subject was present in the intestine prior to the administration, but is increased abundance following the administration. In certain aspects, engraftment is determined by identifying an increase in abundance of a bacterial strain administered to an intestine of the subject after at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14, days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or greater than 6 months following administration of the bacterial strain to the subject.

[0056] In aspects of the present disclosure, engraftment of a bacterial isolate in an intestine of a subject occurs when the bacterial isolate is administered to the subject at or above a threshold dose. In aspects of the present disclosure, engraftment of a bacterial isolate in an intestine of a subject does not occur, or occurs with relative inefficiency (e.g., across patients), when the bacterial isolate is administered to the subject below the threshold dose. For example, engraftment of a bacterial isolate into the intestine of a subject can occur when the bacterial isolate is administered to the subject (e.g., orally or rectally in a pharmaceutical composition described herein) at a dose of at least 10⁶ cells, at least 10⁷ cells, at least 10⁸ cells, at least 10⁹ cells, at least 10¹⁰ cells, at least 10¹¹ cells, or at least 10¹² cells.

[0057] In aspects of the present disclosure, engraftment of a bacterial isolate in an intestine of a subject occurs when the bacterial isolate is administered to the subject at or below a threshold dose. In an aspect, engraftment of a bacterial isolate in an intestine of a subject does not occur, or occurs with relative inefficiency (e.g., across patients), when the bacterial isolate is administered to the subject above the threshold dose. For example, engraftment of a bacterial isolate into the intestine of a subject can occur when the bacterial isolate is administered to the subject (e.g., orally or rectally in a pharmaceutical composition described herein) at a dose of not more than 10⁸ cells, not more than 10⁹ cells, not more than 10¹⁰ cells, not more than 10¹¹ cells, or not more than 10¹² cells. [0058] In an aspect, a dose of one or more bacterial isolates to a patient in need thereof can depend on the engraftment threshold of the bacterial isolate.

[0059] In an aspect, a bacterial isolate in a pharmaceutical composition administered to a subject engrafts in the duodenum of the subject. In an aspect, a bacterial isolate in a pharmaceutical composition administered to a subject engrafts in the jejunum of the subject. In an aspect, abacterial isolate in a pharmaceutical composition administered to a subject engrafts in the ileum of the subject. In an aspect, a bacterial isolate in a pharmaceutical composition administered to a subject engrafts in the colon of the subject.

[0060] In some aspects, a bacterial isolate is a non-pathogenic bacterial strain. In an aspect, a non-pathogenic bacterial strain comprises a genome that lacks genes, or expression thereof, which cause virulence and/or toxicity. For instance, in some aspects, a bacterial cocktail comprising one or more bacterial isolates is substantially free of organisms or entities (e.g., substantially free of pathogenic bacteria) which are capable of causing a disease or disorder in a subject administered the bacterial cocktail.

[0061] In an aspect, a bacterial isolate can be obtained from a laboratory stock or a bacterial cell bank of a bacterial strain originally obtained from a stool sample of a healthy human donor. For example, a fecal microbiota (e.g., purified from a stool sample using methods described herein) can be used as the source of a bacterial isolate incorporated into a pharmaceutical composition described herein. In certain aspects, all or a portion of a fecal microbiota of a stool sample is cultured on a solid media substrate and one or more bacterial isolates are identified as single colonies. In other aspects, all or a portion of a fecal microbiota can be inoculated into liquid culture to produce a mixed bacterial culture that is then serially diluted to produce a culture containing a single cell of a bacterial isolate. In an aspect, an identified bacterial isolate can then be cultured (e.g., in solid or liquid media) using known techniques and expanded. Methods for isolating, purifying, and/or culturing bacterial strains are described in Sadowsky et al, WO 2012/122478 and described in Borody et al, WO 2012/016287, each of which is incorporated herein by reference.

[0062] In an aspect, a pharmaceutical composition comprises a bacterial mixture comprising a preparation of uncultured fecal bacteria, for example non-selected fecal bacteria and/or a substantially complete fecal microbiota of a stool or portion thereof (e.g., from a healthy human donor). Herein the term “substantially complete fecal microbiota” refers to a preparation of uncultured fecal bacteria that comprises viable bacterial cells from all or substantially all of the bacterial taxa represented among the viable bacterial cells in the stool from which the fecal microbiota was extracted. In an aspect, the relative abundance of viable bacterial cells from at least two of the taxa in the substantially complete fecal microbiota is proportional to the relative abundance of the viable cells from those taxa in the stool from which the fecal microbiota was extracted. In an aspect, the bacterial mixture further comprises one or more bacterial isolates. In an aspect, the bacterial mixture does not comprise a bacterial isolate.

[0063] In one aspect, a preparation of uncultured fecal bacteria comprises a donor’s entire or substantially complete fecal microbiota from a stool sample. In one aspect, a preparation of uncultured fecal bacteria comprises a non-selective fecal microbiota. In another aspect, a preparation of uncultured fecal bacteria comprises an isolated or purified population of live non-pathogenic fecal bacteria. In a further aspect, a preparation of uncultured fecal bacteria comprises a non-selective and substantially complete fecal microbiota preparation from a single donor. In another aspect, a pharmaceutical composition used herein comprises a mixture of live, non-pathogenic, bacterial isolates and live, non-pathogenic, purified or extracted, preparation of uncultured fecal bacteria.

[0064] In an aspect, the manufacture of a preparation of uncultured fecal bacteria involves a treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonication. In another aspect, the manufacture of a preparation of uncultured fecal bacteria involves no treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonication. In one aspect, the manufacture of a preparation of uncultured fecal bacteria involves a separation step selected from the group consisting of density gradients, filtration (e.g., sieves, nylon mesh), and chromatography. In another aspect, the manufacture of a preparation of uncultured fecal bacteria involves no separation step selected from the group consisting of density gradients, filtration (e.g., sieves, nylon mesh), and chromatography. In another aspect, a preparation of uncultured fecal bacteria comprises a complete or substantially complete fecal microbiota from a stool or portion thereof of a subject. In another aspect, a pharmaceutical composition administered herein comprises a fecal microbiota substantially free of donor eukaryotic cells.

[0065] In an aspect, a pharmaceutical composition provided or administered herein comprises a preparation of uncultured fecal bacteria comprising a Shannon Diversity Index of greater than or equal to 0.3, greater than or equal to 0.4, greater than or equal to 0.5, greater than or equal to 0.6, greater than or equal to 0.7, greater than or equal to 0.8, greater than or equal to 0.9, greater than or equal to 1.0, greater than or equal to 1.1, greater than or equal to 1.2, greater than or equal to 1.3, greater than or equal to 1.4, greater than or equal to 1.5, greater than or equal to 1.6, greater than or equal to 1.7, greater than or equal to 1.8, greater than or equal to 1.9, greater than or equal to 2.0, greater than or equal to 2.1 , greater than or equal to 2.2, greater than or equal to 2.3, greater than or equal to 2.4, greater than or equal to 2.5, greater than or equal to 3.0, greater than or equal to 3.1, greater than or equal to 3.2, greater than or equal to

3.3, greater than or equal to 3.4, greater than or equal to 3.5, greater than or equal to 3.6, greater than or equal to 3.7, greater than or equal to 3.8, greater than or equal to 3.9, greater than or equal to 4.0, greater than or equal to 4.1, greater than or equal to 4.2, greater than or equal to

4.3, greater than or equal to 4.4, greater than or equal to 4.5, or greater than or equal to 5.0. In another aspect, a pharmaceutical composition comprises fecal microbiota comprising a Shannon Diversity Index of between 0.1 and 3.0, between 0.1 and 2.5, between 0.1 and 2.4, between 0.1 and 2.3, between 0.1 and 2.2, between 0.1 and 2.1, between 0.1 and 2.0, between 0.4 and 2.5, between 0.4 and 3.0, between 0.5 and 5.0, between 0.7 and 5.0, between 0.9 and 5.0, between 1.1 and 5.0, between 1.3 and 5.0, between 1.5 and 5.0, between 1.7 and 5.0, between 1.9 and 5.0, between 2.1 and 5.0, between 2.3 and 5.0, between 2.5 and 5.0, between 2.7 and 5.0, between 2.9 and 5.0, between 3.1 and 5.0, between 3.3 and 5.0, between 3.5 and 5.0, between 3.7 and 5.0, between 31.9 and 5.0, or between 4.1 and 5.0. In one aspect, a Shannon Diversity Index is calculated at the phylum level. In another aspect, a Shannon Diversity Index is calculated at the family level. In one aspect, a Shannon Diversity Index is calculated at the genus level. In another aspect, a Shannon Diversity Index is calculated at the species level. In a further aspect, a pharmaceutical composition comprises a preparation of flora in proportional content that resembles a normal healthy human fecal flora.

[0066] In a further aspect, a pharmaceutical composition comprises fecal bacteria from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different families. In another aspect, a pharmaceutical composition comprises fecal bacteria from at least 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 different families. In yet another aspect, a pharmaceutical composition comprises fecal bacteria from at least 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 different families. In a further aspect, a pharmaceutical composition comprises fecal bacteria from at least 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 different families. In another aspect, a pharmaceutical composition comprises fecal bacteria from at least 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 different families. In another aspect, a pharmaceutical composition comprises fecal bacteria from between 1 and 10, between 10 and 20, between 20 and 30, between 30 and 40, between 40 and 50 different families. In an aspect, a pharmaceutical composition provided or administered herein comprises a preparation of uncultured fecal bacteria comprising no greater than 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% weight non-living material/weight biological material. In another aspect, a pharmaceutical composition provided or administered herein comprises an uncultured fecal microbiota comprising no greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% weight non-living material/weight biological material. In another aspect, a pharmaceutical composition provided or administered herein comprises, consists of, or consists essentially of, particles of non-living material and/or particles of biological material of a fecal sample that passes through a sieve, a column, or a similar filtering device having a sieve, exclusion, or particle filter size of 2.0 mm, 1.0 mm, 0.5 mm, 0.33mm, 0.25 mm, 0.212 mm, 0.180 mm, 0.150 mm, 0.125 mm, 0.106 mm, 0.090 mm, 0.075 mm, 0.063 mm, 0.053 mm, 0.045 mm, 0.038 mm, 0.032 mm, 0.025 mm, 0.020 mm, 0.01 mm, or 0.002 mm. “Non-living material” does not include an excipient, e.g., a pharmaceutically inactive substance, such as a cryoprotectant, added to a processed fecal material. “Biological material” refers to the living material in fecal material, and includes microbes including prokaryotic cells, such as bacteria and archaea (e.g., living prokaryotic cells and spores that can sporulate to become living prokaryotic cells), eukaryotic cells such as protozoa and fungi, and viruses. In one aspect, “biological material” refers to the living material, e.g., the microbes, eukaryotic cells, and viruses, which are present in the colon of a normal healthy human. In an aspect, a pharmaceutical composition provided or administered herein comprises an extract of human stool, wherein the composition is substantially odorless. In an aspect, a pharmaceutical composition provided or administered herein comprises fecal material or a fecal floral preparation in a lyophilized, crude, semi- purified or purified formulation.

[0067] In an aspect, a preparation of uncultured fecal bacteria included in a pharmaceutical composition comprises highly refined or purified fecal flora, e.g., substantially free of nonfloral fecal material. In an aspect, an uncultured fecal microbiota (comprising a preparation of uncultured fecal bacteria) harvested from a donor can be further processed, e.g., to undergo microfiltration before, after, or before and after sieving. In another aspect, a highly purified fecal microbiota product is ultra-filtrated to remove large molecules but retain the therapeutic microflora, e.g., bacteria.

[0068] In another aspect, a preparation of uncultured fecal bacteria in a pharmaceutical composition used herein comprises or consists essentially of a substantially isolated or purified fecal flora or complete (or substantially complete) fecal microbiota that is (or comprises) an isolate of fecal flora that is at least about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% isolated or pure, or having no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecal floral material; or, a substantially isolated, purified, or complete microbiota as described in Sadowsky et al., WO 2012/122478 Al, or as described in Borody et al., WO 2012/016287 A2.

[0069] In an aspect, a preparation of uncultured fecal bacteria included in a pharmaceutical composition comprises a donor’s substantially complete or non-selected fecal microbiota. In another aspect, the fecal microbiota in a pharmaceutical composition comprises no antibiotic resistant population. In another aspect, a pharmaceutical composition comprises an uncultured fecal microbiota and is largely free of extraneous matter (e.g., non-living matter including acellular matter such as residual fiber, DNA, RNA, viral coat material, non-viable material; and living matter such as eukaryotic cells from the fecal matter’s donor).

[0070] In an aspect, a preparation of uncultured fecal bacteria included in a pharmaceutical composition is derived from a disease-screened stool sample of a human donor. In an aspect, a stool sample does not include an antibiotic resistant population. For example, a composition can comprise a preparation of viable flora which can in proportional content, resemble normal healthy human fecal flora which does not include antibiotic resistant populations.

[0071] In one aspect, a preparation of uncultured fecal bacteria described and used herein comprises one or more, two or more, three or more, four or more, or five or more live fecal microorganisms selected from the group consisting of Acidaminococcus, Akkermansia, Alistipes, Anaerotruncus, Bacteroides, Bifidobacterium, Blautia, Butyrivibrio, Clostridium, Collinsella, Coprococcus, Corynebacterium, Dorea, Enterococcus, Escherichia, Eubacterium, Faecalibacterium, Haemophilus, Holdemania, Lactobacillus, Moraxella, Parabacteroides, Prevotella, Propionibacterium, Raoultella, Roseburia, Ruminococcus, Staphylococcus, Streptococcus, Subdoligranulum, and Veillonella. In one aspect, a fecal microbiota preparation comprises one or more, two or more, three or more, four or more, or five or more live fecal microorganisms are selected from the group consisting of Bacteroides fragilis ssp. vulgatus, Collinsella aerofaciens, Bacteroides fragilis ssp. thetaiotaomicron, Peptostreptococcus productus II, Parabacteroides distasonis, Faecalibacterium prausnitzii, Coprococcus eutactus, Peptostreptococcus productus I, Ruminococcus bromii, Bifidobacterium adolescentis, Gemmiger formicilis, Bifidobacterium longum, Eubacterium siraeum, Ruminococcus torques, Eubacterium rectale, Eubacterium eligens, Bacteroides eggerthii, Clostridium leptum, Bacteroides fragilis ssp. A, Eubacterium biforme, Bifidobacterium infantis, Eubacterium rectale, Coprococcus comes, Pseudoflavonifractor capillosus, Ruminococcus albus, Dorea formicigenerans, Eubacterium hallii, Eubacterium ventriosum I, Fusobacterium russi, Ruminococcus obeum, Eubacterium rectale, Clostridium ramosum, Lactobacillus leichmannii, Ruminococcus callidus, Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides fragilis ssp. fragilis, Coprococcus catus, Aerostipes hadrus, Eubacterium cylindroides, Eubacterium ruminantium, , Staphylococcus epidermidis, Eubacterium limosum, Tissirella praeacuta, Fusobacterium mortiferum I, Fusobacterium naviforme, Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes, Ruminococcus flavefaciens, Bacteroides fragilis ssp. ovatus, Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichia coli, Gemella morbillorum, Finegoldia magnus, Streptococcus intermedius, Ruminococcus lactaris, Eubacterium tenue, Eubacterium ramulus, Bacteroides clostridiiformis ssp. clostridliformis, Bacteroides coagulans, Prevotella oralis, Prevotella ruminicola, Odoribacter splanchnicus, and Desuifomonas pigra.

[0072] In one aspect, a fecal microbiota preparation described and used here lacks or is substantially devoid of one or more, two or more, three or more, four or more, or five or more live fecal microorganisms are selected from the group consisting of Acidaminococcus, Akkermansia, Alistipes, Anaerotruncus, Bacteroides, Bifidobacterium, Blautia, Butyrivibrio, Clostridium, Collinsella, Coprococcus, Corynebacterium, Dorea, Enterococcus, Escherichia, Eubacterium, Faecalibacterium, Haemophilus, Holdemania, Lactobacillus, Moraxella, Parabacteroides, Prevotella, Propionibacterium, Raoultella, Roseburia, Ruminococcus, Staphylococcus, Streptococcus, Subdoligranulum, and Veillonella. In one aspect, a fecal microbiota preparation lacks or is substantially devoid of one or more, two or more, three or more, four or more, or five or live more fecal microorganisms are selected from the group consisting of Bacteroides fragilis ssp. vulgatus, Collinsella aerofaciens, Bacteroides fragilis ssp. thetaiotaomicron, Peptostreptococcus productus II, Parabacteroides distasonis, Faecalibacterium prausnitzii, Coprococcus eutactus, Peptostreptococcus productus I, Ruminococcus bromii, Bifidobacterium adolescentis, Gemmiger formicilis, Bifidobacterium longum, Eubacterium siraeum, Ruminococcus torques, Eubacterium rectale, Eubacterium eligens, Bacteroides eggerthii, Clostridium leptum, Bacteroides fragilis ssp. A, Eubacterium biforme, Bifidobacterium infantis, Eubacterium rectale , Coprococcus comes, Pseudoflavonifractor capillosus, Ruminococcus albus, Dorea formicigenerans, Eubacterium hallii, Eubacterium ventriosum I, Fusobacterium russi, Ruminococcus obeum, Eubacterium rectale, Clostridium ramosum, Lactobacillus leichmannii, Ruminococcus callidus, Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides fragilis ssp. fragilis, Coprococcus catus, Aerostipes hadrus, Eubacterium cylindroides, Eubacterium ruminantium, , Staphylococcus epidermidis, Eubacterium limosum, Tissirella praeacuta, Fusobacterium mortiferum I, Fusobacterium naviforme, Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes, Ruminococcus flavefaciens, Bacteroides fragilis ssp. ovatus, Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichia coli, Gemella morbillorum, Finegoldia magnus, Streptococcus intermedius, Ruminococcus lactaris, Eubacterium tenue, Eubacterium ramulus, Bacteroides clostridiiformis ssp. clostridliformis, Bacteroides coagulans, Prevotella oralis, Prevotella ruminicola, Odoribacter splanchnicus, and Desuifomonas pigra.

[0073] In an aspect, a preparation of uncultured fecal bacteria for incorporation into a pharmaceutical composition comprises non-pathogenic spores of one or more, two or more, three or more, or four or more Clostridium species selected from the group consisting of Clostridium absonum, Clostridium argentinense, Clostridium baratii, Clostridium botulinum, Clostridium cadaveris, Clostridium camis, Clostridium celatum, Clostridium chauvoei, Clostridium clostridioforme, Clostridium cochlearium, Clostridium fallax, Clostridium felsineum, Clostridium ghonii, Clostridium glycolicum, Clostridium haemolyticum, Clostridium hastiforme, Clostridium histolyticum, Clostridium indolis, Clostridium irregulare, Clostridium limosum, Clostridium malenominatum, Clostridium novyi, Clostridium oroticum, Clostridium paraputrificum, Clostridium perfringens, Clostridium piliforme, Clostridium putrefaciens, Clostridium putrificum, Clostridium sardiniense, Clostridium sartagoforme, Clostridium scindens, Clostridium septicum, Clostridium sordellii, Clostridium sphenoides, Clostridium spiroforme, Clostridium sporogenes, Clostridium subterminale, Clostridium symbiosum, Clostridium tertium, Clostridium tetani, Clostridium welchii, and Clostridium villosum. In an aspect, a pharmaceutical composition comprises one or more, two or more, three or more, or four or more non-pathogenic Bacteroides species selected from the group of Bacteroides coprocola, Bacteroides plebeius, Bacteroides massiliensis, Bacteroides vulgatus, Bacteroides helcogenes, Bacteroides pyogenes, Bacteroides tectus, Bacteroides uniformis, Bacteroides stercoris, Bacteroides eggerthii, Bacteroides finegoldii, Bacteroides thetaiotaomicron, Bacteroides ovatus, Bacteroides acidifaciens, Bacteroides caccae, Bacteroides nordii, Bacteroides salyersiae, Bacteroides fragilis, Bacteroides intestinalis, Bacteroides coprosuis, Bacteroides distasonis, Bacteroides goldsteinii, Bacteroides merdae, Bacteroides forsythus, Bacteroides splanchnicus, Bacteroides capillosus, Bacteroides cellulosolvens, and Bacteroides ureolyticus.

[0074] In an aspect, a pharmaceutical composition comprises viable non-pathogenic Clostridium and a plurality of viable non-pathogenic microorganisms from one or more genera selected from the group consisting of Collinsella, Coprococcus, Dorea, Eubacterium, and Ruminococcus. In another aspect, a pharmaceutical composition comprises a plurality of viable non-pathogenic microorganisms from one or more genera selected from the group consisting of Clostridium, Collinsella, Coprococcus, Dorea, Eubacterium, and Ruminococcus.

[0075] In an aspect, a pharmaceutical composition comprises two or more genera selected from the group consisting of Collinsella, Coprococcus, Dorea, Eubacterium, and Ruminococcus. In another aspect, a pharmaceutical composition comprises two or more genera selected from the group consisting of Coprococcus, Dorea, Eubacterium, and Ruminococcus. In a further aspect, a pharmaceutical composition comprises one or more, two or more, three or more, four or more, or five or more species selected from the group consisting of Coprococcus catus, Coprococcus comes, Dorea longicatena, Eubacterium eligens, Eubacterium hadrum, Eubacterium hallii, Eubacterium rectale, and Ruminococcus torques.

[0076] In an aspect, a preparation of uncultured fecal bacteria described herein comprises viable cells from 100% of the bacterial taxa represented in the stool from which the fecal bacteria were derived. In an aspect, a preparation of uncultured fecal bacteria described herein comprises viable cells from at least 99% of the bacterial taxa represented in the stool from which the fecal bacteria were derived. In an aspect, a preparation of uncultured fecal bacteria described herein comprises viable cells from at least 98% of the bacterial taxa represented in the stool from which the fecal bacteria were derived. In an aspect, a preparation of uncultured fecal bacteria described herein comprises viable cells from at least 97% of the bacterial taxa represented in the stool from which the fecal bacteria were derived. In an aspect, a preparation of uncultured fecal bacteria described herein comprises viable cells from 96% of the bacterial taxa represented in the stool from which the fecal bacteria were derived. In an aspect, a preparation of uncultured fecal bacteria described herein comprises viable cells from at least 95, 94, 93, 92, 91, 90, 89, 88, 87, 85, 84, 83, 82, 81, 80, 75, 70, 65, 60, 55, 50, 45, or 40% of the bacterial taxa represented in the stool from which the fecal bacteria were derived. [0077] In an aspect, a pharmaceutical composition disclosed herein comprises a sterile fecal filtrate or a non-cellular fecal filtrate. In one aspect, a sterile fecal filtrate originates from a donor stool. In another aspect, a sterile fecal filtrate originates from cultured microorganisms. In another aspect, a sterile fecal filtrate comprises a non-cellular non-particulate fecal component. In one aspect, a sterile fecal filtrate is made as described in W02014/078911, published May 30, 2014. In another aspect, a sterile fecal filtrate is made as described in Ott et al., Gastroenterology 152:799-911(2017).

[0078] In one aspect, a fecal filtrate comprises secreted, excreted or otherwise liquid components or a microbiota, e.g., biologically active molecules (BAMs), which can be antibiotics or anti-inflammatories, are preserved, retained or reconstituted in a flora extract.

[0079] In one aspect, an exemplary pharmaceutical composition comprising a fecal filtrate comprises starting material from a donor from a defined donor pool, where this donor contributes a stool that is homogenized and centrifuged, then filtered with very high-level filtration using e.g., either metal sieving or Millipore filters, or equivalent, to ultimately permit only cells of bacterial origin to remain, e.g., often less than about 5 micrometers diameter. After the initial centrifugation, the solid material can be separated from the liquid, and the solid is then filtered in progressively reducing size filters and tangential filters, e.g., using a Millipore filtration, and optionally, also comprising use of nano-membrane filtering. The filtering can also be done by sieves as described in WO 2012/122478, but in contrast using sieves that are smaller than .0120 mm, down to about .0110 mm, which ultimately result in having only bacterial cells present.

[0080] The supernatant separated during centrifugation can in some aspects be filtered progressively in a filtering scheme, e.g., using a Millipore filtering or equivalent system, to produce a liquid which is finely filtered through an about 0.22 micron filter. This removes all particulate matter including all living matter, including bacteria and viruses. The product then is sterile, but the aim is to remove the bacteria but to keep their secretions, especially antimicrobial bacteriocins, bacteria-derived cytokine-like products and all accompanying Biologically Active Molecules (BAMs), including: thuricin (which is secreted by bacilli in donor stools), bacteriocins (including colicin, troudulixine or putaindicine, or microcin or subtilosin A), lanbiotics (including nisin, subtilin, epidermin, mutacin, mersacidin, actagardine, cinnamycin), lacticins and other antimicrobial or anti-inflammatory compounds. [0081] In one aspect, a pharmaceutical composition comprises reconstituted fecal flora consisting essentially of a combination of a purified fecal microbiota (comprising a preparation of uncultured fecal bacteria) and a non-cellular fecal filtrate. In another aspect, a pharmaceutical composition comprises a purified fecal microbiota (comprising a preparation of uncultured fecal bacteria) supplemented with one or more non-cellular non-particulate fecal components. In one aspect, a pharmaceutical composition comprises one or more non-cellular non-particulate fecal components. In one aspect, one or more non-cellular non-particulate fecal components comprise synthetic molecules, biologically active molecules produced by a fecal microorganism, or both. In another aspect, one or more non-cellular non-particulate fecal components comprise biologically active proteins or peptides, micronutrients, fats, sugars, small carbohydrates, trace elements, mineral salts, ash, mucous, amino acids, nutrients, vitamins, minerals, or any combination thereof. In one aspect, one or more non-cellular nonparticulate fecal components comprise one or more biologically active molecules selected from the group consisting of bacteriocin, lanbiotic, and lacticin. In another aspect, one or more non- cellular non-particulate fecal components comprise one or more bacteriocins selected from the group consisting of colicin, troudulixine, putaindicine, microcin, and subtilosin A. In one aspect, one or more non-cellular non-particulate fecal components comprise one or more lanbiotics selected from the group consisting of thuricin, nisin, subtilin, epidermin, mutacin, mersacidin, actagardine, and cinnamycin. In another aspect, one or more non-cellular nonparticulate fecal components comprise an anti-spore compound, an antimicrobial compound, an anti-inflammatory compound, or any combination thereof. In a further aspect, one or more non-cellular non-particulate fecal components comprise an interleukin, a cytokine, a leukotriene, an eicosanoid, or any combination thereof.

[0082] In another aspect, a pharmaceutical composition comprises both a preparation of uncultured fecal bacteria, e.g., a partial or a complete representation of the human GI microbiota, and an isolated, processed, filtered, concentrated, reconstituted and/or artificial liquid component (e.g., fecal filtrate) of the flora (the microbiota) which comprises, among others ingredients, bacterial secretory products such as e.g., bacteriocins (proteinaceous toxins produced by bacteria, including colicin, troudulixine or putaindicine, or microcin or subtilosin A), lanbiotics (a class of peptide antibiotics that contain a characteristic polycyclic thioether amino acid lanthionine or methyllanthionine, and unsaturated amino acids dehydroalanine and 2-aminoisobutyric acid; which include thuricin (which is secreted by bacilli in donor stools), nisin, subtilin, epidermin, mutacin, mersacidin, actagardine, cinnamycin), a lacticin (a family of pore-forming peptidic toxins) and other antimicrobial or anti-inflammatory compounds and/or additional biologically active molecules (BAMs) produced by bacteria or other microorganisms of the microbiota, and/or which are found in the "liquid component" of a microbiota.

[0083] In one aspect, a pharmaceutical composition comprising a preparation of uncultured fecal bacteria is used concurrently with a fecal non-cellular filtrate-based pharmaceutical composition. In another aspect, a patient is treated with a first fecal non-cellular filtrate-based pharmaceutical composition before being given a second pharmaceutical composition comprising a preparation of uncultured fecal bacteria, or vice versa. In a further aspect, a treatment method comprises three steps: first, antibiotic pretreatment to non-selectively remove infectious pathogen(s); second, a fecal non-cellular filtrate-based treatment step to further suppress selected infectious pathogen(s); and third, treatment with a pharmaceutical composition comprising a preparation of uncultured fecal bacteria to re-establish a functional intestinal microbiome.

[0084] In an aspect, a composition comprising a bacterial mixture comprising a preparation of uncultured fecal bacteria that is administered to a subject (e.g., a patient with a neurodegenerative disease) effects a cure, reduction of the symptoms, or a percentage reduction of symptoms based on replacement of bacterial cells endogenous to the intestinal flora of the subject with bacterial cells from the administered bacterial mixture. The change of flora can be as “near-complete” as possible. Typically, the change in enteric flora comprises introduction of an array of flora derived from the stool of a healthy human donor into the gastro-intestinal system of the subject, which can substantially or completely displace pathogenic enteric flora in a patient requiring such treatment (e.g., a patient with a neurodegenerative disease).

[0085] The pharmaceutical compositions described here can comprise microbes, e.g. bacteria, derived from a stool sample of a donor, e.g. a healthy human donor. In an aspect, a composition incorporates a preparation of uncultured fecal bacteria derived from all or a portion of a fecal microbiota of a stool sample of a healthy human donor. For example, a composition can incorporate a substantially complete fecal microbiota of a stool sample of a healthy human donor. In an aspect, a composition incorporates a bacterial isolate of a fecal microbiota, wherein the bacterial isolate has been purified and/or cultured from all or a portion of the fecal microbiota of a stool sample from a healthy human donor. The harvesting, extraction and/or purification of a fecal microbiota from a stool sample can thus be performed to prepare a composition comprising at least one of a preparation of uncultured fecal bacteria or a bacterial isolate.

[0086] In one aspect, an exemplary fecal microbiota for use in preparing a composition described herein (e.g., comprising a bacterial mixture comprising one or more of a preparation of uncultured fecal bacteria and at least one bacterial isolate) comprises starting material from a human donor. In another aspect, an exemplary fecal microbiota comprises material from one or more healthy human donors. In yet another aspect, an exemplary fecal microbiota comprises starting material from a pool of known, defined donors. In another aspect, a donor is an adult male. In a further aspect, a donor is an adult female. In yet another aspect, a donor is an adolescent male. In another aspect, a donor is an adolescent female. In another aspect, a donor is a female toddler. In another aspect, a donor is a male toddler. In another aspect, a donor is healthy. In one aspect, a human donor is a child below about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1- year-old. In another aspect, a human donor is an elderly individual. In a further aspect, a human donor is an individual above about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old. In another aspect, a donor is between 1 and 5, between 2 and 10, between 3 and 18, between 21 and 50, between 21 and 40, between 21 and 30, between 50 and 90, between 60 and 90, between 70 and 90, between 60 and 80, or between 65 and 75 years old. In one aspect, a donor is a young old individual (65-74 years). In one aspect, a donor is a middle old individual (75- 84 years). In one aspect, a donor is an old individual (>85 years). In yet another aspect, a donor is a carefully screened, healthy, neurotypical human.

[0087] In an aspect, a fecal donor is prescreened for its fecal microbiome profile. In another aspect, a fecal donor is selected for the presence of one or more fecal bacterial class, family, genus, or species in the donor’s stool. In another aspect, a fecal donor is selected for the presence of one or more fecal bacterial class, family, genus, species or strain in the donor’s stool at a level above a threshold abundance. In an aspect, a fecal donor can be selected on the basis of the presence or threshold abundance of one or more bacterial genera in the stool of the donor selected from the group consisting of Lactobacillus, Bifidobacterium, Streptococcus, Prevotella, Desulfovibrio, and a combination thereof. In an aspect, a fecal donor can be selected on the basis of the presence or threshold abundance of one or more bacterial genera in the stool of the donor selected from the group consisting of Clostridium, Bacteroides, Eggerthella, Bifidobacterium, Prevotella, and Desulfovibrio and a combination thereof. In an aspect, a fecal donor can be selected on the basis of the presence or threshold abundance of one or more bacterial taxa in the stool of the donor selected from the group consisting of Prevotella, Coprococcus, Prevotellaceae, and Veillonellaceae, and a combination thereof. In an aspect, a fecal donor can be selected on the basis of the presence or threshold abundance of one or more bacterial genera selected from the group consisting of Lactobacillus, Bifidobacterium, Streptococcus, and a combination thereof.

[0088] In an aspect, a stool or a portion thereof can be selected as a source of a preparation of uncultured fecal bacteria for incorporation into a pharmaceutical composition on the basis of the presence or threshold abundance of one or more bacterial class, family, genus, species or strain in the stool sample. In an aspect, the stool sample can be selected on the basis of the presence or threshold abundance of a member of a bacterial genus selected from the group consisting of Lactobacillus, Bifidobacterium, Streptococcus, and a combination thereof.

[0089] A preparation of uncultured fecal bacteria extracted from the stool of a donor selected on the basis of the presence or abundance of one or more bacterial genera, species or strains can be directly incorporated into a pharmaceutical composition described herein, without adding any bacterial isolate to the preparation, or alternatively can be spiked with a bacterial isolate of the same genera, species or strain as that which was the basis of selection.

[0090] In an aspect, a fecal donor has a higher relative fecal abundance of a bacterial genus, species or strain by ingesting a probiotic and/or prebiotic that promotes the proliferation or presence of the bacterial genus, species or strain in the donor’s gut, compared to a relative fecal abundance of the bacterial genus, species or strain in the absence of ingesting the probiotic and/or prebiotic.

[0091] In another aspect, prior to making a fecal donation, a donor receives or ingests certain prebiotics such as oligofructose, inulin, barley prebiotics, or another dietary fiber. In another aspect, prior to making a fecal donation, a donor receives or ingests a growth stimulant for selected fecal bacteria. In another aspect, prior to making a fecal donation, a donor receives or ingests one or more of apple pectin, N-acetyl glucosamine, cysteine, glutathione, riboflavin, and flavin.

[0092] In an aspect, a carefully screened donor undergoes a complete medical history and physical exam. Donors are excluded if they have a risk of infectious agents. Additional exclusion criteria comprise the following:

1. Known viral infection with Hepatitis B, C or HIV

2. Known exposure to HIV or viral hepatitis at any time

3. High risk behaviors including sex for drugs or money, men who have sex with men, more than one sexual partner in the preceding 12 months, any past use of intravenous drugs or intranasal cocaine, history of incarceration.

4. Tattoo or body piercing within 12 months.

5. Travel to areas of the world where risk of traveler's diarrhea is higher than the US.

6. Current communicable disease, e.g., upper respiratory viral infection.

7. History of irritable bowel syndrome. Specific symptoms can include frequent abdominal cramps, excessive gas, bloating, abdominal distension, fecal urgency, diarrhea, constipation.

8. History of inflammatory bowel disease such as Crohn's disease, ulcerative colitis, microscopic colitis.

9. Chronic diarrhea.

10. Chronic constipation or use of laxatives.

11. History of gastrointestinal malignancy or known colon polyposis.

12. History of any abdominal surgery, e.g., gastric bypass, intestinal resection, appendectomy, cholecystectomy, etc.

13. Use of Probiotics or any other over the counter aids used by the potential donor for purpose of regulating digestion. Yogurt and kefir products are allowed if taken merely as food rather than nutritional supplements.

14. Antibiotics for any indication within the preceding 6 months.

15. Any prescribed immunosuppressive or anti-neoplastic medications.

16. Metabolic Syndrome, established or emerging. Criteria used for definition here are stricter than any established criteria. These include history of increased blood pressure, history of diabetes or glucose intolerance.

17. Known systemic autoimmunity, e.g., connective tissue disease, multiple sclerosis.

18. Known atopic diseases including asthma or eczema.

19. Chronic pain syndromes including fibromyalgia, chronic fatigue syndrome.

20. Ongoing (even if intermittent) use of any prescribed medications, including inhalers or topical creams and ointments.

21. Neurologic, neurodevelopmental, and neurodegenerative disorders including autism, Parkinson's disease.

22. General. Body mass index > 26 kg/ m2, central obesity defined by waste:hip ratio > 0.85 (male) and > 0.80 (female).

23. Blood pressure > 135 mmHg systolic and > 85 mmHg diastolic.

24. Skin — presence of a rash, tattoos or body piercing placed within a year, or jaundice

25. Enlarged lymph nodes.

26. Wheezing on auscultation.

27. Hepatomegaly or stigmata of liver disease.

28. Swollen or tender joints. Muscle weakness.

29. Abnormal neurologic examination.

30. Positive stool Clostridium difficile toxin B tested by PCR.

31. Positive stool cultures for any of the routine pathogens including Salmonella, Shigella, Yersinia, Campylobacter, E. coli 0157:H7.

32. Abnormal ova and parasites examination.

33. Positive Giardia, Cryptosporidium, or Helicobacter pylori antigens.

34. Positive screening for any viral illnesses, including HIV 1 and 2, Viral Hepatitis A IgM, Hepatitis surface antigen and core Ab.

35. Abnormal RPR (screen for syphilis).

36. Any abnormal liver function tests including alkaline phosphatase, aspartate aminotransaminase, alanine aminotransferase.

37. Raised serum triglycerides > 150 mg/Dl

38. HDL cholesterol < 40 mg/dL (males) and < 50 mg/dL (females)

39. High sensitivity CRP > 2.4 mg/L

40. Raised fasting plasma glucose (> 100 mg/dL)

[0093] In one aspect, provided herein is a process for collecting and processing a stool sample to give rise to a preparation of uncultured fecal bacteria and/or one or more bacterial isolates. The process can comprise first collecting a stool sample from one or more healthy (e.g., screened) donor(s). In one aspect, a fresh stool is transported via a stool collection device, which can provide or comprises a suitably oxygen free (or substantially oxygen free) appropriate container. In one aspect, the container can be made oxygen free by e.g., incorporating into the container a built in or clipped-on oxygen-scavenging mechanism, e.g., oxygen scavenging pellets as described e.g., in U.S. Pat. No: 7,541,091, hereby incorporated by reference herein in its entirety. In another aspect, the container itself is made of an oxygen scavenging material, e.g., oxygen scavenging iron, e.g., as described by 02BLOCK™, or equivalents, which uses a purified and modified layered clay as a performance-enhancing carrier of oxygen-scavenging iron; the active iron is dispersed directly in the polymer. In one aspect, oxygen-scavenging polymers are used to make the container itself or to coat the container, or as pellets to be added; e.g., as described in U.S. Pat. App. Pub. 20110045222 (hereby incorporated by reference herein in its entirety), describing polymer blends having one or more unsaturated olefinic homopolymers or copolymers; one or more polyamide homopolymers or copolymers; one or more polyethylene terephthalate homopolymers or copolymers; that exhibit oxygen-scavenging activity. In one aspect, oxygen-scavenging polymers are used to make the container itself or to coat the container, or as pellets to be added; e.g., as described in U.S. Pat. App. Pub. 20110008554 (hereby incorporated by reference herein in its entirety), describing compositions comprising a polyester, a copolyester ether and an oxidation catalyst, wherein the copolyester ether comprises a polyether segment comprising poly(tetramethylene-co-alkylene ether). In one aspect, oxygen-scavenging polymers are used to make the container itself or to coat the container, or as pellets to be added; e.g., as described in U.S. Pat. App. Pub. 201000255231 (hereby incorporated by reference herein in its entirety), describing a dispersed iron/salt particle in a polymer matrix, and an oxygen scavenging film with oxygen scavenging particulates.

[0094] Alternatively, in addition to or in place of the oxygen-scavenging mechanism, the air in the container can be replaced (completely or substantially) with nitrogen and/or other inert non-reactive gas or gases. In one aspect, the container simulates (creates) partially, substantially or completely an anaerobic environment.

[0095] In one aspect, the stool (e.g., fecal sample) is held in an aesthetically acceptable container that will not leak nor smell yet maintain an anaerobic environment. In one aspect, the container is sterile before receiving the fecal flora.

[0096] In one aspect, a stool sample provided herein is maintained at room temperature during most or all of its transportation and/or storage at e.g., a “stool bank”. For example, once delivered to a “processing stool bank” it is stored at ambient temperature, e.g., room temperature. In one aspect, stabilizing agents, such as glycerol, are added to the harvested and/or stored material.

[0097] In one aspect, the stool is tested for various pathogens, as noted above. In one aspect, once cleared of infective agents, a stool sample is homogenized and filtered to remove large particles of matter. In one aspect, the stool is subdivided into desired volumes, e.g., which can be between 5 cc and 3 or more liters. For example, in one aspect, a container comprises a 50 gram (g) stool, which can be held in an appropriate oxygen resistant plastic, e.g., a metallized polyethylene terephthalate polyester film, or a metallized MYLAR™.

[0098] In one aspect, the stool is subject to homogenization by for example, mixing, agitating, stirring or shaking. In certain aspects, a stool sample is diluted with a homogenization buffer prior to homogenization. A homogenization buffer can, for example, contain a cryoprotectant (e.g., trehalose), an antioxidant or reducing agent (e.g., cysteine), and a buffer (e.g., 0.25X PBS at pH 7.4).

[0099] In one aspect, to separate the non-bacterial components from the fecal microbiota, the stool can be homogenized and filtered from rough particulate matter. In one aspect, the microscopic fiber/nonliving matter is then separated from the bacteria. Several methods can be used, including e.g., recurrent filtration with filter sizes, e.g., progressively coming down to the size of a typical bacterium.

[0100] In one aspect, different filters are used to isolate bacterial sp., or a technique as used by Williams in WO 2011/033310A1, which uses a crude technique of filtration with a gauze and is hereby incorporated by reference herein in its entirety.

[0101] In one aspect, a filtration procedure for filtering whole stool is suitably used to reach the highest concentration of almost 100% bacteria. In one aspect, the filtering procedure is a two-step procedure suitably using glass fibre depth filters for initial clarification. In one aspect, the stool is filtered under positive pressure. In one aspect, this would be using a combination or sandwich configuration with a 30 micron PVDF filter. In one aspect, this sandwich procedure will be filtering the product under positive pressure. Later, membrane concentration can, in one aspect, be used as another step to reduce the volume of the filtrate. In one aspect, this can be done prior to freeze drying or spray drying under nitrogen cover.

[0102] Alternative membranes that can be used for filtration include, but are not limited to, nylon filters, cellulose nitrate filters, polyethersulfone (PES) filters, polytetrafluorethylene (PTFE) filters, TEFLON™ filters, mixed cellulose Ester filters, polycarbonate filters, polypropylene filters, Polyvinylchloride (PVC) filters or quartz filters. Various combinations of these can be used to achieve a high purity of bacteria with solids and liquid removed. Pharmaceutical compositions, formulations, and administration

[0103] Described herein are pharmaceutical compositions in various formulations, wherein the compositions comprise oligomannurarate (or a derivative thereof) and/or a bacterial mixture comprising for example a preparation of uncultured fecal bacteria and/or one or more bacterial isolates. A pharmaceutical composition described herein can take the form of tablets, pills, pellets, capsules, capsules containing liquids, capsules containing multiparticulates, powders, solutions, emulsion, drops, suppositories, emulsions, aerosols, sprays, suspensions, delayed-release formulations, sustained-release formulations, controlled-release formulations, or any other form suitable for use.

[0104] The formulations comprising the pharmaceutical compositions can conveniently be presented in unit dosage forms. For example, the dosage forms can be prepared by methods which include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. For example, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by press tableting).

[0105] In another aspect, a pharmaceutical composition can include a pharmaceutically acceptable carrier. As used herein, a “pharmaceutically acceptable carrier” refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with a live bacterium in order to permit the formation of a pharmaceutical composition, e.g., a dosage form capable of administration to the patient. A pharmaceutically acceptable carrier can be liquid (e.g., saline), gel or solid form of diluents, adjuvant, excipients or an acid resistant encapsulated ingredient. Suitable diluents and excipients include pharmaceutical grades of physiological saline, dextrose, glycerol, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like, and a combination thereof. In another aspect, a pharmaceutical composition can contain auxiliary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents. In an aspect, a pharmaceutical composition contains about l%-5%, 5%-10%, 10%-15%, 15-20%, 20%-25%, 25-30%, 30-35%, 40-45%, 50%-55%, l%-95%, 2%-95%, 5%-95%, 10%-95%, 15%-95%, 20%-95%, 25%-95%, 30%-95%, 35%- 95%, 40%-95%, 45%-95%, 50%-95%, 55%-95%, 60%-95%, 65%-95%, 70%-95%, 45%-95%, 80%-95%, or 85%-95% of active ingredient. In an aspect, a pharmaceutical composition contains about 2%-70%, 5%-60%, 10%-50%, 15%-40%, 20%-30%, 25%-60%, 30%-60%, or 35%-60% of active ingredient.

[0106] In an aspect, a pharmaceutical composition can include or be incorporated into tablets, drenches, boluses, capsules, premixes or patches. Formulation of these active ingredients into such dosage forms can be accomplished by means of methods well known in the pharmaceutical formulation arts. See, e.g., U.S. Pat. No. 4,394,377. Filling gelatin capsules with any desired form of the active ingredients readily produces capsules. If desired, these materials can be diluted with an inert powdered diluent, such as sugar, starch, powdered milk, purified crystalline cellulose, or the like to increase the volume for convenience of filling capsules.

[0107] In an aspect, for preparing solid compositions such as tablets, an active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as cornstarch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, or other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a composition described herein. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing a desired amount of an active ingredient (e.g., at least about 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², or 10¹³ CFUs). A pharmaceutical composition described herein can be flavored.

[0108] In an aspect, a pharmaceutical composition comprising at least one of oligomannurarate (or a derivative thereof) and a bacterial mixture described herein (and optionally one or more additional therapeutic agents) is formulated as a composition adapted for a mode of administration described herein.

[0109] In various aspects, the administration of the pharmaceutical compositions is any one of oral, intravenous, intraperitoneal, and parenteral. For example, routes of administration include, but are not limited to, oral, intraperitoneal, intravenous, intramuscular, or rectal. In various aspects, the administration of the pharmaceutical compositions is oral, naso-gastric, antegrade gastrointestinal, retrograde gastrointestinal, endoscopic, or enemic. [0110] In an aspect, a pharmaceutical composition described herein can be formulated as a composition adapted for oral administration. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, sprinkles, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions can comprise one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration to provide sustained delivery of the oligomannurarate (or a derivative thereof) and/or bacterial mixture over an extended period of time. Selectively permeable membranes surrounding an osmotically active agent are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by a driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material, such as glycerol monostearate or glycerol stearate, can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, ethacrylic acid and derivative polymers thereof, and magnesium carbonate. In an aspect, the excipients are of pharmaceutical grade. Suspensions, in addition to the active compounds, can contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, etc., and mixtures thereof.

[0111] In various aspects, a pharmaceutical composition is formulated as a solid dosage form such as a tablet, dispersible powder, granule, or capsule. In an aspect, the pharmaceutical composition is formulated as a capsule. In another aspect, the pharmaceutical composition is formulated as a tablet. In yet another aspect, the pharmaceutical composition is formulated as a soft-gel capsule. In a further aspect, the pharmaceutical composition is formulated as a gelatin capsule.

[0112] In an aspect, a pharmaceutical composition is in the form of: an enema composition which can be reconstituted with an appropriate diluent; an enteric-coated capsule; an enteric- coated microcapsule; an acid-resistant tablet; an acid-resistant capsules; an acid-resistant microcapsule; powder for reconstitution with an appropriate diluent for naso-enteric infusion or colonoscopic infusion; powder for reconstitution with appropriate diluent, flavoring and gastric acid suppression agent for oral ingestion; powder for reconstitution with food or drink; or food or food supplement comprising enteric-coated and/or acid-resistant microcapsules of the composition, powder, jelly, or liquid.

[0113] In various aspects, formulations can additionally comprise a pharmaceutically acceptable carrier or excipient. As one skilled in the art will recognize, the formulations can be in any suitable form appropriate for the desired use and route of administration.

[0114] In some dosage forms, a pharmaceutical composition described herein is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate, etc., and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, silicic acid, microcrystalline cellulose, and Bakers Special Sugar, etc., b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose (HPC), and hydroxymethyl cellulose etc., c) humectants such as glycerol, etc., d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, cross-linked polymers such as crospovidone (cross- linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, etc., e) solution retarding agents such as paraffin, etc., f) absorption accelerators such as quaternary ammonium compounds, etc., g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, etc., h) absorbents such as kaolin and bentonite clay, etc., and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, glyceryl behenate, etc., and mixtures of such excipients. One of skill in the art will recognize that particular excipients can have two or more functions in the oral dosage form. In the case of an oral dosage form, for example, a capsule or a tablet, the dosage form can also comprise buffering agents.

[0115] In an aspect, a pharmaceutical composition comprising a bacterial mixture and/or oligomannurarate (or a derivative thereof) is combined with one or more pharmaceutically acceptable cryoprotectants, lyoprotectants, binders, disintegrants, excipients, fillers, and/or preservatives, acid suppressants, antacids, H2 antagonists, and proton pump inhibitors, or combinations thereof.

[0116] In an aspect, a pharmaceutical composition comprising a bacterial mixture and/or oligomannurarate (or a derivative thereof) is combined with other adjuvants such as antacids to dampen bacterial inactivation in the stomach (e.g., Mylanta, Mucaine, Gastrogel). In another aspect, acid secretion in the stomach could also be pharmacologically suppressed using H2- antagonists or proton pump inhibitors. An example H2-antagonist is ranitidine. An example proton pump inhibitor is omeprazole. In one aspect, an acid suppressant is administered prior to administering, or in co-administration with, a pharmaceutical composition.

[0117] In one aspect, a pharmaceutical composition administered herein further comprises an acid suppressant, an antacid, an H2 antagonist, a proton pump inhibitor or a combination thereof. In one aspect, a pharmaceutical composition administered herein is substantially free of non-living matter. In another aspect, a pharmaceutical composition administered herein substantially free of acellular material selected from the group consisting of residual fiber, DNA, viral coat material, and non-viable material. In another aspect, a pharmaceutical composition administered does not comprise an acid suppressant, an antacid, an H2 antagonist, a proton pump inhibitor or a combination thereof. In yet another aspect, a pharmaceutical composition administered does not comprise an acid suppressant. In another aspect, a pharmaceutical composition administered does not comprise an antacid. In another aspect, a pharmaceutical composition administered does not comprise an H2 antagonist. In another aspect, a pharmaceutical composition administered does not comprise a proton pump inhibitor. In another aspect, a pharmaceutical composition administered does not comprise metoclopramide.

[0118] In an aspect, a bacterial mixture and/or oligomannurarate (or a derivative thereof) is dry, e.g., when it includes lyophilized bacterial cells/spores or comprises dry binders, fillers, and dispersants. Alternately, the bacterial mixture and/or oligomannurarate (or a derivative thereof) can be aqueous, e.g., when it comprises non-dry binders, fillers, and dispersants.

[0119] In an aspect, a bacterial mixture described herein can be subject to lyophilization. As used herein, “lyophilization” or “freeze drying” refers to the process of drying a material by first freezing it and then encouraging the ice within it to sublimate in a vacuum environment.

[0120] In one aspect, a bacterial mixture comprises a lyophilized formulation further comprising a reducing agent and/or antioxidant. In certain aspects, the reducing agent comprises cysteine selected from the group consisting of D-cysteine and L-cysteine. In another aspect, cysteine is at a concentration of at least about 0.025%. In one aspect, cysteine is at a concentration of about 0.025%. In another aspect, cysteine is at a concentration of 0.025%. In another aspect, another reducing agent other than cysteine is used in lieu of, or in combination with cysteine. In an aspect, another reducing agent is selected from the group comprising ascorbic acid, sodium ascorbate, thioglycolic acid, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, glutathione, methionine, thioglycerol, and alpha tocopherol.

[0121] In one aspect, cysteine is at a concentration of at least about 0.005%, at least about 0.01%, at least about 0.015%, at least about 0.02%, at least about 0.025%, at least about 0.03%, at least about 0.035%, at least about 0.04%, at least about 0.045%, at least about 0.05%, at least about 0.055%, at least about 0.06%, at least about 0.065%, at least about 0.07%, at least about 0.075%, at least about 0.08%, at least about 0.085%, at least about 0.09%, at least about 0.095%, at least about 0.1%, at least about 0.12%, at least about 0.14%, at least about 0.16%, at least about 0.18%, at least about 0.2%, at least about 0.25%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 2%, at least about 4%, at least about 6%, at least about 8%, at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 22%, at least about 24%, or at least about 26%.

[0122] In one aspect, a bacterial mixture comprises a cryoprotectant or mixture of cryoprotectants. As used herein, a “cryoprotectant” refers to a substance that is added to a formulation in order to protect an active ingredient during freezing. For example, a cryoprotectant can comprise, consist essentially of, or consist of polyethylene glycol, skim milk, erythritol, arabitol, sorbitol, glucose, fructose, alanine, glycine, proline, sucrose, lactose, ribose, trehalose, dimethyl sulfoxide (DMSO) or equivalent, a glycerol, a polyethylene glycol (PEG) or equivalent, or an amino acid (e.g., alanine, glycine, proline). In an aspect of the present disclosure, a cryoprotectant can be selected from the group comprising 5% sucrose; 10% sucrose; 10% skim milk; 10% trehalose with 2.5% sucrose; 5% trehalose with 2.5% sucrose; 5% mannitol; 5% mannitol with 0.1% Polysorbate 80; 10% mannitol; 10% mannitol with 0.1% Polysorbate 80; 5% trehalose; 5% trehalose with 0.1% Polysorbate 80; 10% trehalose; and 10% trehalose with 0.1% Polysorbate 80.

[0123] In an aspect, a bacterial mixture comprises a lyoprotectant. As used herein, a “lyoprotectant” refers to a substance that is added to a formulation in order to protect an active ingredient during lyophilization. In one aspect, the same substance or the same substance combination is used as both a cryoprotectant and a lyoprotectant. Exemplary lyoprotectants include sugars such as sucrose or trehalose; an amino acid such as monosodium glutamate or histidine; a methylamine such as betaine; a lyotropic salt such as magnesium sulfate; a polyol such as trihydric or higher sugar alcohols, e.g. glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol; propylene glycol; polyethylene glycol; Pluronics; and a combination thereof. In an aspect, a lyoprotectant is a non-reducing sugar, such as trehalose or sucrose. In an aspect, a cryoprotectant or a lyoprotectant consists essentially of, or consists of, one or more substances mentioned in this paragraph and the paragraph above.

[0124] In an aspect, a cryoprotectant or a lyoprotectant comprise an intracellular agent, e.g., DMSO, glycerol, or PEG, which penetrates inside the cell preventing the formation of ice crystals that could result in membrane rupture. In an aspect, a cryoprotectant or a lyoprotectant comprise an extracellular agent, e.g., sucrose, trehalose, or dextrose, which does not penetrate into the cell membrane but acts to improve the osmotic imbalance that occurs during freezing.

[0125] In one aspect, the present disclosure provides a pharmaceutical composition comprising a lyophilized fecal microbe preparation comprising a lyophilization formulation comprising at least about 12.5% trehalose.

[0126] In an aspect, a lyophilized formulation comprises trehalose. In an aspect, a lyophilized formulation comprises 2% to 30%, 3% to 25%, 4% to 20%, 5% to 15%, 6% to 10%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, or 2% to 10% trehalose. In an aspect, a lyophilized formulation comprises at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 15% trehalose. In an aspect, a lyophilized formulation comprises at most 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 15% trehalose. In another aspect, a lyophilized formulation comprises about 5% trehalose. In another aspect, a lyophilized formulation comprises trehalose and sucrose. In another aspect, a lyophilized formulation comprises between about 8% and 12% trehalose with between about 1.5% and 3.5% sucrose and between about 0.5% and 1.5% NaCl.

[0127] In one aspect, a lyophilization formulation comprises at least about 5%, at least about 7.5%, at least about 10%, at least about 12.5%, at least about 13%, at least about 13.5%, at least about 14%, at least about 14.5%, at least about 15%, at least about 15.5%, at least about 16%, at least about 16.5%, at least about 17%, at least about 17.5%, at least about 18%, at least about 18.5%, at least about 19%, at least about 19.5%, at least about 20%, at least about 22.5%, at least about 25%, at least about 27.5%, at least about 30%, at least about 32.5%, at least about 35%, at least about 37.5%, at least about 40%, at least about 42.5%, at least about 45%, at least about 47.5%, at least about 50%, at least about 52.5%, at least about 55%, at least about 57.5%, or at least about 60% of trehalose.

[0128] In an aspect, a pharmaceutical composition provided herein, after at least 12 weeks of storage at ambient temperature or lower, is effective for treating or preventing a disorder in a patient by delivering one or more SCFAs to an intestine of the patient. In an aspect, a pharmaceutical composition remains effective after at least 4, 8, 10, 16, 20, 24, 30, 40, 50, 60, 70, 80 or 100 weeks of storage at ambient temperature or lower.

[0129] In an aspect, a pharmaceutical composition described herein can be lyophilized or freeze dried and stored at ambient temperatures (e.g., room temperature), at a freezing temperature, or at between about 2 °C and 8 °C. In an aspect, freeze-drying allows the majority of cells to remain viable, and produces a powdered form of the product that can be gently pulverized into a powder. The powder, or lyophilized or freeze-dried composition, then can be encapsulated into a carrier, e.g., a tablet, geltab, pill or capsule, e.g., an enteric-coated capsule, or placed into oil-filled capsules for ingestion. Alternatively, the freeze-dried or lyophilized product, or powder, can be reconstituted at ambient temperatures before delivery to an individual in e.g., a fluid, e.g., a sterile fluid, such as saline, a buffer or a media such as a fluid- glucose-cellobiose agar (RGCA) media.

[0130] For freeze-drying, in an aspect, bacteria are held in a liquid that will prevent bursting of cells on thawing. This can include various stabilizers, e.g., glycerol and appropriate buffers, and/or ethylene glycol. In an aspect, the cryoprotecting process uses final concentrations of stabilizer(s) of between about 10% and 80%, 20% and 70%, 30% and 60%, or 40% and 50%, depending on the stabilizer(s) used; in an aspect, this helps stabilize proteins by preventing formation of ice crystals that would otherwise destroy protein structures.

[0131] In an aspect, stabilizers that help reduce destruction of living bacteria include skim milk, erythritol, arabitol, sorbitol, glucose, fructose and other polyols. Polymers such as dextran and polyethylene glycol can also be used to stabilize bacterial cells.

[0132] In an aspect, manufacturing a pharmaceutical composition can comprise steps of: (1) coating the exterior of a dissociated capsule (i.e., comprising separate capsule body and capsule cap) with the exterior enteric coating, (2) filling the capsule body with at least one of oligomannurarate (or a derivative thereof) and a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria), and (3) closing the capsule cap over the capsule body, thereby encapsulating the oligomannurarate (or a derivative thereof) and/or bacterial mixture in the enteric-coated capsule.

[0133] Optionally, manufacturing a pharmaceutical composition can comprise steps of: (1) coating the exterior of a dissociated capsule (i.e., comprising separate capsule body and capsule cap) with the exterior enteric coating, (2) coating the interior of the dissociated capsule with an interior coating, (3) filling the capsule body with at least one of oligomannurarate (or a derivative thereof) and a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria), and (4) closing the capsule cap over the capsule body, thereby encapsulating the oligomannurarate (or a derivative thereof) and/or bacterial mixture in the dual-coated capsule.

[0134] Alternately, manufacturing a pharmaceutical composition can comprise step of: (1) coating the interior of the dissociated capsule (i.e., comprising separate capsule body and capsule cap) with an interior coating, (2) coating the exterior of a dissociated capsule with the exterior enteric coating, (3) filling the capsule body with at least one of oligomannurarate (or a derivative thereof) and a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria), and (4) closing the capsule cap over the capsule body, thereby encapsulating the oligomannurarate (or a derivative thereof) and/or bacterial mixture in the dual-coated capsule.

[0135] In an aspect, one or more additional therapeutic agents can be included in a pharmaceutical composition, and encapsulated by the capsule.

[0136] In an aspect, the bodies and caps of gelatin capsules (e.g., size #00) are separated. An exterior enteric coating suspension is prepared by dispersing one or more enteric coating polymers along with other components in a solution. The exterior enteric coating suspension is applied to the exterior of separated capsule bodies and caps, e.g., using a fluid bed Wurster column coater, Fluid Bed Coater, or an equivalent). The capsules are fluidized in the product bowl and the exterior enteric coating suspension is sprayed to produce the outer coating to a target of between about 2 mg/cm2 and 6 mg/cm2, e.g., 3 mg/cm2. After completion of this step, the capsules are set to dry, e.g., between about 8 hours and 24 hours. After drying, exemplary capsules are weighed to calculate weight gain from the exterior enteric coating. Capsules can be inspected for irregularities.

[0137] In an aspect, EUDRAGIT^® SI 00 (poly(methacrylic acid, methylmethacrylate)), starch, triethyl citrate, and PlasACRY^® T20 are dissolved in a solution of water, ethanol, and n-butanol, mixed, and then charged to a suitable spraying device. The solution is then spray coated on the outer surface of the capsule bodies and capsule caps to a target weight gain. The capsule bodies and capsule caps are allowed to dry for about 8 hours to about 24 hours, or longer, e.g., for a week, a month, or more, before further processing, e.g., filling with oligomannurarate (or a derivative thereof) and/or a bacterial mixture.

[0138] In an aspect, it may be desirable to provide an amount of oligomannurarate (or a derivative thereof) and/ora bacterial mixture to a capsule’s cap in addition to providing the composition in the capsule’s body. In this aspect, more of the composition will be included in a capsule and/or less air will be contained in a closed capsule.

[0139] In an aspect, the interior surface of a capsule comprises an internal coating, for example an internal coating that is water insoluble.

[0140] Any of the above-described compositions and materials (e.g., oligomannurarate (or a derivative thereof), bacterial mixtures, inner coatings, capsules, and/or outer coatings) can be combined into a pharmaceutical composition described herein. A skilled artisan would know how to select an inner coating; capsule, and outer coating according to his/her present need, which could be based, for example, on a specific bacterial isolate(s) incorporated into a bacterial mixture of the composition and/or the desired delivery location in a subject (e.g., in the colon or small intestine, including the ileum, jejunum or duodenum) of a component of the bacterial mixture (e.g. comprising oligomannurarate (or a derivative thereof), a preparation of uncultured fecal bacteria, a bacterial isolate and/or an additional therapeutic agent).

[0141] Additional relevant teachings are disclosed in WO 2007122374, which is hereby incorporated by reference herein in its entirety.

[0142] In an aspect, during the manufacture of a pharmaceutical composition, a pharmaceutically-acceptable cryoprotectant, lyoprotectant, binder, disintegrant, filler, preservative, acid suppressant, antacid, H2 antagonist, and proton pump inhibitor, or combination thereof can be mixed into the pharmaceutical composition (e.g., comprising a bacterial mixture) to promote desirable properties.

[0143] In an aspect, the pharmaceutical composition comprises a surface active agent. Surface active agents suitable for use include, but are not limited to, any pharmaceutically acceptable, non-toxic surfactant. Classes of surfactants suitable for use include, but are not limited to, polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono- and di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters-glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-olyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, ionic surfactants, and mixtures thereof. In some aspects, compositions can comprise one or more surfactants including, but not limited to, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and triethyl citrate.

[0144] In an aspect, the pharmaceutical composition comprises pharmaceutically acceptable plasticizers to obtain the desired mechanical properties such as flexibility and hardness. Such plasticizers include, but are not limited to, triacetin, citric acid esters, triethyl citrate, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers.

[0145] In another aspect, the pharmaceutical composition comprises one or more application solvents. Some of the more common solvents that can be used to apply, for example, a delay ed- release coating composition include isopropyl alcohol, acetone, methylene chloride and the like.

[0146] In yet another aspect, the pharmaceutical composition comprises one or more alkaline materials. Alkaline material suitable for use in compositions include, but are not limited to, sodium, potassium, calcium, magnesium and aluminum salts of acids such as phosphoric acid, carbonic acid, citric acid and other aluminum/magnesium compounds. In addition, the alkaline material can be selected from antacid materials such as aluminum hydroxides, calcium hydroxides, magnesium hydroxides and magnesium oxide.

[0147] Besides inert diluents, the orally administered compositions can also include adjuvants such as sweetening, flavoring, and perfuming agents.

[0148] In various aspects, the pharmaceutical compositions are formulated for systemic or local delivery. In an aspect, administration is systemic. In another aspect, it may be desirable to administer locally to the area in need of treatment.

[0149] Various methods can be used to formulate and/or deliver a pharmaceutical composition (e.g., comprising oligomannurarate (or a derivative thereof), a bacterial mixture and/or additional therapeutic agent) described herein to a location of interest. For example, the pharmaceutical compositions can be formulated for delivery to the GI tract. The GI tract includes organs of the digestive system such as mouth, esophagus, stomach, small intestine, duodenum, jejunum, ileum, large intestine and rectum and includes all subsections thereof (e.g. the small intestine may include the duodenum, jejunum and ileum; the large intestine may include the colon transversum, colon descendens, colon ascendens, colon sigmoidenum and cecum). For example, the compositions can be formulated for delivery of one or more active agents to one or more of the stomach, small intestine, large intestine and rectum, or any subsection thereof (e.g. duodenum, jejunum and ileum, colon transversum, colon descendens, colon ascendens, colon sigmoidenum and cecum). In some aspects, the compositions described herein can be formulated for delivery of one or more active agents to the upper or lower GI tract. In an aspect, a composition can be administered to a subject, by, for example, directly or indirectly contacting the mucosal tissues of the GI tract with the composition.

[0150] In various aspects, the administration of the pharmaceutical compositions is into the GI tract via, for example, oral delivery, nasogastral tube, intestinal intubation (e.g. an enteral tube or feeding tube such as, for example, a jejunal tube or gastro-jejunal tube, etc.), direct infusion (e.g., duodenal infusion), endoscopy, colonoscopy, or enema.

[0151] In one aspect, a method comprises administering a pharmaceutical composition orally, by enema, or via rectal suppository. In one aspect, a pharmaceutical composition administered herein is formulated as an enteric coated (and/or acid-resistant) capsule or microcapsule, or formulated as part of or administered together with a food, a food additive, a dairy-based product, a soy-based product or a derivative thereof, a jelly, a gelatin-based chewable (e.g., gummy), flavored liquid, ice block, ice cream, or a yogurt. In another aspect, a pharmaceutical composition administered herein is formulated as an acid-resistant enteric coated capsule. A pharmaceutical composition can be provided as a powder for sale in combination with a food or drink. A food or drink can be a dairy-based product or a soy -based product. In another aspect, a food or food supplement contains enteric-coated and/or acid-resistant microcapsules containing a pharmaceutical composition.

[0152] In an aspect, a pharmaceutical composition comprises a liquid culture. In another aspect, a pharmaceutical composition is homogenized, lyophilized, pulverized and powdered. It can then be infused, dissolved such as in saline, as an enema. Alternatively, the powder can be encapsulated as enteric-coated and/or acid-resistant delayed release capsules for oral administration. In an aspect, the powder can be double encapsulated with acid-resistant/delayed release capsules for oral administration. These capsules can take the form of enteric-coated and/or acid-resistant delayed release microcapsules. A powder can be provided in a palatable form for reconstitution for drinking or for reconstitution as a food additive. In a further aspect, a food is yogurt. In one aspect, a powder can be reconstituted to be infused via naso-duodenal infusion.

[0153] In another aspect, a pharmaceutical composition administered herein is in a liquid, frozen, freeze-dried, spray-dried, foam-dried, lyophilized, or powder form. In a further aspect, a pharmaceutical composition administered herein is formulated as a delayed or gradual enteric release form. In another aspect, a pharmaceutical composition administered herein comprises an excipient, a saline, a buffer, a buffering agent, or a fluid-glucose-cellobiose agar (RGCA) media. In another aspect, a pharmaceutical composition administered herein comprises a cryoprotectant. In one aspect, a cryoprotectant comprises polyethylene glycol, skim milk, erythritol, arabitol, sorbitol, glucose, fructose, alanine, glycine, proline, sucrose, lactose, ribose, trehalose, dimethyl sulfoxide (DMSO), glycerol, or a combination thereof.

[0154] In various aspects, provided herein are modified-release formulations comprising oligomannurarate (or a derivative thereof) and/or a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria), wherein the formulation releases a substantial amount of the oligomannurarate (or a derivative thereof) and/or bacterial mixture (and optionally additional therapeutic agents) into one or more regions of the GI tract. For example, the formulation can release at least about 60% of the bacterial mixture after the stomach and into one or more regions of the GI tract.

[0155] In various aspects, the modified-release formulation can release at least 60% of one or more of oligomannurarate (or a derivative thereof) and a bacterial mixture (and optionally additional therapeutic agents) after the stomach into one or more regions of the intestine. For example, the modified-release formulation can release at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of one or more of oligomannurarate (or a derivative thereof) and a bacterial mixture (and optionally additional therapeutic agents) in the intestines.

[0156] In various aspects, the modified-release formulation can release at least 60% of one or more of oligomannurarate (or a derivative thereof) and a bacterial mixture (and optionally additional therapeutic agents) in the small intestine. For example, the modified-release formulation can release at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or

100% of one or more of oligomannurarate (or a derivative thereof) and a bacterial mixture (and optionally additional therapeutic agents) in the small intestine (e.g., one or more of duodenum, jejunum, ileum, and ileocecal junction).

[0157] In various aspects, the modified-release formulation can release at least 60% of one or more of oligomannurarate (or a derivative thereof) and a bacterial mixture (and optionally additional therapeutic agents) in the large intestine. For example, the modified-release formulation can release at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or

100% of one or more of oligomannurarate (or a derivative thereof) and a bacterial mixture (and/or additional therapeutic agents) in the large intestine (e.g., one or more of cecum, ascending, transverse, descending or sigmoid portions of the colon, and rectum).

[0158] In some aspects, the pharmaceutical composition is formulated for release in the stomach. In other aspects, the pharmaceutical composition is formulated so as to not substantially release at least one of oligomannurarate (or a derivative thereof) and a bacterial mixture in the stomach.

[0159] In certain aspects, the modified-release formulation releases one or more of oligomannurarate (or a derivative thereof) and a bacterial mixture (and optionally additional therapeutic agents) at a specific pH. For example, in some aspects, the modified-release formulation is substantially stable in an acidic environment and substantially unstable (e.g., dissolves rapidly or is physically unstable) in a near neutral to alkaline environment. In some aspects, stability is indicative of not substantially releasing while instability is indicative of substantially releasing. For example, in some aspects, the modified-release formulation is substantially stable at a pH of about 7.0 or less, or about 6.5 or less, or about 6.0 or less, or about 5.5 or less, or about 5.0 or less, or about 4.5 or less, or about 4.0 or less, or about 3.5 or less, or about 3.0 or less, or about 2.5 or less, or about 2.0 or less, or about 1.5 or less, or about 1.0 or less. In some aspects, the present formulations are stable in lower pH areas and therefore do not substantially release in, for example, the stomach. In some aspects, modified-release formulation is substantially stable at a pH of about 1 to about 4 or lower and substantially unstable at pH values that are greater. In these aspects, the modified-release formulation does not substantially release in the stomach. In these aspects, the modified-release formulation substantially releases in the small intestine (e.g. one or more of the duodenum, jejunum, and ileum) and/or large intestine (e.g. one or more of the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon). In some aspects, modified-release formulation is substantially stable at a pH of about 4 to about 5 or lower and consequentially is substantially unstable at pH values that are greater and therefore is not substantially released in the stomach and/or small intestine (e.g. one or more of the duodenum, jejunum, and ileum). In these aspects, the modified-release formulation substantially releases in the large intestine (e.g. one or more of the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon). In various aspects, the pH values recited herein can be adjusted as known in the art to account for the state of the subject, e.g. whether in a fasting or postprandial state.

[0160] In some aspects, the modified-release formulation is substantially stable in gastric fluid and substantially unstable in intestinal fluid and, accordingly, is substantially released in the small intestine (e.g. one or more of the duodenum, jejunum, and ileum) and/or large intestine (e.g. one or more of the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon).

[0161] In some aspects, the modified-release formulation is stable in gastric fluid or stable in acidic environments. These modified-release formulations release about 30% or less by weight of the pharmaceutical composition (e.g., comprising at least one of oligomannurarate (or a derivative thereof) and a bacterial mixture) in the modified-release formulation in gastric fluid with a pH of about 4 to about 5 or less, or simulated gastric fluid with a pH of about 4 to about 5 or less, in about 15, or about 30, or about 45, or about 60, or about 90 minutes. Modified- release formulations of can release from about 0% to about 30%, from about 0% to about 25%, from about 0% to about 20%, from about 0% to about 15%, from about 0% to about 10%, about 5% to about 30%, from about 5% to about 25%, from about 5% to about 20%, from about 5% to about 15%, from about 5% to about 10% by weight of the composition in the modified-release formulation in gastric fluid with a pH of 4-5, or less or simulated gastric fluid with a pH of 4-5 or less, in about 15, or about 30, or about 45, or about 60, or about 90 minutes. Modified-release formulations can release about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight of the total composition in the modified-release formulation in gastric fluid with a pH of 5 or less, or simulated gastric fluid with a pH of 5 or less, in about 15, or about 30, or about 45, or about 60, or about 90 minutes.

[0162] In some aspects, the modified-release formulation is unstable in intestinal fluid. These modified-release formulations release about 70% or more by weight of at least one of the oligomannurarate (or a derivative thereof) and/or bacterial mixture and/or additional therapeutic agent in the modified-release formulation in intestinal fluid or simulated intestinal fluid in about 15, or about 30, or about 45, or about 60, or about 90 minutes. In some aspects, the modified-release formulation is unstable in near neutral to alkaline environments. These modified-release formulations release about 70% or more by weight of at least one of the oligomannurarate (or a derivative thereof) and/or the bacterial mixture and/or additional therapeutic agent in the modified-release formulation in intestinal fluid with a pH of about 4-5 or greater, or simulated intestinal fluid with a pH of about 4-5 or greater, in about 15, or about 30, or about 45, or about 60, or about 90 minutes. A modified-release formulation that is unstable in near neutral or alkaline environments can release 70% or more by weight of the pharmaceutical composition (e.g., comprising a microbial cocktail) in the modified-release formulation in a fluid having a pH greater than about 5 (e.g., a fluid having a pH of from about 5 to about 14, from about 6 to about 14, from about 7 to about 14, from about 8 to about 14, from about 9 to about 14, from about 10 to about 14, or from about 11 to about 14) in from about 5 minutes to about 90 minutes, or from about 10 minutes to about 90 minutes, or from about 15 minutes to about 90 minutes, or from about 20 minutes to about 90 minutes, or from about 25 minutes to about 90 minutes, or from about 30 minutes to about 90 minutes, or from about 5 minutes to about 60 minutes, or from about 10 minutes to about 60 minutes, or from about 15 minutes to about 60 minutes, or from about 20 minutes to about 60 minutes, or from about 25 minutes to about 90 minutes, or from about 30 minutes to about 60 minutes.

[0163] Examples of simulated gastric fluid and simulated intestinal fluid include, but are not limited to, those disclosed in the 2005 Pharmacopeia 23NF/28USP in Test Solutions at page 2858 and/or other simulated gastric fluids and simulated intestinal fluids known to those of skill in the art, for example, simulated gastric fluid and/or intestinal fluid prepared without enzymes.

[0164] In various aspects, the modified-release formulation can be substantially stable in chyme. For example, there is, in some aspects, a loss of less about 50% or about 40%, or about 30%, or about 20%, or about 10% of the activity or viability of the bacteria in the bacterial mixture in about 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2, or 1 hour from administration.

[0165] In various aspects, the modified-release formulations can be designed for immediate release (e.g. upon ingestion). In various aspects, the modified-release formulations can have sustained-release profiles, i.e. slow release of the active ingredient(s) in the body (e.g., GI tract) over an extended period of time. In various aspects, the modified-release formulations can have a delayed-release profile, i.e. not immediately release the active ingredient(s) upon ingestion; rather, postponement of the release of the active ingredient(s) until the composition is lower in the GI tract; for example, for release in the small intestine (e.g., one or more of duodenum, jejunum, ileum) or the large intestine (e.g., one or more of cecum, ascending, transverse, descending or sigmoid portions of the colon, and rectum). For example, a composition can be enteric coated to delay release of the active ingredient(s) until it reaches the small intestine or large intestine.

[0166] In various aspects, the modified-release formulations can utilize one or more modified- release coatings such as delayed-release coatings to provide for effective, delayed yet substantial delivery of the oligomannurarate (or a derivative thereof) and/or bacterial mixture to the GI tract together with, optionally, additional therapeutic agents.

[0167] In an aspect, the delayed-release coating includes an enteric agent that is substantially stable in acidic environments and substantially unstable in near neutral to alkaline environments. In an aspect, the delayed-release coating contains an enteric agent that is substantially stable in gastric fluid. The enteric agent can be selected from, for example, solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and EUDRAGIT^®-type polymer (poly(methacrylic acid, methylmethacrylate), hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac or other suitable enteric coating polymers. The EUDRAGIT^®-type polymers include, for example, EUDRAGIT^® FS 30D, L 30 D-55, L 100-55, L 100, L 12,5, L 12,5 P, RL 30 D, RL PO, RL 100, RL 12,5, RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5, and S 12,5 P. Similar polymers include Kollicoat^® MAE 30 DP and Kollicoat^® MAE 100 P. In some aspects, one or more of EUDRAGIT® FS 30D, L 30 D- 55, L 100-55, L 100, L 12,5, L 12,5 P RL 30 D, RL PO, RL 100, RL 12,5, RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5 S 12,5 P, Kollicoat^® MAE 30 DP and Kollicoat^® MAE 100 P is used. In various aspects, the enteric agent can be a combination of the foregoing solutions or dispersions.

[0168] In certain aspects, one or more coating system additives are used with the enteric agent. For example, one or more PlasACRYL^® additives can be used as an anti-tacking agent coating additive. Illustrative PlasACRYL^® additives include, but are not limited to, PlasACRYL^® HTP20 and PlasACRYL^® T20.

[0169] In another aspect, the delayed-release coating can degrade as a function of time when in aqueous solution without regard to the pH and/or presence of enzymes in the solution. Such a coating can comprise a water insoluble polymer. Its solubility in aqueous solution is therefore independent of the pH. The term “pH independent” as used herein means that the water permeability of the polymer and its ability to release pharmaceutical ingredients is not a function of pH and/or is only very slightly dependent on pH. Such coatings can be used to prepare, for example, sustained release formulations. Suitable water insoluble polymers include pharmaceutically acceptable non-toxic polymers that are substantially insoluble in aqueous media, e.g., water, independent of the pH of the solution. Suitable polymers include, but are not limited to, cellulose ethers, cellulose esters, or cellulose ether-esters, i.e., a cellulose derivative in which some of the hydroxy groups on the cellulose skeleton are substituted with alkyl groups and some are modified with alkanoyl groups. Examples include ethyl cellulose, acetyl cellulose, nitrocellulose, and the like. Other examples of insoluble polymers include, but are not limited to, lacquer, and acrylic and/or methacrylic ester polymers, polymers or copolymers of acrylate or methacrylate having a low quaternary ammonium content, or mixture thereof and the like. Other examples of insoluble polymers include EUDRAGIT RS^®, EUDRAGIT RL^®, and EUDRAGIT NE^®. Insoluble polymers can include polyvinyl esters, polyvinyl acetals, polyacrylic acid esters, butadiene styrene copolymers, and the like. In an aspect, colonic delivery is achieved by use of a slowly eroding wax plug (e.g., various PEGS, including for example, PEG6000).

[0170] In a further aspect, the delayed-release coating can be degraded by a microbial enzyme present in the gut flora. In an aspect, the delayed-release coating can be degraded by bacteria present in the small intestine. In another aspect, the delayed-release coating can be degraded by bacteria present in the large intestine.

[0171] In various aspects, the modified release formulation can be designed for release in the colon. Various colon-specific delivery approaches can be utilized. For example, the modified release formulation can be formulated using a colon-specific drug delivery system (CODES) as described for example, in Li et al., AAPS PharmSciTech (2002), 3(4): 1 -9, the entire contents of which are incorporated herein by reference. Drug release in such a system is triggered by colonic microflora coupled with pH-sensitive polymer coatings. For example, the formulation can be designed as a core tablet with three layers of polymer. The first coating is an acid-soluble polymer (e.g., EUDRAGIT E), the outer coating is enteric, along with a hydroxypropyl methylcellulose barrier layer interposed in between. In another aspect, colon delivery can be achieved by formulating the pharmaceutical composition (e.g., comprising a microbial cocktail) with specific polymers that degrade in the colon such as, for example, pectin. The pectin can be further gelled or crosslinked with a cation such as a zinc cation. In an aspect, the formulation is in the form of ionically crosslinked pectin beads which are further coated with a polymer (e.g., EUDRAGIT polymer). Additional colon specific formulations include, but are not limited to, pressure-controlled drug delivery systems (prepared with, for example, ethylcellulose) and osmotic controlled drug delivery systems (i.e., ORDS-CT).

[0172] Formulations for colon specific delivery of the oligomannurarate (or a derivative thereof) and/or bacterial mixture (and/or additional therapeutic agents), as described herein, can be evaluated using, for example, in vitro dissolution tests. For example, parallel dissolution studies in different buffers can be undertaken to characterize the behavior of the formulations at different pH levels. Alternatively, in vitro enzymatic tests can be carried out. For example, the formulations can be incubated in fermenters containing suitable medium for bacteria, and the amount of drug released at different time intervals is determined. Drug release studies can also be done in buffer medium containing enzymes or rat or guinea pig or rabbit cecal contents and the amount of drug released in a particular time is determined. In a further aspect, in vivo evaluations can be carried out using animal models such as dogs, guinea pigs, rats, and pigs. Further, clinical evaluation of colon specific drug delivery formulations can be evaluated by calculating drug delivery index (DDI) which considers the relative ratio of RCE (relative colonic tissue exposure to the drug) to RSC (relative amount of drug in blood i.e. that is relative systemic exposure to the drug). Higher drug DDI indicates better colon drug delivery. Absorption of drugs from the colon can be monitored by colonoscopy and intubation. [0173] In various aspects, the present formulations provide for substantial uniform delivery of the oligomannurarate (or a derivative thereof) and/or bacterial mixture (and/or additional therapeutic agent) in the area of release in the GI tract. In an aspect, the present formulations minimize patchy or heterogeneous release of the oligomannurarate (or a derivative thereof) and/or bacterial mixture.

[0174] In various aspects, the present formulations provide for release of multiple doses of one or more bacterial mixtures along the GI tract. For example, the composition and/or formulation can release multiple doses of the same bacterial mixture at different locations along the intestines, at different times, and/or at different pH. Alternatively, the composition and/or formulation can release a dose of different bacterial mixtures at different locations along the intestines, at different times, and/or at a different pH. In an aspect, the pharmaceutical composition comprises a first bacterial mixture comprising one or more bacterial isolates that is released at a first location in the intestine, and a second bacterial mixture comprising a preparation of uncultured fecal bacteria that is released at a second location in the intestine. In an aspect, the first bacterial mixture is released in the ileum, and the second bacterial mixture is released in the colon.

[0175] In various aspects, the present formulations provide for release of multiple doses of oligomannurarate (or derivative thereof) along the GI tract. For example, the composition and/or formulation can release multiple doses of the same oligomannurarate mixture (e.g., such that each dose comprises oligomannurarate polymers having the same degree of polymerization at the same proportion in the mixture) at different locations along the intestines, at different times, and/or at different pH. Alternatively, the composition and/or formulation can release a dose of different oligomannurarate mixtures (e.g., such that each dose comprises oligomannurarate polymers having a different degree of polymerization and/or the same degree of polymerization at a different proportion in the mixture) at different locations along the intestines, at different times, and/or at a different pH. In an aspect, the pharmaceutical composition comprises a first bacterial oligomannurarate mixture that is released at a first location in the intestine, and a second oligomannurarate mixture comprising that is released at a second location in the intestine. In an aspect, the first oligomannurarate mixture is released in the ileum, and the second oligomannurarate mixture is released in the colon.

[0176] The overall release profile of a formulation capable of releasing multiple doses of a pharmaceutically active ingredient can be adjusted using, for example, multiple particle types or multiple layers. For example, in an aspect, a first bacterial mixture or oligomannurarate mixture (or first dose of a bacterial mixture or oligomannurarate mixture) can be formulated for release in, for example, the small intestine (e.g., one or more of duodenum, jejunum, ileum), whereas the second bacterial mixture or oligomannurarate mixture (or second dose of the bacterial mixture or oligomannurarate mixture) is formulated for delayed release in, for example, the large intestine (e.g., one or more of cecum, ascending, transverse, descending or sigmoid portions of the colon, and rectum). In another example, the first bacterial mixture or oligomannurarate mixture (or first dose of a bacterial mixture or oligomannurarate mixture) can be formulated for release in, for example, the small intestine (e.g., one or more of duodenum, jejunum, ileum), whereas the second bacterial mixture or oligomannurarate mixture (or second dose of a bacterial mixture or oligomannurarate mixture) is formulated for delayed release in, for example, another part of the small intestine (e.g., one or more of duodenum, jejunum, ileum). In another aspect, the first bacterial mixture or oligomannurarate mixture (or first dose of a bacterial mixture or oligomannurarate mixture) can be formulated for release in, for example, the large intestine (e.g., one or more of cecum, ascending, transverse, descending or sigmoid portions of the colon, and rectum), whereas the second bacterial mixture or oligomannurarate mixture (or second dose of the bacterial mixture or oligomannurarate mixture) is formulated for delayed release in, for example, another part of the large intestine (e.g., one or more of cecum, ascending, transverse, descending or sigmoid portions of the colon, and rectum). In various aspects, the composition and/or formulation can release at least one dose, at least two doses, at least three doses, at least four doses, or at least five doses of the bacterial mixture or oligomannurarate mixture at different locations along the intestines, at different times, and/or at different pH. Likewise, in various aspects, the composition and/or formulation can release at least one bacterial mixture or oligomannurarate mixture, at least two bacterial mixtures or oligomannurarate mixtures, at least three bacterial mixtures or oligomannurarate mixtures, at least four bacterial mixtures or oligomannurarate mixtures, or at least five bacterial mixtures or oligomannurarate mixtures at different locations along the intestines, at different times, and/or at different pH.

[0177] In another aspect, a delayed or gradual enteric release formulation comprises the use of a bilayer tablet or capsule which comprises a first layer comprising a polyalkylene oxide, a polyvinylpyrrolidone, a lubricant, or a mixture thereof, and a second osmotic push layer comprising polyethylene oxide, carboxy-methylcellulose, or both. In an aspect, a delayed or gradual enteric release formulation comprises the use of a release-retarding matrix material selected from the group consisting of an acrylic polymer, a cellulose, a wax, a fatty acid, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, polyvinylpyrrolidine, a vinyl acetate copolymer, a vinyl alcohol copolymer, polyethylene oxide, an acrylic acid and methacrylic acid copolymer, a methyl methacrylate copolymer, an ethoxyethyl methacrylate polymer, a cyanoethyl methacrylate polymer, an aminoalkyl methacrylate copolymer, a poly(acrylic acid), a poly(methacrylic acid), a methacrylic acid alkylamide copolymer, a poly(methyl methacrylate), a poly(methacrylic acid anhydride), a methyl methacrylate polymer, a polymethacrylate, a poly(methyl methacrylate) copolymer, a polyacrylamide, an aminoalkyl methacrylate copolymer, a glycidyl methacrylate copolymer, a methyl cellulose, an ethylcellulose, a carboxymethylcellulose, a hydroxypropylmethylcellulose, a hydroxymethyl cellulose, a hydroxyethyl cellulose, a hydroxypropyl cellulose, a crosslinked sodium carboxymethylcellulose, a crosslinked hydroxypropylcellulose, a natural wax, a synthetic wax, a fatty alcohol, a fatty acid, a fatty acid ester, a fatty acid glyceride, a hydrogenated fat, a hydrocarbon wax, stearic acid, stearyl alcohol, beeswax, glycowax, castor wax, camauba wax, a polylactic acid, polyglycolic acid, a co-polymer of lactic and glycolic acid, carboxymethyl starch, potassium methacrylate/divinylbenzene copolymer, crosslinked polyvinylpyrrolidone, poly inylalcohols, polyvinylalcohol copolymers, polyethylene glycols, non-crosslinked polyvinylpyrrolidone, polyvinylacetates, polyvinylacetate copolymers, or any combination thereof. In an aspect, a delayed or gradual enteric release formulation comprises the use of a microenvironment pH modifier.

[0178] It will be understood that a pharmaceutical composition described herein can comprise multiple distinct bacterial mixtures, for example to achieve different delivery location profiles for each bacterial mixture. In an aspect, a pharmaceutical composition comprises at least two bacterial mixtures, such that a first bacterial mixture comprises one or more bacterial isolates and a second bacterial mixture comprises a preparation of uncultured fecal bacteria. In an aspect, the second bacterial mixture further comprises one or more bacterial isolates that are different than the bacterial isolate(s) in the first bacterial mixture. Alternatively, the second bacterial mixture can consist essentially of the preparation of uncultured fecal bacteria. In another aspect, the first bacterial mixture can comprise only one bacterial isolate. In another aspect, bacterial mixtures can vary based on the number of colony forming units or viable cells in the mixtures. A pharmaceutical composition can comprise any number of bacterial mixtures, for example one, two, three, four, five, six, seven, eight, nine, ten, or more than ten bacterial mixtures that each contain a different bacterial isolate, a different combination of bacterial isolates, a preparation of uncultured fecal bacteria, a different combination of uncultured fecal bacteria with one or more bacterial isolates, a different number of CFUs, or a combination thereof.

[0179] It will be understood that a pharmaceutical composition described herein can comprise multiple distinct oligomannurarate mixtures (or derivative thereof), for example to achieve different delivery location profiles for each mixture. Oligomannurarate mixtures can vary based on the degree of polymerization of the oligomannurarate polymers in the mixture, the proportion of the total mixture made up by an oligomannurarate polymer of a particular degree of polymerization, the concentration or amount of oligomannurate in the mixture, or a combination thereof. A pharmaceutical composition can comprise any number of oligomannurarate mixtures, for example one, two, three, four, five, six, seven, eight, nine, ten, or more than ten mixtures.

[0180] In an aspect, a pharmaceutical composition can be a drench. In one aspect, a drench is prepared by choosing a saline-suspended form of a pharmaceutical composition. A water- soluble form of one ingredient can be used in conjunction with a water-insoluble form of the other by preparing a suspension of one with an aqueous solution of the other. Water-insoluble forms of either active ingredient may be prepared as a suspension or in some physiologically acceptable solvent such as polyethylene glycol. Suspensions of water-insoluble forms of either active ingredient can be prepared in oils such as peanut, com, sesame oil or the like; in a glycol such as propylene glycol or a polyethylene glycol; or in water depending on the solubility of a particular active ingredient. Suitable physiologically acceptable adjuvants may be necessary in order to keep the active ingredients suspended. Adjuvants can include and be chosen from among the thickeners, such as carboxymethylcellulose, polyvinyl pyrrolidone, gelatin and the alginates. Surfactants generally will serve to suspend the active ingredients, particularly the fat-soluble propionate-enhancing compounds. Most useful for making suspensions in liquid nonsolvents are alkylphenol polyethylene oxide adducts, naphthalenesulfonates, alkylbenzene- sulfonates, and the polyoxyethylene sorbitan esters. In addition many substances, which affect the hydrophilicity, density and surface tension of the liquid, can assist in making suspensions in individual cases. For example, silicone anti-foams, glycols, sorbitol, and sugars can be useful suspending agents.

[0181] In an aspect, a pharmaceutical composition can be administered by a patch. [0182] In some aspects, one or more bacterial isolates described herein are in the form of live, vegetative cells. In some aspects, one or more bacterial isolates described herein are in the form of spores. In some aspects, one or more bacterial isolates described herein are lyophilized. By way of non-limiting example, lyophilization can be via methods known in the art, including those described in US Patent No. 7,799,328, the contents of which are hereby incorporated by reference in their entirety. In some aspects, lyophilized bacterial mixtures described herein are placed in an enterically coated soft gel or capsule.

[0183] In various aspects, formulations can take the form of those described in one or more of US Patent Nos. 8,535,713 and 8,9117,77 and US Patent Publication Nos. 20120141585, 20120141531, 2006/001896, 2007/0292523, 2008/0020018, 2008/0113031, 2010/0203120, 2010/0255087, 2010/0297221, 2011/0052645, 2013/0243873, 2013/0330411, 2014/0017313, and 2014/0234418, the contents of which are hereby incorporated by reference herein in their entirety.

[0184] In various aspects, formulations can take the form of those as described in International Patent Publication No. WO 2008/135090, the contents of which are hereby incorporated by reference herein in their entirety.

[0185] In various aspects, formulations can take the form of those described in one or more of US Patent Nos. 4,196,564; 4,196,565; 4,247,006; 4,250,997; 4,268,265; 5,317,849; 6,572,892; 7,712,634; 8,074,835; 8,398,912; 8,440,224; 8,557,294; 8,646,591; 8,739,812; 8,810,259; 8,852,631; and 8,911,788 and US Patent Publication Nos. 2014/0302132; 2014/0227357; 20140088202; 20130287842; 2013/0295188; 2013/0307962; and

20130184290, the contents of which are hereby incorporated by reference herein in their entirety.

Administration and dosage

[0186] It will be appreciated that the dose of a pharmaceutical composition or the oligomannurarate (or derivative thereof) and/or bacterial cells (e.g., a bacterial mixture comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria) therein will vary according to, for example, the particular dosage form, the mode of administration to a subject, the identity of a bacterial isolate, if any, in the composition, the number of bacterial isolates, if any, in the composition, and the presence or absence of a preparation of uncultured fecal bacteria in the composition. These factors, as well as variables that may modify the activity of oligomannurarate (or derivative thereof) and/or bacteria in a bacterial mixture (e.g., subject body weight, sex and diet, time of administration, route of administration, rate of excretion, condition of the subject, drug combinations, genetic disposition and reaction sensitivities) can be taken into account by those skilled in the art to generate an effective dose or dosage regime for treatment or prevention of at least one symptom of a neurodegenerative disease (e.g., Alzheimer’s Disease) in a patient. Administration can be carried out continuously or in one or more discrete doses within the maximum tolerated dose. Optimal administration rates for a given set of conditions can be ascertained by those skilled in the art using conventional dosage administration tests.

[0187] In various aspects, the dose of the pharmaceutical composition or the oligomannurarate (or derivative thereof) and/or bacterial cells (e.g., a bacterial mixture comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria) therein is effective to modulate a patient’s microbiome to favor an ecological balance, so as to treat or prevent one or more symptoms of a neurodegenerative disease (e.g., Alzheimer’s Disease).

[0188] In one aspect, a pharmaceutically active or therapeutically effective dose of a bacterial isolate administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease comprises at least 10⁵, at least 10⁶, at least 10⁷, at least 10⁸, at least 10⁹, at least 10¹⁰, at least 10¹¹, at least 10¹², at least 10¹³, at least 10¹⁴, or at least 10¹⁵ CFUs of the bacterial isolate. In another aspect, a pharmaceutically active or therapeutically effective dose of a bacterial isolate administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease comprises at most 10⁵, at most 10⁶, at most 10⁷, at most 10⁸, at most 10⁹, at most 10¹⁰, at most 10¹¹, at most 10¹², at most 10¹³, at most 10¹⁴, or at most 10¹⁵ CFUs of the bacterial isolate. In a further aspect, a pharmacologically active or therapeutically effective dose of abacterial isolate administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease is selected from the group consisting of: from 10⁸ CFUs to 10¹⁴ CFUs, from 10⁹ CFUs to 10¹³ CFUs, from 10¹⁰ CFUs to 10¹² CFUs, from 10¹⁰

CFUs to 10¹¹ CFUs, from 10⁹ CFUs to 10¹⁴ CFUs, from 10⁹ CFUs to 10¹² CFUs, from 10⁹

CFUs to 10¹¹ CFUs, from 10⁹ CFUs to 10¹⁰ CFUs, from 10¹⁰ CFUs to 10¹⁴ CFUs, from 10¹⁰

CFUs to 10¹³ CFUs, from 10¹¹ CFUs to 10¹⁴ CFUs, from 10¹¹ CFUs to 10¹³ CFUs, from 10¹²

CFUs to 10¹⁴ CFUS, and from 10¹³ CFUs to 10¹⁴ CFUs of the bacterial isolate. [0189] In an aspect, a pharmaceutical composition comprises one or more bacterial isolates, with each bacterial isolate present in each unit dose at one of the foregoing pharmaceutically active or therapeutically effective doses in a unit weight of about 0.2, 0.4, 0.6, 0.8 or 1.0 gram, or a unit volume of about 0.2, 0.4, 0.6, 0.8 or 1.0 milliliter.

[0190] In one aspect, a pharmaceutically active or therapeutically effective dose of a bacterial isolate administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease (e.g., Alzheimer’s Disease) comprises at least 10⁵, at least 10⁶, at least 10⁷, at least 10⁸, at least 10⁹, at least 10¹⁰, at least 10¹¹, at least 10¹², at least 10¹³, at least 10¹⁴, or at least 10¹⁵ cells or spores of the bacterial isolate. In another aspect, a pharmaceutically active or therapeutically effective dose of a bacterial isolate administered to a subject i.e. in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease comprises at most 10⁵, at most 10⁶, at most 10⁷, at most 10⁸, at most 10⁹, at most 10¹⁰, at most 10¹¹, at most 10¹², at most 10¹³, at most 10¹⁴, or at most 10¹⁵ total cells or spores of the bacterial isolate. In a further aspect, a pharmacologically active or therapeutically effective dose of a bacterial isolate administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease is selected from the group consisting of: from 10⁸ to 10¹⁴, from 10⁹ to 10¹³, from 10¹⁰ to 10¹², from 10¹⁰ to 10¹¹, from 10⁹ to 10¹⁴, from 10⁹ to 10¹², from 10⁹ to 10¹¹, from 10⁹ to 10¹⁰, from 10¹⁰ to 10¹⁴, from 10¹⁰ to 10¹³, from 10¹¹ to 10¹⁴, from 10¹¹ to 10¹³, from 10¹² to 10¹⁴, and from 10¹³ to 10¹⁴ cells or spores of the bacterial isolate.

[0191] In an aspect, the pharmaceutically active or therapeutically effective dose cell count of a bacterial isolate is directed to live cells. In one aspect, a pharmaceutical composition comprises one or more bacterial isolates, with each bacterial isolates present in each dosage unit at one of the foregoing pharmaceutically active or therapeutically effective doses in a unit weight of about 0.2, 0.4, 0.6, 0.8 or 1.0 gram, or a unit volume of about 0.2, 0.4, 0.6, 0.8 or 1.0 milliliter.

[0192] In an aspect, a pharmaceutical composition described herein is in the form of a capsule, and each capsule comprises at least 10⁵, at least 10⁶, at least 10⁷, at least 10⁸, at least 10⁹, at least 10¹⁰, at least 10¹¹, at least 10¹², at least 10¹³, at least 10¹⁴, or at least 10¹⁵ cells or spores of a bacterial isolate. In an aspect, a pharmaceutical composition described herein is in the form of a capsule, and each capsule comprises from 10⁸ to 10¹⁴, from 10⁹ to 10¹³, from 10¹⁰ to 10¹², from 10¹⁰ to 10¹¹, from 10⁹ to 10¹⁴, from 10⁹ to 10¹², from 10⁹ to 10¹¹, from 10⁹ to 10¹⁰, from 10¹⁰ to 10¹⁴, from 10¹⁰ to 10¹³, from 10¹¹ to 10¹⁴, from 10¹¹ to 10¹³, from 10¹² to 10¹⁴, or from

10¹³ to 10¹⁴ cells or spores of abacterial isolate.

[0193] In one aspect, a pharmaceutically active or therapeutically effective dose of a preparation of uncultured fecal bacteria administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease (e.g., Alzheimer’s Disease) comprises at least 10⁵, at least 10⁶, at least 10⁷, at least 10⁸, at least 10⁹, at least 10¹⁰, at least 10¹¹, at least 10¹², at least 10¹³, at least 10¹⁴, or at least 10¹⁵ CFUs of the preparation of uncultured fecal bacteria. In another aspect, a pharmaceutically active or therapeutically effective dose of a preparation of uncultured fecal bacteria administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease comprises at most 10⁵, at most 10⁶, at most 10⁷, at most 10⁸, at most 10⁹, at most 10¹⁰, at most 10¹¹, at most 10¹², at most 10¹³, at most 10¹⁴, or at most 10¹⁵ CFUs of the preparation of uncultured fecal bacteria. In a further aspect, a pharmacologically active or therapeutically effective dose of a preparation of uncultured fecal bacteria administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease is selected from the group consisting of: from 10⁸ CFUs to 10¹⁴ CFUs, from 10⁹ CFUs to 10¹³ CFUs, from 10¹⁰ CFUs to 10¹² CFUs, from 10¹⁰ CFUs to 10¹¹ CFUs, from 10⁹ CFUs to 10¹⁴

CFUs, from 10⁹ CFUs to 10¹² CFUs, from 10⁹ CFUs to 10¹¹ CFUs, from 10⁹ CFUs to 10¹⁰

CFUs, from 10¹⁰ CFUs to 10¹⁴ CFUs, from 10¹⁰ CFUs to 10¹³ CFUs, from 10¹¹ CFUs to 10¹⁴

CFUs, from 10¹¹ CFUs to 10¹³ CFUs, from 10¹² CFUs to 10¹⁴ CFUs, and from 10¹³ CFUs to

10¹⁴ CFUs of the preparation of uncultured fecal bacteria.

[0194] In an aspect, a preparation of uncultured fecal bacteria is present in each unit dose of a pharmaceutical composition at one of the foregoing pharmaceutically active or therapeutically effective doses in a unit weight of about 0.2, 0.4, 0.6, 0.8 or 1.0 gram, or a unit volume of about 0.2, 0.4, 0.6, 0.8 or 1.0 milliliter.

[0195] In one aspect, a pharmaceutically active or therapeutically effective dose of a preparation of uncultured fecal bacteria administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease (e.g., Alzheimer’s Disease) comprises at least 10⁵, at least 10⁶, at least 10⁷, at least 10⁸, at least 10⁹, at least 10¹⁰, at least 10¹¹, at least 10¹², at least 10¹³, at least 10¹⁴, or at least 10¹⁵ cells or spores of the preparation of uncultured fecal bacteria. In another aspect, a pharmaceutically active or therapeutically effective dose of a preparation of uncultured fecal bacteria administered to a subject i.e. in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease comprises at most 10⁵, at most 10⁶, at most 10⁷, at most 10⁸, at most 10⁹, at most 10¹⁰, at most 10¹¹, at most 10¹², at most 10¹³, at most 10¹⁴, or at most 10¹⁵ total cells or spores of the preparation of uncultured fecal bacteria. In a further aspect, a pharmacologically active or therapeutically effective dose of a preparation of uncultured fecal bacteria administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease is selected from the group consisting of: from 10⁸ to 10¹⁴, from 10⁹ to 10¹³, from 10¹⁰ to 10¹², from 10¹⁰ to 10¹¹, from 10⁹ to 10¹⁴, from 10⁹ to 10¹², from 10⁹ to 10¹¹, from 10⁹ to 10¹⁰, from 10¹⁰ to 10¹⁴, from 10¹⁰ to 10¹³, from 10¹¹ to 10¹⁴, from 10¹¹ to 10¹³, from 10¹² to 10¹⁴, and from 10¹³ to 10¹⁴ cells or spores of the preparation of uncultured fecal bacteria.

[0196] In an aspect, the pharmaceutically active or therapeutically effective dose cell count of a preparation of uncultured fecal bacteria is directed to live cells. In one aspect, a preparation of uncultured fecal bacteria is present in each unit dose of a pharmaceutical composition at one of the foregoing pharmaceutically active or therapeutically effective doses in a unit weight of about 0.2, 0.4, 0.6, 0.8 or 1.0 gram, or a unit volume of about 0.2, 0.4, 0.6, 0.8 or 1.0 milliliter.

[0197] In an aspect, a pharmaceutical composition described herein is in the form of a capsule, and each capsule comprises at least 10⁵, at least 10⁶, at least 10⁷, at least 10⁸, at least 10⁹, at least 10¹⁰, at least 10¹¹, at least 10¹², at least 10¹³, at least 10¹⁴, or at least 10¹⁵ cells or spores of a preparation of uncultured fecal bacteria. In an aspect, a pharmaceutical composition described herein is in the form of a capsule, and each capsule comprises from 10⁸ to 10¹⁴, from 10⁹ to 10¹³, from 10¹⁰ to 10¹², from 10¹⁰ to 10¹¹, from 10⁹ to 10¹⁴, from 10⁹ to 10¹², from 10⁹ to 10¹¹, from 10⁹ to 10¹⁰, from 10¹⁰ to 10¹⁴, from 10¹⁰ to 10¹³, from 10¹¹ to 10¹⁴, from 10¹¹ to 10¹³, from 10¹² to 10¹⁴, or from 10¹³ to 10¹⁴ cells or spores of a preparation of uncultured fecal bacteria.

[0198] In an aspect, a pharmaceutically active or therapeutically effective dose of oligomannurarate (or derivative thereof) administered to a subject (i.e., in single or multiple administrations) to treat at least one symptom of a neurodegenerative disease (e.g., Alzheimer’s Disease) comprises at least 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105,

110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200,

210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390,

400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780, 800, 820, 840, 860, 880, 900, 920, 940, 960, 980, 1000, 1050, 1100, 1150, 1200, 1250, 13000, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000 mg of oligomannurarate (or derivative thereof), or greater than 2000 mg of oligomannurarate (or derivative thereof).

[0199] A subject can be administered oligomannurarate (or derivative thereof) and a bacterial mixture (e.g., comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria) for treatment of one or more symptoms of a neurodegenerative disease. In such cases, the oligomannurarate (or derivative thereof) and bacterial mixture can be administered to the subject together in the same pharmaceutical composition, or in separate compositions. Further, a pharmaceutical composition can be administered to the subject in a single unit dose or multiple unit doses, for example as part of a dosage regime. In an aspect, the dosage of a preparation of uncultured fecal bacteria (e.g. measured by CFU or cell/spore count) administered to a subject is greater than the dosage of a bacterial isolate. Alternatively, the dosage of the preparation of uncultured fecal bacteria (e.g. measured by CFU or cell/spore count) administered to the subject can be less than the dosage of the bacterial isolate. In another aspect, the dosage of the preparation of uncultured fecal bacteria (e.g. measured by CFU or cell/spore count) can be about the same as the dosage of the bacterial isolate.

[0200] The pharmaceutical compositions described herein can include one or more of oligomannurarate (or derivative thereof) and a bacterial mixture, which can be administered to a subject in need thereof in a method described herein. The oligomannurarate (or derivative thereof) can be administered simultaneous or sequential with a bacterial mixture (e.g., comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria) described herein. For example, the oligomannurarate (or derivative thereof) can be combined into a single formulation with a bacterial mixture comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria.

[0201] In an aspect, the oligomannurarate (or derivative thereof) and bacterial mixture can be administered to a subject simultaneously. The term “simultaneously” as used herein, means that the oligomannurarate (or derivative thereof) and the bacterial mixture are administered with a time separation of no more than about 60 minutes, such as no more than about 30 minutes, no more than about 20 minutes, no more than about 10 minutes, no more than about 5 minutes, or no more than about 1 minute. Administration of the oligomannurarate (or derivative thereof) and the bacterial mixture can be by simultaneous administration of a single formulation (e.g., a formulation comprising the oligomannurarate (or derivative thereof) and a bacterial mixture) or of separate formulations (e.g. , a first formulation including the oligomannurarate (or derivative thereof) and a second formulation including the bacterial mixture).

[0202] Co-administration does not require oligomannurarate (or derivative thereof) to be administered simultaneously with a bacterial mixture, if the timing of its administration is such that the pharmacological activities of the oligomannurarate (or derivative thereof) and the bacterial mixture (e.g., comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria) overlap in time. For example, the oligomannurarate (or derivative thereof) and the bacterial mixture can be administered sequentially. The term “sequentially” as used herein means that the oligomannurarate (or derivative thereof) and the bacterial mixture are administered with a time separation of more than about 60 minutes. For example, the time between the sequential administration of the oligomannurarate (or derivative thereof) and the bacterial mixture can be more than about 60 minutes, more than about 2 hours, more than about 5 hours, more than about 10 hours, more than about 1 day, more than about 2 days, more than about 3 days, or more than about 1 week apart. The optimal administration times will depend on the rates of metabolism, excretion, and/or the pharmacodynamic activity of the oligomannurarate (or derivative thereof) and the bacterial mixture being administered. Either of the oligomannurarate (or derivative thereof) or the bacterial mixture can be administered first.

[0203] In a further aspect, the oligomannurarate (or derivative thereof) and the bacterial mixture can be administered to a subject simultaneously but the release of oligomannurarate (or derivative thereof) and the bacterial mixture from their respective dosage forms (or single unit dosage form if co-formulated) in the GI tract can occur sequentially.

[0204] Co-administration also does not require oligomannurarate (or derivative thereof) to be administered to the subject by the same route of administration as a bacterial mixture. Rather, the oligomannurarate (or derivative thereof) and bacterial mixture can be administered by any appropriate route, for example, parenterally or non-parenterally.

[0205] In an aspect, the number of cells of a bacterial isolate administered to a subject to treat one or more symptoms of a neurodegenerative disease is about the same or greater than the total number of cells of a preparation of uncultured fecal bacteria administered to the subject. Alternatively, the number of cells of a bacterial isolate administered to a subject to treat one or more symptoms of a neurodegenerative disease can be about the same or less than the total number of cells of a preparation of uncultured fecal bacteria administered to the subject.

[0206] In an aspect, a pharmaceutical composition comprises a bacterial mixture that comprises multiple bacterial isolates. In another aspect, at least two bacterial isolates are present at about the same amount or dosage (e.g., about the same number of viable cells or spores, or about the same CFUs). In another aspect, at least three bacterial isolates, at least four bacterial isolates, at least five bacterial isolates, at least six bacterial isolates, at least seven bacterial isolates, at least eight bacterial isolates, at least nine bacterial isolates, at least ten bacterial isolates, or more than ten bacterial isolates are present in the pharmaceutical composition at about the same amount or dosage (e.g., about the same number of viable cells or spores, or about the same CFUs). In another aspect, all of the bacterial isolates in a bacterial mixture are present in about the same amounts.

[0207] In an aspect, a pharmaceutical composition comprises a bacterial mixture comprising multiple bacterial isolates, and at least two of the multiple bacterial isolates are present at different amounts or dosages (e.g., different numbers of viable cells or spores, or different CFUs). In another aspect, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more than ten bacterial isolates are present in the bacterial mixture at different amounts or dosages.

[0208] A pharmaceutical composition can comprise a bacterial mixture comprising multiple bacterial isolates in combination with a preparation of uncultured fecal bacteria (and optionally oligomannurarate (or derivative thereof)). In an aspect, each bacterial isolate is present in the composition at an amount or dosage that is greater than the amount or dosage of the preparation of uncultured fecal bacteria (e.g., measured as numbers of viable cells or spores, or CFUs). In another aspect, each bacterial isolate is present in the composition at an amount or dosage that is less than the amount or dosage of the preparation of uncultured fecal bacteria (e.g., measured as numbers of viable cells or spores, or CFUs). In another aspect, at least one bacterial isolate is present in the composition at an amount or dosage that is greater than the amount or dosage of the preparation of uncultured fecal bacteria, and at least one bacterial isolate is present in the composition at an amount or dosage that is less than the amount or dosage of the preparation of uncultured fecal bacteria (e.g., measured as numbers of viable cells or spores, or CFUs).

[0209] In an aspect, a pharmaceutical composition comprises one or more bacterial isolates at an amount or dosage which is at or above the minimum amount or dosage of the bacterial isolate required to be administered to a subject for engraftment of the bacterial isolate to occur in the intestine of the subject. For example, a minimum dosage of the bacterial isolate required for engraftment of the bacterial isolate into the intestine of the subject can be at least 10⁶ cells, at least 10⁷ cells, at least 10⁸ cells, at least 10⁹ cells, at least 10¹⁰ cells, at least 10¹¹ cells, or at least 10¹² cells. In an aspect a first and second bacterial isolate of a microbial cocktail engraft in the intestine of a subject at different minimal dosages or amounts, and a dosage or amount of each of the first and second bacterial isolate in the microbial cocktail varies corresponding to the respective minimal dosage or amount required for engraftment of the respective bacterial isolate.

[0210] Individual doses of the pharmaceutical composition (e.g., comprising a bacterial mixture and/or oligomannurarate (or derivative thereof)) can be administered in unit dosage forms (e.g., tablets or capsules) containing, for example, from about 0.01 mg to about 5,000 mg, from about 0.01 mg to about 4,000 mg, from about 0.01 mg to about 3,000 mg, from about 0.01 mg to about 2,000 mg, from about 0.01 mg to about 1,000 mg, from about 0.01 mg to about 950 mg, from about 0.01 mg to about 900 mg, from about 0.01 mg to about 850 mg, from about 0.01 mg to about 800 mg, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 700 mg, from about 0.01 mg to about 650 mg, from about 0.01 mg to about 600 mg, from about 0.01 mg to about 550 mg, from about 0.01 mg to about 500 mg, from about 0.01 mg to about 450 mg, from about 0.01 mg to about 400 mg, from about 0.01 mg to about 350 mg, from about 0.01 mg to about 300 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to about 200 mg, from about 0.01 mg to about 150 mg, from about 0.01 mg to about 100 mg, from about 0.1 mg to about 90 mg, from about 0.1 mg to about 80 mg, from about 0.1 mg to about 70 mg, from about 0.1 mg to about 60 mg, from about 0.1 mg to about 50 mg, from about 0.1 mg to about 40 mg, from about 0.1 mg to about 30 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 3 mg, from about 0.1 mg to about 1 mg of the active ingredient per unit dosage form, or from about 5 mg to about 80 mg per unit dosage form. For example, a unit dosage form can include about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, , about 2,000 mg, about 3,000 mg, about 4,000 mg, or about 5,000 mg of one or more active ingredients (e.g., abacterial mixture and/or oligomannurarate (or derivative thereof)), inclusive of all values and ranges therebetween.

[0211] In an aspect, the pharmaceutical composition (e.g., comprising a bacterial mixture and/or oligomannurarate (or derivative thereof)) is administered at an amount of from about 0.01 mg to about 100 mg daily, an amount of from about 0.01 mg to about 5,000 mg daily, about 0.01 mg to about 4,000 mg daily, about 0.01 mg to about 3,000 mg daily, about 0.01 mg to about 2,000 mg daily, about 0.01 mg to about 1,000 mg daily, from about 0.01 mg to about 950 mg daily, from about 0.01 mg to about 900 mg daily, from about 0.01 mg to about 850 mg daily, from about 0.01 mg to about 800 mg daily, from about 0.01 mg to about 750 mg daily, from about 0.01 mg to about 700 mg daily, from about 0.01 mg to about 650 mg daily, from about 0.01 mg to about 600 mg daily, from about 0.01 mg to about 550 mg daily, from about 0.01 mg to about 500 mg daily, from about 0.01 mg to about 450 mg daily, from about 0.01 mg to about 400 mg daily, from about 0.01 mg to about 350 mg daily, from about 0.01 mg to about 300 mg daily, from about 0.01 mg to about 250 mg daily, from about 0.01 mg to about 200 mg daily, from about 0.01 mg to about 150 mg daily, from about 0.1 mg to about 100 mg daily, from about 0.1 mg to about 95 mg daily, from about 0.1 mg to about 90 mg daily, from about 0.1 mg to about 85 mg daily, from about 0.1 mg to about 80 mg daily, from about 0.1 mg to about 75 mg daily, from about 0.1 mg to about 70 mg daily, from about 0.1 mg to about 65 mg daily, from about 0.1 mg to about 60 mg daily, from about 0.1 mg to about 55 mg daily, from about 0.1 mg to about 50 mg daily, from about 0.1 mg to about 45 mg daily, from about 0.1 mg to about 40 mg daily, from about 0.1 mg to about 35 mg daily, from about 0.1 mg to about 30 mg daily, from about 0.1 mg to about 25 mg daily, from about 0.1 mg to about 20 mg daily, from about 0.1 mg to about 15 mg daily, from about 0.1 mg to about 10 mg daily, from about 0.1 mg to about 5 mg daily, from about 0.1 mg to about 3 mg daily, from about 0.1 mg to about 1 mg daily, or from about 5 mg to about 80 mg daily. In various aspects, the bacterial mixture (and/or additional therapeutic agents) is administered at a daily dose of about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, or about 5,000 mg inclusive of all values and ranges therebetween.

[0212] In some aspects, a suitable dosage of the pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) is in a range of about 0.01 mg/kg to about 100 mg/kg of body weight of the subject, for example, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, 1.9 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 60 mg/kg body weight, about 70 mg/kg body weight, about 80 mg/kg body weight, about 90 mg/kg body weight, or about 100 mg/kg body weight, inclusive of all values and ranges therebetween. In other aspects, a suitable dosage of the composition in a range of about 0.01 mg/kg to about 100 mg/kg of body weight, in a range of about 0.01 mg/kg to about 90 mg/kg of body weight, in a range of about 0.01 mg/kg to about 80 mg/kg of body weight, in a range of about 0.01 mg/kg to about 70 mg/kg of body weight, in a range of about 0.01 mg/kg to about 60 mg/kg of body weight, in a range of about 0.01 mg/kg to about 50 mg/kg of body weight, in a range of about 0.01 mg/kg to about 40 mg/kg of body weight, in a range of about 0.01 mg/kg to about 30 mg/kg of body weight, in a range of about 0.01 mg/kg to about 20 mg/kg of body weight, in a range of about 0.01 mg/kg to about 10 mg/kg of body weight, in a range of about 0.01 mg/kg to about 9 mg/kg of body weight, in a range of about 0.01 mg/kg to about 8 mg/kg of body weight, in a range of about 0.01 mg/kg to about 7 mg/kg of body weight, in a range of 0.01 mg/kg to about 6 mg/kg of body weight, in a range of about 0.05 mg/kg to about 5 mg/kg of body weight, in a range of about 0.05 mg/kg to about 4 mg/kg of body weight, in a range of about 0.05 mg/kg to about 3 mg/kg of body weight, in a range of about 0.05 mg/kg to about 2 mg/kg of body weight, in a range of about 0.05 mg/kg to about 1.5 mg/kg of body weight, or in a range of about 0.05 mg/kg to about 1 mg/kg of body weight.

[0213] In accordance with certain aspects, the pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) can be administered, for example, more than once daily, about once per day, about every other day, about every third day, about once a week, about once every two weeks, about once every month, about once every two months, about once every three months, about once every six months, or about once every year.

[0214] In an aspect, a pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) can be administered to a patient in need thereof at least once daily for at least two consecutive days. In another aspect, a pharmaceutical composition is administered at least once daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In another aspect, a pharmaceutical composition is administered at least once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In another aspect, a pharmaceutical composition is administered at least twice, three times, four times, or five times per week for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In another aspect, a pharmaceutical composition is administered at least once daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or weeks. In a further aspect, a pharmaceutical composition is administered at least once daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months. In yet another aspect, a pharmaceutical composition is administered at least once for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject’s entire life span, or an indefinite period of time.

[0215] In an aspect, a pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) can be administered to a patient in need thereof at least twice daily for at least two consecutive days. In an aspect, a pharmaceutical composition is administered at least twice daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In another aspect, a pharmaceutical composition is administered at least twice daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In another aspect, a pharmaceutical composition is administered at least twice daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or week. In another aspect, a pharmaceutical composition is administered at least twice daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months. In another aspect, a pharmaceutical composition is administered at least twice for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject’s entire life span, or an indefinite period of time.

[0216] In an aspect of the present disclosure, a pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) can be administered to a patient in need thereof at least three times daily for at least two consecutive days. In an aspect, a pharmaceutical composition is administered at least three times daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In an aspect, a pharmaceutical composition is administered at least three times daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In an aspect, a pharmaceutical composition is administered at least three times daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or weeks. In an aspect, a pharmaceutical composition is administered at least three times daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months. In an aspect, a pharmaceutical composition is administered at least three times for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject’s entire life span, or an indefinite period of time.

[0217] In an aspect, a pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) can be administered to a patient twice per day for a treatment period of 5 weeks, 10 weeks, 15 week, 20 weeks, 25 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks 49 weeks, 50 weeks, 55 weeks, 60 weeks, 65 weeks, 70 weeks, or greater than 70 weeks. In an aspect, a pharmaceutical composition comprises about 450 mg oligomannurarate (or derivative thereof) and is administered to a subject twice per day for at least 36 weeks.

[0218] In an aspect, a pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) can be administered to a patient in need thereof at a dosing schedule of at least once or twice daily for at least three consecutive days or weeks. In an aspect, a dose is administered at least once, twice, or three times daily for a period between 1 and 12 weeks, between 2 and 12 weeks, between 3 and 12 weeks, between 4 and 12 weeks, between 5 and 12 weeks, between 6 and 12 weeks, between 7 and 12 weeks, between 8 and 12 weeks, between 9 and 12 weeks, between 10 and 12 weeks, between 1 and 2 weeks, between 2 and 3 weeks, between 3 and 4 weeks, between 4 and 5 weeks, between 5 and 6 weeks, between 6 and 7 weeks, between 7 and 8 weeks, between 8 and 9 weeks, between 9 and 10 weeks, or between 10 and 11 weeks.

[0219] In an aspect, a pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) can be administered to a patient in need thereof at a dosing schedule of once-a-week, twice-a-week, or thrice-a-week. The term “once-a-week” means that a dose is administered typically only once in a week, for example, on the same day of each week. “Twice-a-week” means that a dose is administered typically only two times in a week, for example, on the same two days of each weekly period. “Thrice-a-week” means that a dose is administered typically only three times in a week, for example, on the same three days of each weekly period.

[0220] In an aspect, a pharmaceutical composition (e.g., comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture) can be administered to a patient in need thereof, wherein the administration comprises a first dosing schedule followed by a second dosing schedule. In an aspect, a first dosing schedule comprises a treatment or induction dose. In an aspect, a second dosing schedule comprises a maintenance dose. For example, a pharmaceutically active maintenance dose of a second dosage schedule can be lower than or equal to a pharmaceutically active induction dose of a first dosing schedule. In other examples, a maintenance dose of a second dosing schedule can be higher than an induction dose of a first dosing schedule.

[0221] At least one of a first and second dosing schedule for administering a pharmaceutical composition can comprise administration of the composition at least once daily for at least one day. In an aspect, at least one of a first or second dosing schedule comprises administration of the composition at least once daily for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In an aspect, at least one of a first or second dosing schedule comprises administration of the composition at least once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In an aspect, at least one of a first or second dosing schedule comprises administration of the composition for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or weeks. In an aspect, at least one of a first or second dosing schedule comprises administration of the composition for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks or months. In an aspect, at least one of a first or second dosing schedule comprises administration of the composition for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject’s entire life span, or an indefinite period of time.

[0222] In an aspect, at least one of a first or second dosing schedule used in a method can be once-a-week, twice-a-week, or thrice-a-week.

[0223] In an aspect, at least one of a first and second dosing schedule can last for at least about 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, or 96 months. In an aspect, a second dosing schedule lasts permanently, for a treated subject’s entire life span, or an indefinite period of time. In an aspect, at least one of a first and second dosing schedule is a continuous dosing schedule. In an aspect, at least one of a first and second dosing schedule is an intermittent dosing schedule. In an aspect, at least one of a first and second dosing schedule is an intermittent dosing schedule comprising a treatment period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days followed by a resting period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In an aspect, at least one of a first and second dosing schedule comprises administering a dose every other day, every two days, or every 3, 4, 5, 6, 7, 8 days. In an aspect, a dose is administered for an extended period of time with or without titration (or otherwise changing the dosage or dosing schedule).

[0224] In an aspect, the interval between a first and a second dosing schedule is at least about 1, 2, 3, 4, 5, 6, or 7 days, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or at least about 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, or 12 months.

[0225] In an aspect, a second dosing schedule (e.g. , a maintenance dose) comprises a dosage about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 75, 100, 200, 400, 800, 1000, 5000 or more fold lower than the dosage used in a first dosing schedule (e.g. , an initial induction dose). In another aspect, a second dosing schedule (e.g., a maintenance dosing schedule) has an equal or lower dosing frequency than a first dosing schedule (e.g. , an initial treatment dosing schedule). In an aspect, a second dosing schedule (e.g., a maintenance dosing schedule) has a higher dosing interval than a first dosing schedule (e.g. , an initial treatment dosing schedule).

[0226] In an aspect, a first dosing schedule comprises administration of a single dose of a pharmaceutical composition to a subject. In an aspect, a second dosing schedule comprises administration of either a single dose or multiple doses of the pharmaceutical composition to the subject, wherein the dose of the pharmaceutical composition during the second dosing schedule is less than the dose of the pharmaceutical composition during the first dosing schedule. In an aspect, the dose of the active ingredient (e.g., oligomannurarate (or derivative thereof)) in the first dosing schedule is at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, or greater than 1000 mg. In an aspect, the dose of the active ingredient (e.g., oligomannurarate (or derivative thereof)) in the second dosing schedule is at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, or greater than 500 mg.

[0227] In various aspects, methods described herein are useful in treatment of a human subject. In some aspects, the human is a pediatric human. In other aspects, the human is an adult human. In other aspects, the human is a geriatric human. In other aspects, the human may be referred to as a patient. In some aspects, the human is a female. In some aspects, the human is a male.

[0228] In certain aspects, the human has an age in a range of from about 1 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old.

[0229] In one aspect, a subject being treated is a human patient. In one aspect, a patient is a male patient. In one aspect, a patient is a female patient. In one aspect, a patient is a premature newborn. In one aspect, a patient is a term newborn. In one aspect, a patient is a neonate. In one aspect, a patient is an infant. In one aspect, a patient is a toddler. In one aspect, a patient is a young child. In one aspect, a patient is a child. In one aspect, a patient is an adolescent. In one aspect, a patient is a pediatric patient. In one aspect, a patient is a geriatric patient. In one aspect, a human patient is a child patient below about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1-year- old. In another aspect, a human patient is an adult patient. In another aspect, a human patient is an elderly patient. In a further aspect, a human patient is a patient above about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old. In another aspect, a patient is about between 1 and 5, between 2 and 10, between 3 and 18, between 21 and 50, between 21 and 40, between 21 and 30, between 50 and 90, between 60 and 90, between 70 and 90, between 60 and 80, or between 65 and 75 years old. In one aspect, a patient is a young old patient (65-74 years). In one aspect, a patient is a middle old patient (75-84 years). In one aspect, a patient is an old patient (>85 years).

Additional therapeutic agents and co-formulation

[0230] The pharmaceutical compositions described herein can include one or more therapeutic agents in addition to oligomannurarate (or derivative thereof) and/or a bacterial mixture, which can be administered to a subject in need thereof in a method described herein. The additional therapeutic agent can be administered simultaneous or sequential with oligomannurarate (or derivative thereof) and/or a bacterial mixture (e.g., comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria) described herein. Further, the present compositions and formulations can comprise the additional therapeutic agent (e.g. via co-formulation). For example, the additional therapeutic agent can be combined into a single formulation with at least one of oligomannurarate (or derivative thereof) or a bacterial mixture comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria.

[0231] In an aspect, the additional therapeutic agent and at least one of oligomannurarate (or derivative thereof) or a bacterial mixture are administered to a subject simultaneously. Administration of the additional therapeutic agent and the oligomannurarate (or derivative thereof) and/or bacterial mixture can be by simultaneous administration of a single formulation (e.g., a formulation comprising the additional therapeutic agent and oligomannurarate (or derivative thereof) and/or a bacterial mixture) or of separate formulations (e.g., a first formulation including the additional therapeutic agent and a second formulation including oligomannurarate (or derivative thereof) and/or the bacterial mixture).

[0232] Co-administration does not require an additional therapeutic agent to be administered simultaneously, if the timing of its administration is such that the pharmacological activities of the additional therapeutic agent and the oligomannurarate (or derivative thereof) and/or bacterial mixture (e.g., comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria) overlap in time. For example, the additional therapeutic agent and the oligomannurarate (or derivative thereof) and/or bacterial mixture can be administered sequentially. The term “sequentially” as used herein means that the additional therapeutic agent and the oligomannurarate (or derivative thereof) and/or bacterial mixture are administered with a time separation of more than about 60 minutes. For example, the time between the sequential administration of the additional therapeutic agent and the oligomannurarate (or derivative thereof) and/or bacterial mixture can be more than about 60 minutes, more than about 2 hours, more than about 5 hours, more than about 10 hours, more than about 1 day, more than about 2 days, more than about 3 days, or more than about 1 week apart. The optimal administration times will depend on the rates of metabolism, excretion, and/or the pharmacodynamic activity of the additional therapeutic agent and the oligomannurarate (or derivative thereof) and/or bacterial mixture being administered. Either of the additional therapeutic agent or the bacterial mixture can be administered first.

[0233] In a further aspect, the additional therapeutic agent and the oligomannurarate (or derivative thereof) and/or bacterial mixture can be administered to a subject simultaneously but the release of additional therapeutic agent and the oligomannurarate (or derivative thereof) and/or bacterial mixture from their respective dosage forms (or single unit dosage form if coformulated) in the GI tract can occur sequentially.

[0234] Co-administration also does not require multiple additional therapeutic agents to be administered to the subject by the same route of administration as a bacterial mixture. Rather, each additional therapeutic agent can be administered by any appropriate route, for example, parenterally or non-parenterally.

[0235] In some aspects, the additional therapeutic agent is an agent used to treat one or more symptoms of a neurodegenerative disease in a subject. In some aspects, the additional therapeutic agent is selected from the group consisting of isperidone, fluoxetine, aripiprazole, vitamin D, levocamitine, and a combination thereof.

[0236] In some aspects, the additional therapeutic agent is a cholinesterase inhibitor. Nonlimiting examples of a cholinesterase inhibitor that can be administered to a subject in a pharmaceutical composition as an additional pharmaceutical agent include galantamine (Razadyne^®), rivastigmine (Exelon^®), donepezil (Aricept^®), tacrine (Cognex^®), and a combination thereof.

[0237] In some aspects, the additional therapeutic agent is an N-methyl-D-aspartate (NMD A) antagonist. Non-limiting examples of an NMDA inhibitor that can be administered to a subject in a pharmaceutical composition as an additional pharmaceutical agent include memantine (Namenda^®), amantadine (Symmetrel^®), methoxetamine, and nitromemantine. [0238] In some aspects, both a cholinesterase inhibitor and an NMDA inhibitor are administered to a subject as additional therapeutic agents. For example, a subject can be administered a formulation comprising both donepezil and memantine (Namzaric^®).

[0239] In some aspects, the additional therapeutic agent is a dopamine agonist. Non-limiting examples of a dopamine agonist that can be administered to a subject in a pharmaceutical composition as an additional pharmaceutical agent include ergoline, a non-ergoline agonist such as bromocriptine, cabergoline, pergolide, pramipexole (Mirapex^®), ropinirole (Requip^®), rotigotine (Neupro^®), apomorphine (Apokyn^®), and a combination thereof.

[0240] In some aspects, the additional therapeutic agent is an anticholinergic medication. Non-limiting examples of an anticholinergic medication that can be administered to a subject in a pharmaceutical composition as an additional pharmaceutical agent include benzotropine (Cogentin^®), trihexyphenidyl (Artane^®), and a combination thereof.

[0241] In some aspects, the additional therapeutic agent is an amino acid. An example of an amino acid that can be administered to a subject in a pharmaceutical composition as an additional pharmaceutical agent is L-DOPA, also known as levodopa. In some aspects, levodopa is administered in combination with carbidopa, for example as Sinemet^®, Parcopa^® or Rytary^®. In some aspects, levodopa is administered in combination with entacapone, with or without carbidopa. In some aspects, levodopa is administered in combination with both entacopone and carbidopa, for example as Stalevo^®.

[0242] In some aspects, the additional therapeutic agent is a catechol-O-methyltransferase (COMT) inhibitor. Non-limiting examples of a COMT inhibitor that can be administered to a subject in a pharmaceutical composition as an additional pharmaceutical agent include tolcapone (Tasmar^®), entacopone (Comtan^®), opicapone (Ongentys^®), and a combination thereof.

[0243] In some aspects, the additional therapeutic agent is a monoamine oxidase (MAO) inhibitor. Non-limiting examples of an MOA inhibitor that can be administered to a subject in a pharmaceutical composition as an additional pharmaceutical agent include selegiline (Carbex^®), selegiline hydrochloride (Eldepryl^® or Zelapar^®), rasagiline (Azilect^®), safinamide (Xadago^®), and a combination thereof.

[0244] Other examples of additional pharmaceutical agents that can be administered in a pharmaceutical composition include antipsychotic medications such as risperidone, haloperidol, and chlorpromazine, benzodiazepines such as clonazepam and diazepam, and tetrabenazine.

[0245] In some aspects, the additional therapeutic agent is an anti-inflammatory agent such as steroidal anti-inflammatory agents or non-steroidal anti-inflammatory agents (NSAIDS). Steroids, particularly the adrenal corticosteroids and their synthetic analogues, are well known in the art. Non-limiting examples of corticosteroids that can be administered to a subject as an additional therapeutic agent include hydroxyltriamcinolone, alpha-methyl dexamethasone, beta-methyl betamethasone, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol valerate, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate. (NSAIDS) that can be used, include but are not limited to, salicylic acid, acetyl salicylic acid, methyl salicylate, glycol salicylate, salicylmides, benzyl-2, 5-diacetoxybenzoic acid, ibuprofen, fulindac, naproxen, ketoprofen, etofenamate, phenylbutazone, indomethacin, and a combination thereof. Additional anti-inflammatory agents are described, for example, in U.S. Patent No. 4,537,776, the entire contents of which is incorporated by reference herein.

[0246] In some aspects, an additional therapeutic agent that can be incorporated into a pharmaceutical composition is a prebiotic. A prebiotic is a compound or compounds (e.g. comprising one or more nutrients) administered to a subject to promote the growth, proliferation, or activity of one or more microorganisms (e.g., bacteria) in the intestine of the subject (e.g., by providing a substrate to be metabolized by the one or more microorganisms). Without wishing to be bound by theory, prebiotics can be added to a pharmaceutical composition to nutritionally supplement bacteria in the endogenous microbiome of the subject and/or in the pharmaceutical composition itself, e.g., to stimulate the growth or activity of one or more strains of a preparation of uncultured fecal bacteria and/or one or more bacterial isolates. Additionally, one or more prebiotics can be added to a composition to buffer against “shock” to bacteria cells when transitioning those cells to a new environment, for example, subsequent to the isolation and/or purification of a preparation of uncultured fecal bacteria, or before or after freezing, freeze-drying, spray-drying, reconstitution in solution and the like.

[0247] Non-limiting examples of prebiotics that can be added to a pharmaceutical composition include amino acids, lactic acid, ammonium nitrate, amylose, barley mulch, biotin, carbonate, cellulose, chitin, choline, fructooligosaccharides (FOSs), fructose, galactooligosaccharides (GOSs), glucose, glycerol, heteropolysaccharide, histidine, homopolysaccharide, hydroxyapatite, inulin, isomaltulose, lactose, lactulose, maltodextrins, maltose, mannooligosaccharides, nitrogen, oligodextrose, oligofructoses, oligofructose- enriched inulin, oligosaccharides, pectin, phosphate salts, phosphorus, polydextroses, polyols, potash, potassium, sodium nitrate, starch, sucrose, sulfur, sun fiber, tagatose, thiamine, trans- galactooligosaccharides, trehalose, vitamins, a water-soluble carbohydrate, xylooligosaccharides (XOSs), and a combination thereof. Illustrative prebiotics include complex carbohydrates, amino acids, peptides, or other essential nutritional components for the survival of the bacterial composition.

[0248] In an aspect, a subject is not pretreated with a prebiotic prior to treatment with a pharmaceutical composition. In another aspect, the pharmaceutical composition is not supplemented with a prebiotic.

[0249] In an aspect, a prebiotic can be included (e.g., in dry or liquid forms) in a pharmaceutical composition described herein, for example, comprising a bacterial mixture.

[0250] Alternately, or additionally, a prebiotic to be administered to a subject (e.g. having one or more symptoms of a neurodegenerative disorder) can be included (e.g., in dry or liquid forms) in a distinct pharmaceutical composition lacking a bacterial mixture.

[0251] A prebiotic can be administered to a subject before, contemporaneously with, and/or after administration of a pharmaceutical composition comprising oligomannurarate (or derivative thereof) and/or a bacterial mixture, either in the same pharmaceutical composition or in a separate pharmaceutical composition.

[0252] A prebiotic can be provided and administered in a single dose or in multiple doses. When provided as a single dose, a single composition can comprise only one prebiotic or a mixture of prebiotics. When provided in multiple doses, each composition dosed to the subject can comprise a single prebiotic or a mixture of prebiotics, and/or a first composition dosed to the subject can comprise a different prebiotic or prebiotics than a second composition dosed to the subject.

[0253] As examples, when multiple doses are provided, a first composition comprising a prebiotic can include a first prebiotic, e.g., inulin, and a second composition can include a different prebiotic, e.g., pectin, with or without the first prebiotic. Alternately, a first composition can include a combination of prebiotics, e.g., inulin and pectin and a second composition can include a different combination of prebiotics, e.g., inulin and a FOS. A first composition can include a combination of prebiotics and a second composition can include only one prebiotic.

[0254] The amount of prebiotic included in a composition depends on the specific prebiotic, the specific bacterial strain or strains targeted by the prebiotic, and/or the disease state of the subject/patient.

[0255] In some aspects, an additional therapeutic agent that can be incorporated into a pharmaceutical composition is an antidiarrheal agent. Non-limiting examples of antidiarrheal agents suitable for inclusion in a pharmaceutical composition described herein include, but are not limited to, DPP-IV inhibitors, natural opioids, such as tincture of opium, paregoric, and codeine, synthetic opioids, such as diphenoxylate, difenoxin and loperamide, bismuth subsalicylate, lanreotide, vapreotide and octreotide, motiln antagonists, COX2 inhibitors like celecoxib, glutamine, thalidomide and traditional antidiarrheal remedies, such as kaolin, pectin, berberine and muscarinic agents, and a combination thereof.

[0256] In some aspects, the additional therapeutic agent incorporated into a pharmaceutical composition can be an analgesic. Analgesics useful in the compositions and methods described herein include, without limitation, morphine, codeine, heroine, methadone and related compounds, thebaine, orpiavine, and their derivatives, buprenorphine, the piperidines, morphinans, benzomorphans, tetrahydroisoquinolines, thiambutanes, benzylamines, tilidine, viminol, nefopam, capsaicin(8-methyl-N-vanillyl-6E-nonenamide), "synthetic" capsaicin(N- vanillylnonamide) and related compounds, and a combination thereof.

[0257] In some aspects, the additional therapeutic agent is an anti-bacterial agent, which includes, but is not limited to, cephalosporin antibiotics (cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole); fluoroquinolone antibiotics (cipro, Levaquin, floxin, tequin, avelox, and norflox); tetracycline antibiotics (tetracycline, minocycline, oxytetracy cline, and doxy cy cline); penicillin antibiotics (amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, vancomycin, and methicillin); monobactam antibiotics (aztreonam); carbapenem antibiotics (ertapenem, doripenem, imipenem/cilastatin, and meropenem); and a combination thereof. In some aspects, the anti-bacterial agent can be any of the penicillin, cephalosporin, monobactam, and carbapenem antibiotics, or a combination thereof.

[0258] In one aspect, a method further comprises pretreating a subject with an antibiotic composition prior to administering a therapeutic bacterial mixture and/or oligomannurarate (or derivative thereof). In one aspect, an antibiotic composition administered herein comprises an antibiotic selected from the group consisting of rifabutin, clarithromycin, clofazimine, vancomycin, rifampicin, nitroimidazole, chloramphenicol, and a combination thereof. In another aspect, an antibiotic composition administered herein comprises an antibiotic selected from the group consisting of rifaximin, rifamycin derivative, rifampicin, rifabutin, rifapentine, rifalazil, bicozamycin, aminoglycoside, gentamycin, neomycin, streptomycin, paromomycin, verdamicin, mutamicin, sisomicin, netilmicin, retymicin, kanamycin, aztreonam, aztreonam macrolide, clarithromycin, dirithromycin, roxithromycin, telithromycin, azithromycin, bismuth subsalicylate, vancomycin, streptomycin, fidaxomicin, amikacin, arbekacin, neomycin, netilmicin, paromomycin, rhodostreptomycin, tobramycin, apramycin, and a combination thereof. In another aspect, a subject is not pretreated with an antibiotic composition prior to administering a bacterial mixture and/or oligomannurarate (or derivative thereof). In another aspect, the pharmaceutical composition is not supplemented with an antibiotic composition. In a further aspect, a method further comprises pretreating a subject with an anti-inflammatory drug prior to administration of a bacterial mixture and/or oligomannurarate (or derivative thereof). In yet another aspect, a subject is not pretreated with an anti-inflammatory drug prior to administering a bacterial mixture and/or oligomannurarate (or derivative thereof). In another aspect, a pharmaceutical composition comprising a bacterial mixture and/or oligomannurarate (or derivative thereof) is not supplemented with an antiinflammatory.

[0259] Delivery of an additional therapeutic agent can be targeted to various parts of the GI tract, as described herein.

[0260] The pharmaceutical compositions described herein (e.g. comprising oligomannurarate (or derivative thereof) and/or one or more bacterial mixtures comprising for example one or more bacterial isolates and/or a preparation of uncultured fecal bacteria) can be administered to a subject in need thereof for the treatment or prevention of one or more disorders, diseases, or conditions. In an aspect, a pharmaceutical composition is administered to a subject to prevent or treat one or more symptoms of a neurodegenerative disease in the subject.

[0261] Provided herein is a method of treating or preventing one or more symptoms of a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition described herein. Herein a neurodegenerative disease is a chronic, generally incurable condition resulting in the progressive loss of structure and/or function of neurons, including the death of neurons. Non-limiting examples of a neurodegenerative disease that can be treated by administering a pharmaceutical composition to a subject include amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington’s Disease, motor neuron disease (MND), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA). In embodiments, such syndromes are related to an intestinal dysbiosis of a subject.

[0262] In an aspect, a pharmaceutical composition administered to a subject with a neurodegenerative disease treats, inhibits or prevents one or more of ataxia and dementia. Herein “dementia” refers to a clinical syndrome characterized by progressive acquired global impairments of cognitive skills and ability to function independently.

[0263] The methods provided herein can result in, or are aimed at achieving, a detectable improvement in one or more indicators or symptoms of a neurodegenerative disease including, but not limited to, changes in reflexes, coordination, muscle tone, muscle strength, eye tracking, eye movement, speech, sensation, verbal and nonverbal communication problems, mood disturbances, repetitive behaviors, intellectual disability, impaired motor coordination, attention or focus issues, sleep disturbances, memory loss, difficulty planning or solving problems, difficulty performing familiar tasks, confusion, impaired reasoning skills, impaired cognition, impaired judgment or decision-making abilities, misplacing objects, physical health issues such as gastrointestinal disturbances, and a combination thereof. In an aspect, compositions and methods provided here can delay or halt, or are aimed at delaying or halting the progression of one or more indicators or symptoms of a neurodegenerative disease (e.g., Alzheimer's or any indicators or symptoms descripted in this paragraph). In another aspect, such delay or halt can be by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, or 36 weeks or months. In a further aspect, compositions and methods provided here can maintain or substantially maintain an improvement in one or more indicators or symptoms of a neurodegenerative disease. Such maintenance of symptom improvement can last at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, or 36 weeks or months.

[0264] Several screening instruments or scales are known in the art for evaluating dementia in a subject, and can be used as aids in screening for and detecting changes in the severity of impairment in neural function arising from a neurodegenerative disorder, as well as measures of treatment outcome in a subject administered a pharmaceutical composition described herein. Instruments that can be used to evaluate a subject (e.g., to provide an indicia of treatment after administering a pharmaceutical composition) include the Mini-Mental State Examination (MMSE), Abbreviated Mental Test Score (AMTS), Clock-drawing test, 6-CIT, General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, Test Your Memory (TYM), and a combination thereof. These instruments are further described in Sheehan, “Assessment scales in dementia” Therapeutic Advances in Neurological Disorders (2012) 5: 349-358, which is hereby incorporated by reference herein in its entirety.

[0265] Subjects appropriate for treatment according to a method provided herein may not present with or report gastrointestinal distress symptoms prior to initiating a method as provided herein. In some cases, for example, a human subject appropriate for treatment according to a method provided herein manifests no gastrointestinal symptoms prior to or at the time at which treatment is begun. In one aspect, a subject having a neurodegenerative disease treated herein exhibits one or more or two or more GI symptoms selected from the group consisting of abdominal pain, reflux, indigestion, irritable bowel syndrome, chronic persistent diarrhoea, diarrhoea, flatulence, constipation, and alternating constipation/diarrhoea.

[0266] Regardless of the presence or absence of gastrointestinal distress symptoms, human subjects appropriate for the methods provided herein typically have significantly fewer species of gut bacteria before said method of treatment as compared to a neurotypical human. In some cases, the human subject to be treated by the method exhibits at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% fewer species of gut bacteria prior to administration of the pharmaceutical composition as compared to a neurotypical human.

[0267] In one aspect, a treated subject has reduced adverse events during treatment. In another aspect, a treated subject has no adverse events during treatment. In an aspect of the present disclosure, an adverse event is selected from the group consisting of abdominal cramping, fullness, flatulence, bloating, diarrhea, blood in stool, fever, and a combination thereof. In another aspect, an adverse event is any signs or symptoms, regardless of severity, any clinically significant laboratory abnormality, or any abnormality detected during physical examination. In yet another aspect, an adverse event is ascribed to the pharmaceutically active dose. In a further aspect, an adverse event is not ascribed to the pharmaceutically active dose. In yet another aspect, an adverse event comprises a solicited adverse event, an unsolicited adverse event, a serious adverse event, or a combination thereof. In an aspect, serious adverse events require inpatient hospitalization or prolongation of existing hospitalization; result in persistent or significant disability and/or incapacity, result in a congenital anomaly and/or birth defect; or is any important medical event, based on medical and scientific judgment, which may not be immediately life-threatening or result in death or hospitalization, but may pose substantial risks to the patient or may require medical intervention to prevent 1 of the other outcomes listed above.

[0268] In an aspect of the present disclosure, a treated subject has reduced or no adverse events through 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 weeks of treatment.

[0269] Also provided herein are methods for reducing the severity of at least one symptom in a subject with a neurodegenerative disorder. In an aspect, the method comprises or consists essentially of the following steps: administering a bacterial mixture comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria from a healthy human donor to the human subject, and administering an oligomannurarate (or derivative thereof) to the subject, wherein the human subject exhibits a significant reduction in a symptom of the neurodegenerative disorder after said method as compared to before initiating the method. In some cases, the human subject exhibits at least a 10% or 20 % reduction in symptom severity as assessed by at least one of the Mini-Mental State Examination (MMSE), Abbreviated Mental Test Score (AMTS), Clock-drawing test, 6-CIT, General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, and Test Your Memory (TYM). In aspects, the bacterial mixture and the oligomannurarate (or derivative thereof) are administered to the subject in the same pharmaceutical composition of formulation. In aspects, the bacterial mixture and the oligomannurarate (or derivative thereof) are administered to the subject in different pharmaceutical formulations. In aspects, the oligomannurarate (or derivative thereof) and the bacterial mixture are co-administered to the subject in different pharmaceutical formulations. In aspects, the oligomannurarate (or derivative thereof) and the bacterial mixture are simultaneously co-administered to the subject in different pharmaceutical formulations. In aspects, a pharmaceutical composition comprising oligomannurarate (or derivative thereof) is administered to the subject prior to a pharmaceutical composition comprising the bacterial mixture. In aspects, a pharmaceutical composition comprising oligomannurarate (or derivative thereof) is administered to the subject after a pharmaceutical composition comprising the bacterial mixture.

[0270] In an aspect, a method of treating or preventing a neurodegenerative disorder in a subject comprises: orally-administering a non-absorbable antibiotic to the subject; subjecting the subject to a bowel cleanse; administering a bacterial mixture comprising one or more bacterial isolates and/or a preparation of uncultured fecal bacteria from a healthy human donor to the human subject, and administering an oligomannurarate (or derivative thereof) to the subject, wherein the human subject exhibits a significant reduction in a symptom of the neurodegenerative disorder after said method as compared to before initiating the method. In some cases, the human subject exhibits at least a 10% or 20 % reduction in symptom severity as assessed by at least one of the Mini-Mental State Examination (MMSE), Abbreviated Mental Test Score (AMTS), Clock-drawing test, 6-CIT, General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, and Test Your Memory (TYM).

[0271] In one aspect, the present disclosure provides a method for treating or preventing a neurodegenerative disease in a subject in need thereof, where the method comprises orally administering to the subject a pharmaceutically active dose of at least one pharmaceutical composition described herein, wherein the pharmaceutically active dose is administered with at least 50 ml of water. In another aspect, a method comprises administering a bacterial mixture no less than 2 hours after consumption of food or liquids besides water. In yet another aspect, a method comprises consumption of food or water no less than one hour after administering a bacterial mixture. In an aspect, the present disclosure provides a method for treating a neurodegenerative disease in a subject in need thereof by administering a pharmaceutical composition described herein, wherein the method comprises administering the pharmaceutical composition at least 2 hours after any solid or liquid caloric intake. In another aspect, the method comprises administering the pharmaceutical composition at least 1 hour prior to any solid or liquid caloric intake.

[0272] In one aspect, the present disclosure provides a method for treating a neurodegenerative disease in a subject in need thereof comprising administering to the subject an amount of a pharmaceutical composition effective at providing at least a 10% improvement in assessment score (e.g., using one or more of the instruments Mini-Mental State Examination (MMSE), Abbreviated Mental Test Score (AMTS), Clock-drawing test, 6-CIT, General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, and Test Your Memory (TYM)). In an aspect, the pharmaceutical composition comprises one or more of oligomannurarate (or derivative thereof) and a bacterial mixture. In another aspect, the subject has a GI symptom of constipation with less than 3 complete spontaneous bowel movements per week for a period of time. In yet another aspect, the subject exhibits an improvement in assessment score after the treatment as compared to before initiating the treatment, and wherein the assessment score is based on an assessment system selected from the group consisting of Mini-Mental State Examination (MMSE), Abbreviated Mental Test Score (AMTS), Clock-drawing test, 6-CIT, General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, and Test Your Memory (TYM).

[0273] In one aspect, the present disclosure provides a method for treating a neurodegenerative disease in a subject in need thereof by administering an amount of a pharmaceutical composition described herein, where the subject in need thereof has a GI symptom of constipation with less than 3 complete spontaneous bowel movements per week. In another aspect, the subject in need thereof has a GI symptom of constipation with less than 2 complete spontaneous bowel movements per week. In a further aspect, the subject in need thereof has a GI symptom of constipation with less than 2 complete spontaneous bowel movements per week. In yet another aspect, the subject in need thereof has a GI symptom of constipation with less than 1 complete spontaneous bowel movement per week. In an aspect, the subject in need thereof has a GI symptom of constipation for a period of time selected from the group consisting of about 1, 2, 3, and 4 weeks. In another aspect, the subject in need thereof has a GI symptom of constipation for a period of time selected from the group consisting of about 10, 20, 30, and 40 days. In another aspect, the subject in need thereof has a GI symptom of constipation for a period of between 10 and 15, 15 and 20, 20 and 25, 25 and 30, 30 and 35, 35 and 40 days.

[0274] In one aspect, the present disclosure provides a method for treating a neurodegenerative disease in a subject in need thereof by administering a pharmaceutical composition described herein, where the subject in need thereof has a GI symptom of constipation which improves by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 complete spontaneous bowel movements (CSBM) per week after at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks of treatment. In another aspect, the subject in need thereof has a GI symptom of constipation which improves by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 complete spontaneous bowel movements (CSBM) per week after between 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more weeks of treatment. In a further aspect, the subject in need thereof has a GI symptom of constipation which remains improved for at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks after the completion of treatment.

[0275] In an aspect, the present disclosure provides a method for treating a neurodegenerative disease in a subject in need thereof by administering a pharmaceutical composition described herein, wherein the method comprises analyzing the subject’s metabolite profile in blood, stool, or urine before, during, and after treatment. In another aspect, the method further comprises analyzing a subject’s metabolite profile in blood, stool or urine at least twice during treatment and at least once post-treatment. In another aspect, the method further comprises analyzing the subject’s metabolite profile in blood prior to initiating the treatment.

[0276] In another aspect, the subject in need thereof does not have any serious medical disorders requiring medication dose adjustments, wherein the serious medical disorder is selected from the group consisting of single-gene disorder, major brain malformation, tube feeding, severe GI problems that require immediate treatment (life-threatening), diagnosed Celiac Disease, Eosinophilic Gasteroenteritis, severely underweight/malnourished, and recent/scheduled surgeries.

[0277] In an aspect, the present disclosure provides a method for screening an individual for adherence by administering capsules containing placebo for at least 7 consecutive days. In another aspect, placebo capsules are administered for at least 14 consecutive days.

[0278] In one aspect, the present disclosure provides a method for treating a neurodegenerative disease in a subject in need thereof, where the method comprises administering to the subject a pharmaceutically active or therapeutically effective dose of a pharmaceutical composition described herein. In one aspect, the present disclosure provides a method for treating a neurodegenerative disease in a subject in need thereof, where the method comprises administering daily to the subject a therapeutically effective dose of a pharmaceutical composition described herein. In one aspect, a pharmaceutical composition is administered to a patient in need thereof at least once daily for at least two consecutive days. In one aspect, a pharmaceutical composition is administered at least once daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In another aspect, a pharmaceutical composition is administered at least once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive weeks. In one aspect, a pharmaceutical composition is administered at least once daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or weeks. In another aspect, a pharmaceutical composition is administered at least once daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive weeks or months. In a further aspect, a pharmaceutical composition is administered at least once for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive months or years, chronically for a subject’s entire life span, or an indefinite period of time.

[0279] In one aspect, a pharmaceutical composition is administered to a patient in need thereof at least twice daily for at least two consecutive days. In one aspect, a pharmaceutical composition is administered at least twice daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In another aspect, a pharmaceutical composition is administered at least twice daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive weeks. In one aspect, a pharmaceutical composition is administered at least twice daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or week. In another aspect, a pharmaceutical composition is administered at least twice daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive weeks or months. In a further aspect, a pharmaceutical composition is administered at least twice for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject’s entire life span, or an indefinite period of time.

[0280] In one aspect, a pharmaceutical composition is administered to a patient in need thereof at least three times daily for at least two consecutive days. In one aspect, a pharmaceutical composition is administered at least three times daily for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days. In another aspect, a pharmaceutical composition is administered at least three times daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive weeks. In one aspect, a pharmaceutical composition is administered at least three times daily for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or weeks. In another aspect, a pharmaceutical composition is administered at least three times daily for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive weeks or months. In a further aspect, a pharmaceutical composition is administered at least three times for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronically for a subject’s entire life span, or an indefinite period of time.

[0281] In one aspect, the present disclosure provides a method for treating or preventing a neurodegenerative disease in a subject in need thereof, where the method comprises administering orally to the subject a therapeutically active dose of a pharmaceutical composition comprising a bacterial mixture, where the dose is administered at a dosing schedule of at least once or twice daily for at least three consecutive days or weeks. In another aspect, a dose is administered at least once, twice, or three times daily for a period between 1 and 16 weeks, between 2 and 16 weeks, between 3 and 16 weeks, between 4 and 16 weeks, between 5 and 16 weeks, between 6 and 16 weeks, between 7 and 16 weeks, between 8 and 16 weeks, between 10 and 16 weeks, between 12 and 16 weeks, between 1 and 12 weeks, between 2 and 12 weeks, between 3 and 12 weeks, between 4 and 12 weeks, between 5 and 12 weeks, between 6 and 12 weeks, between 7 and 12 weeks, between 8 and 12 weeks, between 9 and 12 weeks, between 10 and 12 weeks, between 1 and 2 weeks, between 2 and 3 weeks, between 3 and 4 weeks, between 4 and 5 weeks, between 5 and 6 weeks, between 6 and 7 weeks, between 7 and 8 weeks, between 8 and 9 weeks, between 9 and 10 weeks, or between 10 and 11 weeks.

[0282] In one aspect, the present disclosure provides a method for treating or preventing a neurodegenerative disease in a subject in need thereof by administering a pharmaceutical composition described herein, where the method comprises a single dosing schedule. In one aspect, the dosing schedule comprises a treatment period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 consecutive weeks. In an aspect, a dosing schedule comprises administering a dose every day, every other day, every two days, or every 3, 4, 5, 6, 7, 8 days.

[0283] In one aspect, the present disclosure provides a method for treating or preventing a neurodegenerative disease in a subject in need thereof by administering a pharmaceutical composition described herein, where the method comprises a first dosing schedule followed by a second dosing schedule. In one aspect, a first dosing schedule comprises a treatment or induction dose. In one aspect, a first dosing schedule comprises a continuous dosing schedule. In another aspect, a first dosing schedule comprises a dosing schedule of two consecutive days. In another aspect, a first dosing schedule comprises a dosing schedule of two consecutive days of an equivalent dose. In another aspect, a first dosing schedule comprises a dose on a single day. In another aspect, a first dosing schedule comprises a dosing schedule of three consecutive days. In another aspect, a first dosing schedule comprises a dosing schedule of four consecutive days. In another aspect, a first dosing schedule comprises a dosing schedule of five consecutive days. In another aspect, a first dosing schedule comprises a dosing schedule of six consecutive days. In another aspect, a first dosing schedule comprises a dosing schedule of seven consecutive days. In another aspect, a first dosing schedule comprises a dosing schedule of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive days. In another aspect, a second dosing schedule comprises a maintenance dose lower than or equal to a pharmaceutically active dose of a first dosing schedule. In another aspect, a second dosing schedule lasts for at least about 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48, 72, or 96 weeks. In another aspect, a second dosing schedule comprises a dosing schedule of at least 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48, 72, or 96 consecutive weeks. In another aspect, a second dosing schedule comprises a dosing schedule of at least 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48, 72, or 96 consecutive weeks. In another aspect, a second dosing schedule comprises a dosing schedule of at least 12, 14, 21, 28, 35, 42, 49, 56, 63, 70, or 77 consecutive days. In one aspect, a second dosing schedule lasts permanently, for a treated subject’s entire life span, or an indefinite period of time. In one aspect, a second dosing schedule is a continuous dosing schedule. In another aspect, a second dosing schedule is an intermittent dosing schedule. In a further aspect, a second dosing schedule is an intermittent dosing schedule comprising a treatment period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days followed by a resting period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In another aspect, a second dosing schedule comprises administering a second dose (e.g. , a maintenance dose) every other day, every two days, or every 3, 4, 5, 6, 7, 8 days. In another aspect, a maintenance dose is administered for an extended period of time with or without titration (or otherwise changing the dosage or dosing schedule). In one aspect, there is no interval between a first and a second dosing schedule. In another aspect, the interval between a first and a second dosing schedule is at least 1, 2, 3, 4, 5, 6, or 7 days. In one aspect, the interval between a first and a second dosing schedule is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks. In another aspect, a second dosing schedule (e.g., a maintenance dose) comprises a dosage about 2, 3, 4, 5, 10, 50, 100, 200, 400, or 500 folds lower than the dosage used in a first dosing schedule (e.g., an initial treatment dose). In another aspect, a second dosing schedule (e.g., a maintenance dosing schedule) has an equal or lower dosing frequency than a first dosing schedule (e.g., an initial treatment dosing schedule). In another aspect, a second dosing schedule (e.g., a maintenance dosing schedule) has a higher dosing interval than a first dosing schedule (e.g. , an initial treatment dosing schedule).

[0284] In one aspect, the present disclosure provides a method for treating a subject in need thereof, where the method comprises administering to the subject a pharmaceutically active dose of a pharmaceutical composition comprising a bacterial mixture that comprises a preparation of uncultured fecal bacteria of multiple carefully screened, healthy donors. In an aspect, a subject is administered a pharmaceutical composition over a dosing period wherein a first dose comprises at least one pharmaceutical composition comprising a preparation of uncultured fecal bacteria of a single donor, and a second dose of a pharmaceutical composition comprising a preparation of uncultured fecal bacteria of a single donor different from the donor of the first dose. In another aspect, a first dose comprises a pharmaceutical composition comprising a preparation of uncultured fecal bacteria of a single donor and a second dose comprises a preparation of uncultured fecal bacteria of a donor pool. The first and second dose do not indicate the order of administration to a subject, but rather that the preparation of uncultured fecal bacteria from separate donors may be used in a non-blended form. In yet another aspect, the preparation of uncultured fecal bacteria from multiple carefully screened, healthy donors is provided in a blended form.

[0285] In an aspect, a pharmaceutical composition used herein comprises a bacterial mixture comprising a preparation of uncultured fecal bacteria derived from a donor with preselected desirable characteristics or receiving certain pre-treatment(s). In an aspect, a donor has no current or previous diagnosis of a neurodegenerative disorder or has no symptom of a neurodegenerative disorder. In another aspect, a donor has no family member or direct relative diagnosed with a neurodegenerative disorder or exhibiting a neurodegenerative disorder symptom. In another aspect, a donor has no siblings, parents, or children diagnosed with a neurodegenerative disorder or exhibiting a neurodegenerative disorder symptom. In an aspect, a donor has not previously received any fecal microbiota transplantation. In an aspect, a fecal donor for neurodegenerative disorder treatment previously donated a stool for treating a GI disorder, e.g., a C. difficile infection or Inflammatory Bowel Disease (IBD).

[0286] In an aspect, the present disclosure provides for methods for treating a subject in need thereof by administering to the subject one or more pharmaceutical compositions comprising pharmaceutically active doses of oligomannurarate (or derivative thereof) and a bacterial mixture comprising a preparation of uncultured fecal bacteria of a single donor. In another aspect, the administering is followed by testing to determine the efficacy of the pharmaceutically active dose of the pharmaceutical composition(s). In another aspect, the testing of the subject provides results to determine if the active dose of the pharmaceutical composition(s) should be adjusted. In another aspect, the testing is followed by administration of one or more pharmaceutical compositions comprising oligomannurarate (or derivative thereof) and a preparation of uncultured fecal bacteria blended from multiple donors. In one aspect of the present disclosure, methods provide for treating a subject in need thereof comprising: (1) administering to the subject a first pharmaceutically active dose of one or more pharmaceutical compositions comprising oligomannurarate (or derivative thereof) and a preparation of uncultured fecal bacteria of a single donor; (2) testing of the subject to determine efficacy, if an additional dose is necessary, or if the dose should be adjusted; (3) administration of one or more second pharmaceutical compositions comprising oligomannurarate (or derivative thereof) and a preparation of uncultured fecal bacteria blended from multiple donors; (4) optionally testing of the subject to determine efficacy, if an additional dose is necessary, or if the dose should be adjusted; and (5) optionally administration of one or more third pharmaceutical compositions comprising oligomannurarate (or derivative thereof) and a preparation of uncultured fecal bacteria blended from multiple donors, where the multiple donors (a) comprise all donors from the second pharmaceutical composition and additional donors, (b) comprise donors of fecal bacteria not included in the second pharmaceutical composition, (c) comprise some but not all of the donors of fecal bacteria included in the second pharmaceutical composition, or comprise donors of fecal bacteria not included in the second pharmaceutical composition. In another aspect, the first, second, and third pharmaceutical compositions are administered in a different order (i.e., first, third, second; third, second, first; third, first, second; second, first, third, etc.).

[0287] In another aspect, the present disclosure provides for methods for treating a subject in need thereof with capsules containing one or more pharmaceutical compositions comprising oligomannurarate (or derivative thereof) and/or a preparation of uncultured fecal bacteria from a single donor. In another aspect, a capsule comprises a pharmaceutical composition comprising a preparation of uncultured fecal bacteria from multiple donors. In one aspect, a subject is administered two or more pills comprising a preparation of uncultured fecal bacteria from a single but different donor.

[0288] In one aspect, the present disclosure provides for methods for treating a subject in need thereof comprising administering a pharmaceutical composition comprising a preparation of uncultured fecal bacteria of a single donor similar to or different from a prior administration in a treatment period. In another aspect, a treatment period includes administration of a first dose comprising a pharmaceutical composition comprising a preparation of uncultured fecal bacteria of a single donor and administration of a second dose comprising a pharmaceutical composition comprising a preparation of uncultured fecal bacteria of multiple donors.

[0289] In an aspect, a preparation of uncultured fecal bacteria and one or more bacterial isolates are administered to a subject according a method described herein in the same pharmaceutical composition. In an aspect, a preparation of uncultured fecal bacteria and one or more bacterial isolates are administered to a subject according to a method described herein in different pharmaceutical compositions. In an aspect, multiple bacterial isolates are administered to a subject according to a method described herein in the same pharmaceutical composition. In an aspect, multiple bacterial isolates are administered to a subject according to a method described herein in different pharmaceutical compositions. For example, a method can comprise administering to a subject in need thereof an effective amount of a plurality of pharmaceutical compositions, e.g., two or more pharmaceutical compositions, three or more pharmaceutical compositions, four or more pharmaceutical compositions, or five or more pharmaceutical composition, as disclosed herein. The plurality of pharmaceutical compositions can be provided simultaneously or sequentially. Thus, if a subject is to be treated with, for example, a preparation of uncultured fecal bacteria and two bacterial isolates, a first composition can comprise two of the bacterial isolates and the second composition can comprise the preparation of uncultured fecal bacteria. In a different example, if a subject is to be treated with a preparation of uncultured fecal bacteria and two bacterial isolates, a first composition can comprise the preparation of uncultured fecal bacteria in combination with (or “spiked” with) a first bacterial isolate, and a second composition can comprise the second bacterial isolate. In a different example, if a subject is to be treated with a preparation of uncultured fecal bacteria and three bacterial isolates, a first composition can comprise the first bacterial isolate, a second composition can comprise the second bacterial isolate, a third composition can comprise the third bacterial isolate, and a fourth composition can comprise the preparation of uncultured fecal bacteria.

[0290] In an aspect, a method for treating one or more symptoms of a neurodegenerative disease in a subject in need thereof comprises administering to the subject: (i) oligomannurarate (or derivative thereof); (ii) a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria and/or one or more bacterial isolates); and (iii) one or more antibiotics. The different components of (i)-(iii) can be administered to the subject in any order. For example, a subject can be administered one or more antibiotics, followed by the oligomannurarate (or derivative thereof), followed by a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria and/or one or more bacterial isolates). In another example, a subject can be administered one or more antibiotics, followed by a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria and/or one or more bacterial isolates), followed by oligomannurarate (or derivative thereof). In another example, the subject can be administered one or more antibiotics, followed by a bacterial mixture comprising one or more bacterial isolates, followed by a bacterial mixture comprising a preparation of uncultured fecal bacteria, followed by oligomannurarate (or derivative thereof). In another example, the subject can be administered one or more antibiotics, followed by oligomannurarate (or derivative thereof), followed by a bacterial mixture comprising one or more bacterial isolates, followed by a bacterial mixture comprising a preparation of uncultured fecal bacteria. In another example, the subject can be administered one or more antibiotics, followed by a bacterial mixture comprising one or more bacterial isolates, followed by oligomannurarate (or derivative thereof), followed by a bacterial mixture comprising a preparation of uncultured fecal bacteria. In another example, the subject can be administered one or more antibiotics, followed by a bacterial mixture comprising a preparation of uncultured fecal bacteria, followed by oligomannurarate (or derivative thereof), followed by a bacterial mixture comprising one or more bacterial isolates. For each of the above examples, it is further understood that any given component in a method of treatment can be administered multiple times. For example, an antibiotic can be administered to the subject, followed by a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria and/or one or more bacterial isolates), followed by oligomannurarate (or derivative thereof), followed by a second administration of the bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria and/or one or more bacterial isolates).

[0291] In an aspect, a method for treating one or more symptoms of a neurodegenerative disorder in a subject in need thereof comprises administering to the subject: (i) one or more bacterial isolates; (ii) a preparation of uncultured fecal bacteria; and (iii) one or more prebiotics. The different components of (i)-(iii) can be administered to the subject in any order. For example, a subject can be administered one or more prebiotics, followed by a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria and/or one or more bacterial isolates), followed by oligomannurarate (or derivative thereof). In another example, a subject can be administered one or more prebiotics, followed by oligomannurarate (or derivative thereof), followed by a bacterial mixture (e.g., comprising a preparation of uncultured fecal bacteria and/or one or more bacterial isolates). In another example, the subject can be administered one or more prebiotics, followed by a bacterial mixture comprising one or more bacterial isolates, followed by a bacterial mixture comprising a preparation of uncultured fecal bacteria, followed by oligomannurarate (or derivative thereof). In another example, the subject can be administered one or more prebiotics, followed by oligomannurarate (or derivative thereof), followed by a bacterial mixture comprising one or more bacterial isolates, followed by a bacterial mixture comprising a preparation of uncultured fecal bacteria. In another example, the subject can be administered one or more prebiotics, followed by a bacterial mixture comprising one or more bacterial isolates, followed by oligomannurarate (or derivative thereof), followed by a bacterial mixture comprising a preparation of uncultured fecal bacteria. In another example, the subject can be administered one or more prebiotics, followed by a bacterial mixture comprising a preparation of uncultured fecal bacteria, followed by oligomannurarate (or derivative thereof), followed by a bacterial mixture comprising one or more bacterial isolates. For each of the above examples, it is further understood that any given component in a method of treatment can be administered multiple times. For example, a bacterial mixture can be administered to a subject, followed by oligomannurarate (or derivative thereof), followed by a prebiotic, followed by a second administration of the bacterial mixture.

[0292] In an aspect, a method for treating one or more symptoms of a neurodegenerative disorder in a subject in need thereof comprises administering to the subject: (i) one or more bacterial isolates; (ii) a preparation of uncultured fecal bacteria; (iii) one or more prebiotics; and (iv) one or more antibiotics. The different components of (i)-(iv) can be administered to the subject in any order. For example, a subject can be administered one or more antibiotics, followed by one or more prebiotics, followed by a bacterial mixture, followed by oligomannurarate (or derivative thereof). In another example, a subject can be administered one or more antibiotics, followed by one or more prebiotics, followed by oligomannurarate (or derivative thereof), followed by a bacterial mixture. In another example, the prebiotic can be administered after administering one or both of the bacterial mixture and/or the oligomannurarate (or derivative thereof). For each of the above examples, it is further understood that any given component in a method of treatment can be administered multiple times. For example, an antibiotic can be administered to a subject, followed by a preparation of uncultured fecal bacteria, followed by oligomannurarate (or derivative thereof), followed by a prebiotic, followed by a second administration of the preparation of uncultured fecal bacteria.

[0293] In each of the above combination treatments, the duration of time between different treatments (e.g., between administration of a bacterial mixture and oligomannurarate (or derivative thereof)) can be at least 1 hour, at least 2 hours, at least 6 hours, at least 12 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, or greater than 8 weeks. [0294] In one aspect, a subject being treated is a subject already with a disorder (e.g., a neurodegenerative disorder). Administration of a disclosed pharmaceutical composition to clinically, asymptomatic human subject who is genetically predisposed or prone to a disorder (e.g., a neurodegenerative disorder) is also useful in preventing the onset of clinical symptoms. A human subject genetically predisposed or prone to a neurodegenerative disorder can be a human subject having a close family member or relative exhibiting or having suffered a disorder (e.g., a neurodegenerative disorder). In another aspect, a subject being treated is a subject in which a neurodegenerative disorder is to be prevented. In another aspect, a subject being treated is predisposed or susceptible to a disorder (e.g, a neurodegenerative disorder). In another aspect, a subject being treated is a subject diagnosed as having a disorder (e.g, a neurodegenerative disorder). In one aspect, a subject being treated is a patient in need thereof.

[0295] In one aspect, a subject being treated is a human patient. In one aspect, a patient is a male patient. In one aspect, a patient is a female patient. In one aspect, a patient is a premature newborn. In one aspect, a patient is a term newborn. In one aspect, a patient is a neonate. In one aspect, a patient is an infant. In one aspect, a patient is a toddler. In one aspect, a patient is a young child. In one aspect, a patient is a child. In one aspect, a patient is an adolescent. In one aspect, a patient is a pediatric patient. In one aspect, a patient is a geriatric patient. In one aspect, a human patient is a child patient below about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In another aspect, a human patient is an adult patient. In another aspect, a human patient is an elderly patient. In a further aspect, a human patient is a patient above about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old. In another aspect, a patient is about between 1 and 5, between 2 and 10, between 3 and 18, between 21 and 50, between 21 and 40, between 21 and 30, between 50 and 90, between 60 and 90, between 70 and 90, between 60 and 80, or between 65 and 75 years old. In one aspect, a patient is a young old patient (65-74 years). In one aspect, a patient is a middle old patient (75-84 years). In one aspect, a patient is an old patient (>85 years).

[0296] In one aspect, a method comprises administering a pharmaceutical composition orally, by enema, or via rectal suppository. In one aspect, a pharmaceutical composition is formulated as a geltab, pill, microcapsule, capsule, or tablet. In one aspect, a pharmaceutical composition is formulated as an enteric coated capsule or microcapsule, acid-resistant capsule or microcapsule, or formulated as part of or administered together with a food, a food additive, a dairy-based product, a soy-based product or a derivative thereof, a jelly, or a yogurt. In another aspect, a pharmaceutical composition is formulated as an acid-resistant enteric coated capsule. A pharmaceutical composition can be provided as a powder for sale in combination with a food or drink. A food or drink can be a dairy-based product or a soy -based product. In another aspect, a food or food supplement contains enteric-coated and/or acid-resistant microcapsules containing a pharmaceutical composition.

[0297] Described herein are kits comprising any herein-disclosed pharmaceutical composition and instructions for use. For example, a kit can include unit dosage forms comprising one or more bacterial mixtures and/or oligomannurarate (or derivative thereof). Such a kit could include oligomannurarate (or derivative thereof) and/or one or more bacterial mixtures comprising at least one of a preparation of uncultured fecal bacteria and one or more bacterial isolates and, optionally, a delivery device to administer the composition(s) to the subject or instructions for administering the dosage to a subject via an appropriate delivery route. In some cases, the dosage form comprises any suitable form of live bacteria (fresh, frozen, lyophilized, etc.) and is formulated for administration to a human subject orally, by nasogastric tube, by colonoscopy, or anally. As described herein, dosage forms suitable for kits provided herein include, without limitation, liquid solutions, capsules, tablets, powders, granules, and lyophilized forms.

[0298] The instructions of a kit can describe, for example, dosing information of the one or more pharmaceutical compositions in the kit. As examples, the frequency of administration and dose of a composition, e.g., the number of capsules of a pharmaceutical composition to be administered at a given time, and the number of times of administration per day/week). In an aspect in which the kit comprises more than one composition (e.g., multiple bacterial mixtures or an additional pharmaceutical composition lacking a bacterial mixture), the instructions can describe the dosing of each composition. For example, one composition can be administered before another composition, e.g., sequential administration of the two pharmaceutical compositions separated by minutes, hours, days, weeks, months, or longer. Alternately, two compositions can be administered simultaneously.

[0299] In a further aspect, provided herein is use of a bacterial mixture described herein for manufacture of a medicament for treating a neurodegenerative disorder or for reducing the severity of one or more symptoms of a neurodegenerative disorder.

[0300] Disclosed herein is a method comprising administering an oligomannurarate (or derivative thereof) to a stool donor and, following the oligomannurarate (or derivative thereof) administration, collecting a stool from the donor to be used as a source of fecal bacteria for manufacturing a preparation of a uncultured fecal bacteria. Such a preparation of uncultured fecal bacteria prepared from a stool of a donor administered oligomannurarate (or derivative thereof) can be administered to a subject having a neurodegenerative disease, either on its own as a bacterial mixture or in combination with oligomannurarate (or derivative thereof). In an aspect, prior to making a fecal donation, a stool donor can ingest oligomannurarate (or derivative thereof) to induce the selective proliferation of beneficial bacterial taxa. A preparation of uncultured fecal bacteria from the stool of a donor that has ingested oligomannurarate (or derivative thereof) can be directly incorporated into a pharmaceutical composition described herein, without adding any additional bacterial isolate to the preparation, or alternatively can be spiked or enriched with a dose of a bacterial isolate.

[0301] In an aspect, a duration of time between ingestion of an oligomannurarate (or derivative thereof) by a stool donor and collection of a stool from the donor can vary; for example the duration can be at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, at least 26 hours, at least 28 hours, at least 30 hours, at least 32 hours, at least 34 hours, at least 36 hours, at least 38 hours, at least 40 hours, at least 42 hours, at least 44 hours, at least 46 hours, at least 48 hours, at least 50 hours, at least 52 hours, at least 54 hours, at least 56 hours, at least 58 hours, at least 60 hours, at least 62 hours, at least 64 hours, at least 66 hours, at least 68 hours, at least 70 hours, at least 72 hours, or greater than 72 hours.

[0302] In an aspect, a donor can ingest a dose of oligomannurarate (or derivative thereof) once or multiple times to facilitate an increase in relative abundance of beneficial strains of bacteria in stool of the donor. In one aspect, a dose of oligomannurarate (or derivative thereof) can be ingested by the donor at least once or twice daily for at least three consecutive days or weeks. In another aspect, a dose of oligomannurarate (or derivative thereof) is ingested at least once, twice, or three times daily for a period between 1 and 16 weeks, between 2 and 16 weeks, between 3 and 16 weeks, between 4 and 16 weeks, between 5 and 16 weeks, between 6 and 16 weeks, between 7 and 16 weeks, between 8 and 16 weeks, between 10 and 16 weeks, between 12 and 16 weeks, between 1 and 12 weeks, between 2 and 12 weeks, between 3 and 12 weeks, between 4 and 12 weeks, between 5 and 12 weeks, between 6 and 12 weeks, between 7 and 12 weeks, between 8 and 12 weeks, between 9 and 12 weeks, between 10 and 12 weeks, between 1 and 2 weeks, between 2 and 3 weeks, between 3 and 4 weeks, between 4 and 5 weeks, between 5 and 6 weeks, between 6 and 7 weeks, between 7 and 8 weeks, between 8 and 9 weeks, between 9 and 10 weeks, or between 10 and 11 weeks.

[0303] Disclosed herein is a method of manufacturing a pharmaceutical composition, the method comprising: extracting a bacterial population from a stool of a healthy human donor; and incorporating the extracted bacterial population into the pharmaceutical composition, wherein the donor ingested oligomannurarate (or derivative thereof) prior to releasing the stool.

[0304] Disclosed herein is a method of manufacturing a pharmaceutical composition comprising a bacterial population of a healthy human donor, the method comprising: receiving a stool from the donor following ingestion by the donor of oligomannurarate (or derivative thereof); extracting the bacterial population from the stool; and incorporating the bacterial population into the pharmaceutical composition, wherein the bacterial population is not cultured. Also disclosed is a method to identify a preferred fecal donor based on testing a fecal or blood level of an oligomannurarate or derivative thereof in the donor (regardless whether a tested donor ingests an oligomannurarate or a derivative thereof. Further disclosed is a method to identify a preferred fecal donor based on a relative fecal abundance of an oligomannurarate- producing bacteria in the donor. Further disclosed is a method to identify a preferred fecal donor based on a relative fecal abundance of one or more bacteria from a genus that changes its level (e.g., increasing or decreasing its relative abundance) in response to oligomannurarate intake (e.g., those described in Figure 4 of Wang et al., Cell Research (2019) 29:787-803).

[0305] It will be appreciated that compositions, dosage forms, and medicaments as described herein include combination pharmaceutical compositions in which one or more additional compounds or medications are added to or otherwise co-administered with a purified fecal microbiota composition.

[0306] The disclosure may be better understood by reference to the following non-limiting Examples, which are provided as exemplary of the disclosure. The following examples are presented in order to more fully illustrate the preferred aspects of the disclosure and should in no way be construed, however, as limiting the broad scope of the disclosure. Therefore, the scope of the appended claims should not be limited to the description of the aspects contained herein.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject (i) an oligomannurarate or derivative thereof; and (ii) a bacterial mixture comprising a preparation of uncultured fecal bacteria derived from a stool of a healthy human donor.

2. The method of claim 1 , wherein the healthy human donor has not been diagnosed with the neurodegenerative disease.

3. The method of claim 1 or claim 2, wherein the preparation of uncultured fecal bacteria comprises non-selected fecal bacteria.

4. The method of any one of claims 1 to 3, wherein the preparation of uncultured fecal bacteria comprises a substantially complete fecal microbiota.

5. The method of any one of claims 1 to 4, wherein the bacterial mixture comprises a bacterial isolate.

6. The method of any one of claims 1 to 5, wherein the oligomannurarate or derivative thereof consists of oligomannurarate polymers having only one degree of polymerization.

7. The method of any one of claims 1 to 5, wherein the oligomannurarate or derivative thereof comprises oligomannurarate polymers having different degrees of polymerization.

8. The method of claim 7, wherein the oligomannurarate or derivative thereof comprises polymers having degrees of polymerization ranging from dimers to decamers.

9. The method of claim 7, wherein the oligomannurarate or derivative thereof consists of polymers having degrees of polymerization ranging from dimers to decamers.

10. The method of any one of claims 1 to 9, wherein the oligomannurarate or derivative thereof and the bacterial mixture are administered to the subject in the same pharmaceutical composition.

11. The method of any one of claims 1 to 9, wherein the oligomannurarate or derivative thereof and the bacterial mixture are administered to the subject in different pharmaceutical compositions.

12. The method of claim 11, wherein the oligomannurarate or derivative thereof is administered to the subject before the bacterial mixture is administered to the subject.

13. The method of claim 11, wherein the oligomannurarate or derivative thereof is administered to the subject after the bacterial mixture is administered to the subject.

14. The method of any one of claims 1 to 13, further comprising administering an antibiotic to the subject prior to administering the oligomannurarate or derivative thereof, or prior to administering the bacterial mixture.

15. The method of any one of claims 1 to 14, further comprising administering a prebiotic to the subject.

16. The method of any one of claims 1 to 15, wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington’s Disease, motor neuron disease (MND), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA).

17. The method of claim 16, wherein the neurodegenerative disease is Alzheimer’s Disease.

18. The method of any one of claims 1 to 17, wherein the donor ingested an oligomannurarate or derivative thereof prior to releasing the stool.

19. A pharmaceutical composition comprising an oligomannurarate or derivative thereof and a bacterial mixture comprising a preparation of uncultured fecal bacteria derived from a stool of a healthy human donor.

20. The pharmaceutical composition of claim 19, wherein the healthy human donor has not been diagnosed with the neurodegenerative disease.

21. The pharmaceutical composition of claim 19 or claim 20, wherein the preparation of uncultured fecal bacteria comprises non-selected fecal bacteria.

22. The pharmaceutical composition of any one of claims 19 to 21 , wherein the preparation of uncultured fecal bacteria comprises a substantially complete fecal microbiota.

23. The pharmaceutical composition of any one of 19 to 22, wherein the bacterial mixture further comprises a bacterial isolate.

24. The pharmaceutical composition of any one of claims 19 to 23, wherein the oligomannurarate or derivative thereof consists of oligomannurarate polymers having only one degree of polymerization.

25. The pharmaceutical composition of any one of claims 19 to 23, wherein the oligomannurarate or derivative thereof comprises oligomannurarate polymers having different degrees of polymerization.

26. The pharmaceutical composition of claim 25, wherein the oligomannurarate or derivative thereof comprises polymers having degrees of polymerization ranging from dimers to decamers.

27. The pharmaceutical composition of claim 25, wherein the oligomannurarate or derivative thereof consists of polymers having degrees of polymerization ranging from dimers to decamers.

28. A method of manufacturing a pharmaceutical composition comprising a community of fecal bacteria, the method comprising: receiving a stool from a healthy human donor following ingestion by the donor of an oligomannurarate or derivative thereof; extracting the community of fecal bacteria from the stool; and formulating the community of fecal bacteria as the pharmaceutical composition, wherein the fecal bacteria are not cultured.

29. The method of claim 28, wherein the formulating comprises encapsulating the community of fecal bacteria.

30. The method of claim 28, wherein the method further comprises determining a fecal or blood level of an oligomannurarate or derivative thereof in the healthy human donor and selecting the healthy human donor based on the determined fecal or blood level.

31. A pharmaceutical composition comprising (i) a bacterial mixture comprising a preparation of uncultured fecal bacteria derived from a stool of a healthy human donor, and (ii) a bacterial isolate capable of producing an oligomannurarate or a derivative thereof.

32. The pharmaceutical composition of claim 31, wherein the bacterial isolate is from a genus selected from the group consisting of Pseudomonas and Azotobacter.

33. The pharmaceutical composition of claim 31 or 32, wherein the pharmaceutical composition further comprises an oligomannurarate or derivative thereof.

34. The pharmaceutical composition of claim 23, wherein the bacterial isolate is capable of producing an oligomannurarate or a derivative thereof.

35. The pharmaceutical composition of claim 34, wherein the bacterial isolate is from a genus selected from the group consisting of Pseudomonas and Azotobacter.