WO2023154966A1

WO2023154966A1 - Compositions and methods for sequestering metabolites in the gastrointestinal tract

Info

Publication number: WO2023154966A1
Application number: PCT/US2023/062601
Authority: WO
Inventors: Anthony Stewart CAMPBELL; Christopher Robert MEYER; Mary CONRAD; Gregory Preston; Srinivas Rao; David H. Donabedian
Original assignee: Axial Therapeutics, Inc.
Priority date: 2022-02-14
Filing date: 2023-02-14
Publication date: 2023-08-17

Abstract

The present disclosure describes methods and compositions for the treatment of neurological disorders and related symptoms by the in vivo sequestration and excretion of intestinal metabolites. These metabolites are related to neurological disorders such as autism spectrum disorder and Parkinson's disease, as well as intestinal hyperpermeability (leaky gut), intestinal dysbiosis and gastrointestinal comorbidities associated with such disorders.

Description

COMPOSITIONS AND METHODS FOR SEQUESTERING METABOLITES IN THE GASTROINTESTINAL TRACT GOVERNMENT SUPPORT [0001] This invention was made with government support awarded by Center for Environmental Microbial Interactions, MRI grant 1920364 awarded by National Science Foundation, P50 GM082545-08, MH100556 and AG063744 awarded by the National Institutes of Health. The government has certain rights in the invention FIELD [0002] The present disclosure relates to methods of treating, inhibiting, or ameliorating a behavioral symptoms of a neurological disorder, such as autism, and associated pathologies including intestinal hyperpermeability or leaky gut. BACKGROUND [0003] Current estimates of ASD prevalence reach 1 in 44 children born in the US¹, and recent clinical failures^2–9 highlight the need to expand drug development efforts. Behavioral features and severity are measured by validated observational assessment tools, as there are no imaging-based or molecular biomarkers that reliably and objectively diagnose ASD. Further, autism manifests across a broad spectrum from minimally affected individuals to those who require intense support, and there are no approved drugs for core symptoms. The etiology of ASD is poorly understood and likely multifactorial, but is known to involve complex genetic risks, with over a hundred genes implicated to date, each with a small effect size¹¹. A role for environmental risks in ASD has also been proposed, encompassing diet¹², maternal infection¹³, exposure to toxins¹⁴ and changes in the gut microbiome¹⁵. The notion that fixed genetic predispositions coupled with variable environmental risks together manifest symptom severity is intriguing from a therapeutic perspective, because correcting mutations in the genome remains challenging while reducing potential environmental contributors is likely more tractable. Recent studies suggest that molecules produced in the gastrointestinal tract can enter systemic circulation and impact immunity¹⁶, metabolism¹⁷, and behavior¹⁸. Altered immune and metabolic profiles have been associated with various neuropsychiatric disorders such as ASD^19– ²¹, and the microbiome and metabolome are altered in individuals with ASD^19,22, anxiety²³, depression²⁴ and schizophrenia²⁵. Notably, over a dozen studies have shown changes in the fecal microbiome in several ASD cohorts compared to controls²⁶, though these associations do not resolve cause or effect. Dietary habits likely contribute to the ASD microbiome²⁷. Several studies have also revealed changes in the metabolome of individuals with ASD from diverse geographies^19,28–30, with reports showing dysregulation of the fecal metabolome^19,31–33. [0004] The identification of several intestinal metabolites that correlate with ASD-like symptoms in mice was previously reported, along with the finding that administration of one of these metabolites, 4-ethylphenyl sulfate (4EPS), to naïve animals induced an anxiety-like phenotype³⁴. 4EPS, and several structurally related molecules, are dysregulated in the feces and plasma of ASD individuals compared to control populations¹⁹. Further, an open-label fecal transplant study described improvements in gastrointestinal and behavioral parameters in 18 ASD subjects^35,36, with a partial restoration of metabolomic profiles³⁷. However, these early studies remain speculative, and the identification of intestinal metabolites that modulate behavioral symptoms associated with neurological disorders such as ASD remains incomplete. [0005] Non-absorbable, non-digestible, biocompatible polymers have been used for lowering cholesterol and systemic phosphate levels by targeting adsorption of cholesterol and free phosphate in the gut. These products are biocompatible ion exchange resins that are not absorbed to any significant extent and are excreted from the gastrointestinal (GI) tract after binding their target molecules. For example, the ion exchange resin, cholestyramine, has been used for sequestering bile acids, which are cholesterol derivatives, so as to lower cholesterol. Additionally, non-absorbable, non-digestible, biocompatible activated carbon preparations have been investigated to counteract the effects of toxins in poisoning and drug overdoses (e.g., Dillon et al. (1989), Ann. Emerg. Med.18(5):547-52; Kieslichova et al. (2018), Transplantation Proc. 50:192-197), and uremic toxins in the treatment of chronic kidney disease (e.g., Schulman et al. (2016), BMC Nephrology 17:141). For example, an activated carbon particle preparation has been developed and utilized for delaying dialysis in subjects suffering from chronic kidney disease, but the clinical utility of this approach has not been roundly accepted, multiple meta- analyses have indicated no clear clinical benefit, and a later stage clinical trial in the US failed to prove efficacy. [0006] AB-2004, known otherwise as AST-120, is a high surface-area spherical carbon adsorbent that has affinity for uremic toxins including those of gut bacterial origin, such as the simple phenols, 4EPS, p-cresyl sulfate (pCS), and p-cresol glucuronide (pCG), as well as the indole derivative, 3- indoxyl sulfate (3IS) and hippuric acid³⁹, based on evidence from rodent models and patients with chronic kidney disease⁴⁰ and IBS⁴¹. SUMMARY [0007] The present application is based, at least in part, on the realization that sequestrants (such as activated carbon) that reduce certain intestinal metabolites (e.g., 3-hydroxyhippurate (HHA), 3-(3-hydroxyphenyl)-3-hydroxypropionate (HPHPA), 3-(4-hydroxyphenyl)propionate (HPPA), 3-hydroxyphenylacetate (HPAA), 3- carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), and imidazolepropionate (IPA)) improve certain behavioral symptoms associated with neurological disorders such as ASD. More specifically, this disclosure is based on clinical data that show that AB-2004 absorbs certain intestinal metabolites (e.g., 4-EPS, 3IS, HHA and HPHPA) associated with behavioral symptoms (e.g., anxiety and irritability) associated with ASD, and that modulation or reduction of these metabolites in the gut of a subject, provides improvement in behavioral symptoms. [0008] In one aspect, the invention provides sequestrant compositions for use in the treatment of a subject having a behavioral symptom of a neurological disorder. In some embodiments, the behavioral symptom of a neurological disorder is associated with intestinal hyperpermeability (or leaky gut) or intestinal dysbiosis. These compositions comprise a multiplicity of biocompatible particles and/or polymers which are non-digestible and non-absorbable by the gastrointestinal tract of the subject. The sequestrant compositions bind to at least a fraction of at least one intestinal metabolite present in the gastrointestinal tract of the subject to form a sequestrant- metabolite complex, which may include covalent or non-covalent bonds. As a result of the formation of the sequestrant-metabolite complex, the intestinal metabolite is eliminated from the gastrointestinal tract along with the sequestrant composition, rather than interacting with or being absorbed by the tissues of the gastrointestinal tract. The intestinal metabolites which are bound by the sequestrant compositions are associated with the development or presence of the behavioral symptom and, thus, the elimination of the intestinal metabolite aids in the treatment of the behavioral symptom and neurological disorder. [0009] In another aspect, the invention provides sequestrant compositions for use in the treatment of a subject having a behavioral symptom of a neurological disorder associated with intestinal hyperpermeability (or leaky gut), intestinal dysbiosis, or accumulation of one or more intestinal metabolites (e.g., in the gut as indicated by an increased level in blood, plasma, urine, or stool). [0010] In another aspect, provided herein is a sequestrant composition for use in the treatment of a subject having deleterious levels of an intestinal metabolite. In some embodiments, the intestinal metabolite is associated with a disease (e.g., a neurological disease) or a behavioral symptom thereof. In some embodiments, a deleterious level of intestinal metabolite is a level of a metabolite measured in a biological sample from the subject (e.g., blood, plasma, urine, or stool) that is comparable to levels of the metabolite found in a similar biological sample from individuals known to suffer from the behavioral symptom or the neurological disease. For example, a subject having a level of pCS in their blood that is comparable to levels of pCS found in blood samples of individuals diagnosed with ASD or known to suffer from one or more behavioral symptoms of ASD, may be treated with any one of the sequestrant compositions described herein. In some embodiments, a deleterious level of intestinal metabolite is one that is statistically higher than levels of the same metabolite measured in samples from individuals known not to suffer from a particular neurological disease, or are otherwise believed to be healthy individuals. In some embodiments, a deleterious level of an intestinal metabolite is associated with intestinal hyperpermeability or intestinal dysbiosis. [0011] In another aspect, provided herein is a sequestrant composition for use in reducing the level of one or more intestinal metabolites that are associated with intestinal hyperpermeability, intestinal dysbiosis, and/or a neurological disease or behavioral symptom thereof. In some embodiments, such an intestinal metabolite is one that has been found by experimental data (e.g., by measurement in a group of individuals suffering from anxiety, irritability, or ASD). In some embodiments, an intestinal metabolite is one that is described in the Example section of this disclosure. [0012] In another aspect, provided herein is a sequestrant composition for use in treatment of intestinal hyperpermeability or intestinal dysbiosis. [0013] In another aspect, the invention provides methods of treating a subject having a behavioral symptom of a neurological disorder associated with intestinal hyperpermeability, intestinal dysbiosis, or accumulation of one or more intestinal metabolites (e.g., in the gut as indicated by an increased level in blood, plasma, urine, or stool). These methods comprise administering to the subject a sequestrant composition of the invention which binds to at least a fraction of at least one intestinal metabolite present in the gastrointestinal tract of the subject. As described above, the sequestrant and metabolite form a sequestrant-metabolite complex, such that the intestinal metabolite is eliminated from the gastrointestinal tract along with the sequestrant composition, rather than interacting with or being absorbed by the tissues of the gastrointestinal tract. Because the intestinal metabolites are associated with the development or presence of the behavioral symptom, the binding of the sequestrant compositions promotes the elimination of the intestinal metabolite and aids in the treatment of the behavioral symptom and neurological disorder. [0014] In another aspect, the invention provides methods of reducing the amount of one or more intestinal metabolites from a subject having a behavioral symptom of a neurological disorder. In some embodiments, the behavioral symptom of a neurological disorder is associated with intestinal hyperpermeability, intestinal dysbiosis, or accumulation of one or more intestinal metabolites (e.g., in the gut as indicated by an increased level in blood, plasma, urine, or stool). The methods comprise administering to the subject a sequestrant composition which binds to at least a fraction of at least one intestinal metabolite present in the gastrointestinal tract of the subject. As described above, the sequestrant and intestinal metabolite form a sequestrant- metabolite complex, such that the intestinal metabolite is eliminated from the gastrointestinal tract along with the sequestrant composition, rather than interacting with or being absorbed by the tissues of the gastrointestinal tract. Thus, the binding of the sequestrant compositions to intestinal metabolites which are associated with the development or presence of the behavioral symptom promotes the elimination of the intestinal metabolites and aids in the treatment of the behavioral symptom and neurological disorder. [0015] In each of the foregoing aspects, in some embodiments the sequestrant composition comprises a multiplicity of particles which are biocompatible with, non-digestible by, and/or non-absorbable by the gastrointestinal tract of the subject. [0016] In each of the foregoing aspects, in some embodiments, the sequestrant composition comprises activated carbon, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a zeolite, a polymer, or a resin. In some embodiments, a polymer is a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate polymer, a polyglucosamine polymer, a cholestyramine polymer, a tetraethylenepentamine polymer, a boronic acid-presenting polymer, or a catechin- presenting polymer. In some embodiments, a resin is a phenolic resin or an ion exchange resin. [0017] In each of the foregoing aspects, in some embodiments, the sequestrant composition comprises an AB-2004 preparation. The AB-2004 compositions of the invention comprise spherical activated carbon particles. In some embodiments, the spherical activated carbon particles have a minimum average specific surface area determined by the Brunauer-Emmett- Teller (BET) method of at least 500 m²/g and a maximum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method less than 4000 m²/g. In some embodiments, the spherical activated carbon particles have a minimum average particle diameter of at least 0.005 and a maximum average particle diameter of less than 1.5 mm. In some embodiments, the spherical activated carbon particles have both (a) a minimum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method of at least 500 m²/g and a maximum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method less than 4000 m²/g, and (b) a minimum average particle diameter of at least 0.005 and a maximum average particle diameter of less than 1.5 mm. [0018] In each of the foregoing aspects, in some embodiments, the sequestrant composition of the invention is formulated for controlled release in the lower gastrointestinal tract. Such compositions can be administered orally or as a suppository. [0019] In each of the foregoing aspects, in each of the foregoing embodiments, the neurological disorder can be selected from any of: autism spectrum disorder, an anxiety disorder, major depressive disorder, post traumatic stress disorder, Parkinson’s Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer’s Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, pure autonomic failure, or any combination thereof. [0020] In each of the foregoing aspects, in some embodiments, the behavioral symptom is selected from: tremors, paralysis, dyskinesia, repetitive behaviors, communicative symptoms, cognitive disorders, stereotyped behaviors, attachment to physical objects, aphasia, obsessive behaviors, unusual or inappropriate body language, gestures, and/or facial expressions and/or sensorimotor issues, lack of interest in other people, lack of empathy, difficulty grasping nonverbal cues, touch aversion, difficulty in socialization, social motivation, social awareness, social communication, social cognition, inappropriate speech, hyperactivity/noncompliance, social withdrawal, speech delays, abnormal vocal tone or pitch, vocal repetition, perseveration, conversational difficulty, difficulty communicating needs or desires, inability to understand simple statements or questions, difficulties in processing language subtext, obsessive attachment to unusual objects, preoccupation, intolerance of changes in routine or environment, clumsiness, abnormal posture, odd ways of moving, fascination with particular objects, hyper- or hypo- reactivity to sensory input, and clinical irritability. [0021] In each of the foregoing aspects, in some embodiments, the neurological disorder is autism spectrum disorder and the behavioral symptom is selected from: repetitive behaviors, social motivation, social awareness, social communication, social cognition, inappropriate speech, hyperactivity/noncompliance, social withdrawal, communicative symptoms, stereotyped behaviors, anxiety and clinical irritability. [0022] In some embodiments, the subject indicates a neurological disorder or is diagnosed with suffering from one or more behavioral symptoms of a neurological disorder according to diagnostic test. In some embodiments, a diagnostic test is an anxiety rating scale, optionally Pediatric Anxiety Rating Scale (PARS), an aberrant behavior test, optionally Aberrant Behavior Checklist (ABC), a social behavior test, optionally Social Responsiveness Scale (SRS-2), a repetitive behavior test, optionally, Repetitive Behavior Scale Revised (RBS-R), or an adaptive behavior test, optionally Vineland Adaptive Behavior Scales (VABS-3). [0023] In each of the foregoing aspects, in some embodiments, the subject does not have clinical anxiety or an anxiety disorder. [0024] In each of the foregoing aspects, in some embodiments, the subject does not have chronic kidney disease. [0025] In each of the foregoing aspects, in some embodiments, the intestinal metabolite is selected from: 4-ethylphenol (4-EP), 4-ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate (3IS), 3-hydroxy indole,indole, coumaric acid, 3-(3- hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-(3-hydroxyphenyl)propanoic acid, 3-(4- hydroxy-phenyl)propanoic acid (HPPA)), 3-hydroxy hippuric acid (3HHA), 3-carboxy-4- methyl-5-propyl-2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4- hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid, p-cresol glucuronide (pCG); and imidazolepropionate (IPA). In some embodiments, an intestinal metabolite is a conjugate base of the aforementioned metabolites, e.g., 3-hydroxyphenylacetate (HPAA), 3-(3- hydroxyphenyl)-3-hydroxypropionate (HPHPA), or 3-(4-hydroxyphenyl)propionate (HPPA), 3- hydroxyhippurate (HHA). [0026] In each of the foregoing aspects, in some embodiments, the intestinal metabolite is selected from the group consisting of: p-cresol glucuronide (pCG), 3-indoxyl sulfate (3IS), and 3-hydroxyphenylacetate (HPAA). [0027] In each of the foregoing aspects, in some embodiments, the method of treatment comprises monitoring intestinal metabolite levels of the subject during the course of treatment. [0028] In each of the foregoing aspects, in some embodiments, the method of treatment comprises monitoring changes in the behavior of the subject. [0029] In each of the foregoing aspects, in some embodiments, the method of treatment comprises administering the sequestrant composition following the appearance of behavioral symptoms of the neurological disorder. [0030] In each of the foregoing aspects, in some embodiments, the method of treatment comprises administering the sequestrant composition prior the appearance of behavioral symptoms of the neurological disorder. [0031] In each of the foregoing aspects, in some embodiments, the method of treatment is repeated as necessary to maintain reduced levels of intestinal metabolites relative to the levels identified prior to the first administration of the composition. In some embodiments, for a given administration, the composition is different from a composition previously administered. [0032] In each of the foregoing aspects, in some embodiments, the method of treatment comprises monitoring changes in the behavior of the subject. [0033] Thus, described herein are methods for the treatment, inhibition, or amelioration of one or more or a plurality of neurological disorders, leaky gut comorbid with a neurological disorder, or leaky gut independent of a neurological disorder, associated with alterations in the intestinal microbiome. In some embodiments, the methods comprise the step of administering to a subject a composition that sequesters intestinal metabolites associated with alterations in the intestinal microbiome and, after having sequestered the intestinal metabolites, is eliminated from the gastrointestinal tract without being metabolized. In some embodiments, the methods further comprise the step of identifying and/or selecting a subject having elevated levels of one or more intestinal metabolites associated with alterations in the intestinal microbiome, having symptoms of a disorder associated with alterations in the intestinal microbiome, diagnosed with a disorder associated with alterations in the intestinal microbiome, or at increased risk of developing a disorder associated with alterations in the intestinal microbiome. The compositions to be administered according to the methods of the present disclosure may comprise biocompatible particles. In some embodiments, biocompatible particles comprise activated carbon, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a zeolite, a polymer, or a resin. In some embodiments, a polymer is a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate polymer, a polyglucosamine polymer, a cholestyramine polymer, a tetraethylenepentamine polymer, a boronic acid-presenting polymer, or a catechin-presenting polymer. In some embodiments, a polymer is an antibody, e.g., a plastic antibody. In some embodiments, a polymer is one made via molecular imprinting. See, e.g., Okishima et al. (2019), Biomacromolecules 20(4):1644-1654. In some embodiments, a resin is a phenolic resin or an ion exchange resin. In some embodiments, biocompatible particles comprise an adsorbent material. In some embodiments, biocompatible particles comprise activated carbon, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a zeolite, a polymer, or a resin. In some embodiments, a polymer is a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate polymer, a cholestyramine polymer, a tetraethylenepentamine polymer, a boronic acid-presenting polymer, or a catechin-presenting polymer. In some embodiments, a resin a phenolic resin or an ion exchange resin. In some embodiments, biocompatible particles comprise an adsorbent, polymer, clay, or resin, which may comprise, consist essentially of, or consist of one or more of an activated carbon, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate, an ion exchange resin, a cholestyramine polymer, a tetraethylenepentamine polymer, a phenolic resin, a boronic acid-presenting polymer, a catechin-presenting polymer, a zeolite, and/or a nanoparticle, or any combination thereof. The compositions to be administered according to the methods of the present disclosure may comprise, consist essentially of, or consist of preparations of high surface-area activated-carbon particles referred to as AB-2004 herein. The compositions to be administered according to the methods of the present disclosure may further be formulated for controlled release in the lower gastrointestinal tract. [0034] The methods of the present disclosure can be applied to address one or more or a plurality of neurological disorders, e.g., one or more of autism spectrum disorder, schizophrenia, an anxiety disorder, depression (also referred to as clinical depression or major depressive disorder), Parkinson's Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer’s Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha- synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, pure autonomic failure, or any combination thereof. The methods of the present disclosure may further be applied to address a neurological disorder, wherein the neurological disorder presents a leaky gut (intestinal hyperpermeability) in said subject, as well as leaky gut symptoms associated with such neurological disorders, and/or leaky gut symptoms not associated with a neurological disorder. [0035] The methods according to the present disclosure promote the sequestration of intestinal metabolites associated with intestinal hyperpermeability (leaky gut) or intestinal dysbiosis (i.e., deleterious changes in the intestinal microbiome), including both microbial metabolites and products of host metabolism of microbial metabolites. Such intestinal metabolites include, without limitation, those generated from the metabolism of tryptophan (e.g., serotonin, 5-hydroxyindoleacetate, kynurenine, kynurenate, anthranilate, xanthurenate, quinolinate, nicotinate, nicotinamide, indole, 3-hydroxy indole, 3-indoxyl sulfate, indole pyruvate, indole propionate, indole-3-acetic acid, indole lactate, indole acetate, tryptamine), those generated from the metabolism of tyrosine (e.g., 4-ethylphenol (4-EP), 4- ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), p-cresol glucuronide (pCG), 4-hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate,), those generated from the metabolism of tyrosine (e.g., dopamine, or norepinephrine), those generated from the metabolism of arginine (e..g, homocitrulline), and those generated from the metabolism of benzoate (e.g., benzoate, hippurate, catechol, catechol sulfate), as well as N-acetylserine, beta-alanine, glutamine, transurocanate, imidazolepropionate (IPA), phenylacetylglycine, phenol, phenyl sulfate, coumaric acid, 3-hydroxyphenylacetate (HPAA), 3-(4-hydroxyphenyl)propionate (HPPA), 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-(3- hydroxyphenyl)propanoic acid, 3-(4-hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5-propyl-2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 3-methyl-2-oxovalerate, 4-methyl-2-oxopentaoate, cysteine, arginine, ornithine, 5- methylthioadenosine, glycylvaline, Fibrinogen Cleavage Peptide, 3-phosphoglycerate, phosphoenolpyruvate, ribose, xylose, docosapentaenoate (n3 DPA; 22:5n3), docosapentaenoate (n6 DPA; 22:5n6), docosahexaenoate (DHA; 22:6n3), stearate, eicosenoate, dihomo-linoleate (20:2n6), adrenate, 13-HODE+9-HODE, octadecanedioate, 12-HETE, myo-inositol, 1- palmitoylglycerophosphoethanolamine, N-alpha-acetyl-l-arginine, methyl guanidine, phenylacetylglutamine, 1-oleoylglycerophosphoethanolamine, 1-pentadecanoylglycero- phosphocholine, 1-palmitoleoylglycerophosphocholine, 1-stearoylglycerophosphoinositol, 1- palmitoylplasmenylethanolamine, bilirubin (E,E), pantothenate, glycolate (hydroxyacetate), ergothioneine, equol, and/or equol sulfate, or any combination thereof. [0036] Without being bound by any theory, in some embodiments, a intestinal metabolite results from a metabolic pathway involving tyrosine. In some embodiments, said intestinal metabolite is p-cresol. In some embodiments, said intestinal metabolite is 4-ethyl phenol. In some embodiments, said metabolite is p-cresol sulfate. In some embodiments, said intestinal metabolite is 4-ethyl phenyl sulfate. [0037] Without being bound by any theory, in some embodiments, a intestinal metabolite is an aromatic or heteroaromatic alcohol or sulfate thereof, resulting from the sulfation or sulfonation of said aromatic or heteroaromatic alcohol. In some embodiments, the aromatic alcohol is p-cresol. In some embodiments, the aromatic alcohol is 4-ethyl phenol. In some embodiments, the aromatic sulfate is 4-ethyl phenyl sulfate. [0038] In some embodiments, said aromatic or heteroaromatic alcohol or sulfate thereof is monocyclic. In some embodiments, said aromatic or heteroaromatic alcohol is bicyclic, tricyclic, or polycyclic. In some embodiments, the heteroaromatic bicyclic alcohol is 3-hydroxy indole. In some embodiments the heteroaromatic bicyclic sulfate is 3-indoxyl sulfate. [0039] The terms “aromatic”, “heteroaromatic”, “alcohol”, “sulfate”, “sulfation”, “sulfonation”, “monocyclic”, “bicyclic”, and “polycyclic” are art-recognized terms of organic chemistry, medicinal chemistry, or pharmaceutical chemistry, and would be readily recognized as such by a person of ordinary skill in the art of organic chemistry, medicinal chemistry, or pharmaceutical chemistry. [0040] As used herein, “aromatic” groups (or “aryl” or “arylene” groups) include aromatic carbocyclic ring systems (e.g., phenyl) and fused polycyclic aromatic ring systems (e.g., naphthyl, biphenyl, and 1,2,3,4-tetrahdronaphthyl). [0041] The terms "heteroaryl", “heteroaromatic” or "heteroarylene" as used herein, include aromatic ring systems, including, but not limited to, monocyclic, bicyclic and tricyclic rings, and have 5 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention: azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4- d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrazolyl, thiadiazolyl, thienyl, 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazinyl, 6H-imidazo[1,5-a]pyrrolo[2,3- e]pyrazinyl, 1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine, 3H-3,4,6,8a-tetraaza- asindacenyl, 3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinyl, pyrazolo[3,4-d]pyrrolo[2,3-b]pyridinyl, 1,6-dihydro-1,2,5,6-tetraza-as-indacenyl, 3H-3,4,8a-triaza-as-indacenyl, 6H-3-oxa-2,5,6-triaza- as-indacenyl, 3,6-dihydro-2,3,6-tetraaza-as-indacenyl, 1,6-dihydro-dipyrrolo[2,3-b; 2'3'- d]pyridinyl, 6H-3-thia-2,5,6-triaza-as-indacenyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one, 3,4- dihydroquinolin-2(1H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, or 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazinyl or 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine. [0042] The methods according to the present disclosure may comprise dosing schedules wherein at least one of the sequestrant compositions disclosed herein is administered multiple times per day, daily, or less frequently than daily. According to the methods described herein, dosing of the disclosed compositions may occur every second day, every third day, every fourth day, every fifth day, every sixth day, or every seventh day. According to the methods described herein, dosing may initiate prior to, concurrent with, or following the appearance of one or more or a plurality of symptoms of a neurological disorder, such as autism and/or associated pathologies including intestinal hyperpermeability (leaky gut) in a subject. The methods as described herein may also incorporate monitoring or a determining of one or more intestinal metabolite levels (e.g., in the gut as indicated by an increased level in blood, plasma, urine, or stool), changes in behavior, and /or changes in gastrointestinal symptoms in a subject before, during, or after the course of therapy. [0043] The methods described herein can be repeated as necessary to treat or prevent one or more of a plurality of symptoms of a neurological disorder, as well as leaky gut symptoms associated with such neurological disorders, and/or leaky gut symptoms not associated with a neurological disorder, and/or to maintain reduced levels of intestinal metabolites relative to the levels identified prior to the first administration of the composition. For each administration according to the methods described herein, the composition can be the same as a composition previously administered or can be different from a composition previously administered. [0044] In some embodiments, a neurological disorder as contemplated herein comprises one or more symptoms selected from the group consisting of: tremors, paralysis, dyskinesia, repetitive behaviors, communicative symptoms, cognitive disorders, stereotyped behaviors, attachment to physical objects, aphasia, obsessive behaviors, unusual or inappropriate body language, gestures, and/or facial expressions and/or sensorimotor issues, lack of interest in other people, lack of empathy, difficulty grasping nonverbal cues, touch aversion, difficulty in socialization, social motivation, social awareness, social communication, social cognition, inappropriate speech, hyperactivity/noncompliance, social withdrawal, speech delays, abnormal vocal tone or pitch, vocal repetition, perseveration, conversational difficulty, difficulty communicating needs or desires, inability to understand simple statements or questions, difficulties in processing language subtext, obsessive attachment to unusual objects, preoccupation, intolerance of changes in routine or environment, clumsiness, abnormal posture, odd ways of moving, fascination with particular objects, and hyper- or hypo-reactivity to sensory input, clinical irritability or any combination thereof. In some embodiments, the neurological disorder comprises one or more of autism spectrum disorder, schizophrenia, an anxiety disorder, depression, major depressive disorder, post traumatic stress disorder, Parkinson's Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer’s Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, pure autonomic failure, or any combination thereof. In some embodiments, the neurological disorder may comprise autism spectrum disorder that comprises a symptom other than clinical anxiety. In some embodiments, the neurological disorder does not comprise an anxiety disorder. In some embodiments, the neurological disorder may comprise autism spectrum disorder that comprises clinical irritability symptoms. [0045] In some embodiments, a neurological disorder is indicated by, or a subject is diagnosed as suffering from one or more behavioral symptoms of a neurological disorder according to a diagnostic test. Any established diagnostic test can be used. Non-limiting examples include an anxiety rating scale, optionally Pediatric Anxiety Rating Scale (PARS), an aberrant behavior test, optionally Aberrant Behavior Checklist (ABC) ⁵⁵, a social behavior test, optionally Social Responsiveness Scale (SRS-2) ⁵⁶, a repetitive behavior test, optionally, Repetitive Behavior Scale Revised (RBS-R) ⁵⁷, or an adaptive behavior test, optionally Vineland Adaptive Behavior Scales (VABS-3) ⁵⁸. In some embodiments, a subject suffering from a neurological disorder also manifests gastrointestinal symptoms or discomfort. Such symptoms may be assessed using any one of several tests for measuring gastrointestinal symptom metrics, such as Bristol Stool Scale (BSS)⁵⁹, Gastrointestinal Severity Index (6-GSI; Adams et al. (2011). Gastrointestinal flora and gastrointestinal status in children with autism—comparisons to neurotypical children and correlation with autism severity. BMC Gastroenterol 11(1):22), and Gastrointestinal Symptom Rating Scale tool (GSRS)⁶⁰. [0046] In some embodiments, the methods provided may further comprise monitoring, after said administering, changes in a symptom selected from the group consisting of: tremors, paralysis, dyskinesia, repetitive behaviors, communicative symptoms, cognitive disorders, stereotyped behaviors, attachment to physical objects, aphasia, obsessive behaviors, unusual or inappropriate body language, gestures, and/or facial expressions and/or sensorimotor issues, lack of interest in other people, lack of empathy, difficulty grasping nonverbal cues, touch aversion, difficulty in socialization, social motivation, social awareness, social communication, social cognition, inappropriate speech, hyperactivity/noncompliance, social withdrawal, speech delays, abnormal vocal tone or pitch, vocal repetition, perseveration, conversational difficulty, difficulty communicating needs or desires, inability to understand simple statements or questions, difficulties in processing language subtext, obsessive attachment to unusual objects, preoccupation, intolerance of changes in routine or environment, clumsiness, abnormal posture, odd ways of moving, fascination with particular objects, and hyper- or hypo-reactivity to sensory input, clinical irritability or any combination thereof. [0047] In some embodiments, the neurological disorder comprises autism spectrum disorder, and the methods as described herein further comprise monitoring the amelioration of a symptom of autism spectrum disorder other than clinical anxiety following the administration of a composition as described herein. In some embodiments, the symptoms of autism spectrum disorder comprise one or more of the following: repetitive behaviors, communicative symptoms, cognitive disorders, difficulty in socialization, and irritability. In some embodiments, the sequestrant composition to be administered comprises an AB-2004 preparation. BRIEF DESCRIPTION OF THE DRAWINGS [0048] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. It is to be understood that the data illustrated in the drawings in no way limit the scope of the disclosure. [0049] FIGs.1A-1B. Demographics of clinical trial participants and trial schedule. FIG.1A, Trial demographics and metadata summary of participants. FIG.1B, Phase I clinical trial schedule. Participants were screened during a 4-week run in period, followed by dose escalation in weeks 0-2, 2-4, and 4-8, with a follow-up 4-weeks after trial. Abbreviations: MRI, magnetic resonance imaging; BMI, body mass index; ADOS, Autism Diagnostic Observation Schedule; CGI-S, Clinical Global Impression Severity; PARS, Pediatric Anxiety Rating Scale; 6-GSI, Gastrointestinal Severity Index; BSS, Bristol Stool Scale; NRS, Numerical Rating Scale; GSRS, Gastrointestinal Symptom Rating Scale; ABC-I, Aberrant Behavior Checklist-Irritability; ABC- SW, Aberrant Behavior Checklist-Social Withdrawal; SRS-2, Social Responsiveness Scale; RBS-R, Repetitive Behavior Scale Revised; VABS, Vineland Adaptive Behavior Scales; BL, baseline; EOT, end of treatment, FV, final visit. [0050] FIGs.2A-2G. Oral AB-2004 treatment reduces levels of several bacterial metabolites. FIGs.2A-2G, Metabolite levels in urine from baseline (BL), end of treatment (EOT), and final visit (FV) timepoints from all participants, normalized to creatinine (µg metabolite/mmol creatinine) on log2 scale. Chemical structures shown above associated data panels. Urine from one subject could not be obtained due to incontinence. Abbreviations: BL, baseline; EOT, end of treatment; FV, final visit; 4EPS, 4-ethylphenyl sulfate; pCG, p-cresyl glucuronide; pCS; p-cresyl sulfate; 3IS, 3-indoxyl sulfate; HPAA, 3-hydroxyphenylacetate; HPHPA, 3-(3-hydroxyphenyl)- 3-hydroxypropionate. Data analysis was conducted on the completers group (n=26, with two missing data points in the FV timepoint because two subjects missed assessment due to parental illness). Analysis is exploratory and post hoc in nature, shown as mean and 95% confidence interval analyzed with a Linear Mixed Effects Model with Geisser-Greenhouse correction, multiple comparisons, and false discovery rate correction across all metabolites (nominal p values: * p adj. ≤ 0.05; ** p adj. ≤ 0.01; *** p adj. ≤ 0.001; **** p adj. ≤ 0.0001). [0051] FIGs.3A-3D. AB-2004 administration improves anxiety and irritability, especially in individuals with high baseline scores. FIG.3A, Anxiety (measured by PARS) scores of all eligible study participants at baseline (BL), the end of treatment (EOT), and final visit (FV) time points, with mean test scores represented as bars. Dotted line indicates threshold for anxiety (n=24). FIG.3B, PARS anxiety scores of the subset of individuals scoring ≥ 10 at BL, showing individual change to EOT and FV (n=15). FIG.3C, Irritability (measured by ABC-I) scores of all eligible study participants at BL, EOT, and FV time points. Dotted line indicates threshold for the top quartile of irritability severity among the ASD population (BL, EOT n=26; FV n=24 due to a missing final visit value for two individuals). FIG.3D, Irritability (ABC-I) scores of the subset of individuals scoring ≥ 15 at BL, showing individual change to EOT and FV (n=11). Abbreviations: PARS, Pediatric Anxiety Rating Scale; ABC, Aberrant Behavior Checklist; BL, baseline; EOT, end of treatment, FV, final visit. Data analysis was conducted on the completers group (n=26, with two missing data points in the FV timepoint in ABC-I and at all time points in PARS because two subjects missed assessments due to parental illness). Analysis is exploratory and post hoc in nature, shown as mean and 95% confidence interval. Analyses were performed by repeated measures one-way ANOVA (FIGs.3A, 3B, and 3D) or the Linear Mixed Effects model (FIG.3C) with Geisser-Greenhouse correction, multiple comparisons, and false discovery rate correction within each test (nominal p values:* p adj. ≤ 0.05; ** p adj. ≤ 0.01). [0052] FIGs.4A-4J. AB-2004 administration lowers 4EPS levels in gnotobiotic mice and ameliorates anxiety-like behavior. FIG.4A, Bacterial strain pairs were engineered to produce 4- ethylphenol (4EP+) or not (4EP-). See Methods for details.4EP is converted to 4EPS by the mouse. FIG.4B, Timeline schematic for colonization of germ-free mice, AB-2004 administration, and metabolite and behavioral analysis. FIG.4C, Separate groups of mice were each colonized with either the 4EP+ or 4EP- strain pair.4EPS levels quantified in urine of mice two weeks after dietary administration of AB-2004 or control diets. Limit of detection is 10ng/ml (n number left to right: n=18, 20, 12,18). FIG.4D, Weight gain of mice on diet containing 5% AB-2004 compared to controls (n=10 each). FIG.4E, Colonization of mice with 4EP producing strain pairs of Lactobacillus plantarum and Bacteroides ovatus. Both bacterial strains equally colonize 4EP+ and 4EP- groups of mice, independent of diet (n number left to right: n=4, 4, 3, 4). FIGs.4F-4J, Behavioral test results from mice administered AB-2004 or control diet. FIG. 4F, Visual representations of the behavioral assays open field, elevated plus maze, marble burying and grooming. FIG.4G, Open field (OF) test results presented as, from left to right, a ratio of time spent in the center of the arena over time spent in thigmotaxis along the perimeter during the 10-minute testing period, total distance mice traveled, time in center, and time in thigmotaxis along the perimeter of the arena (n number left to right: n=31, 33, 26, 26). FIG.4H, Elevated plus maze (EPM) results presented, from left to right, as a ratio of time spent in the open arms of the maze over time spent in the closed arms during the 5-minute testing period, time mice spent in the open arms, time spent in the closed arms, and total time at the terminus (outermost third of open arms)(n number left to right: n=27, 29, 23, 25). FIG.4I, Number of marbles buried during the 10-minute testing period (n number left to right: n=31, 33, 25, 26). FIG.4J, Amount of time spent grooming during the 10-minute testing period (n number left to right: n=26, 32, 22, 25). Abbreviations: 4EP, 4-ethylphenol; 4EPS, 4-ethylphenyl sulfate. Data represent mean ± SEM analyzed by ordinary two-way ANOVA test with FDR correction, with individual variances computed for each comparison (* p adj. ≤ 0.05; ** p adj. ≤ 0.01; *** p adj. ≤ 0.001; **** p adj. ≤ 0.0001). [0053] FIGs.5A-5C. Consort flow diagram, CGI-S, and CGI-I data in clinical samples. FIG. 5A, A total of 41 individuals were screened for eligibility across 3 sites in New Zealand and Australia between April 2019 and January 2020.30 participants were enrolled following meeting predefined criteria for study (see methods and Table 2).27 participants completed treatment and 25 completed the follow up visit. FIG.5B, Clinical global impression improvement scores (CGI- I) for all participants at visit 4, EOT and FV time points (n=26 with two missing participants for FV due to parental illness). All participants’ scores were normalized to a 4 at BL, thus this data is relative to 4; lower number = improvement, higher number = worsening. FIG.5C, Clinical global impression severity (CGI-S) score distribution for completers group at baseline (BL), visit 2, visit 4, end of treatment (EOT), and final visit (FV) time points (n=26 with two missing participants for FV due to parental illness). Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; CGI-S, clinical global impression severity; CGI-I, clinical global improvement; rACC2, rostral anterior cingulate cortex; BL, baseline; V2, visit 2; V4, visit 4; EOT, end of treatment; FV, final visit. [0054] FIGs.6A-6D. Quantitative values of metabolites in plasma and correlations between urine and plasma metabolite levels. FIG.6A, Metabolite levels in urine that were not altered from baseline (BL), end of treatment (EOT), and final visit (FV) timepoints from the completers group, normalized to creatinine (µg metabolite/mmol creatinine) on log2 scale. Chemical structures shown above associated data panels. Urine from one subject could not be obtained due to incontinence, and two participants did not complete the FV timepoint due to parental illness (BL, EOT n=25; FV n=23). HPPA measured below the limit of quantification in >50% of individuals; no imputation was performed, missing values not shown. FIG.6B, Quantitative values of metabolites in plasma samples at baseline (BL) and end of trial (EOT) timepoints with ng/ml levels (log2 scale) along the y-axis (n=26). FIG.6C, Pearson correlation between plasma (ng/ml) and urine (ug/mmol creatinine) levels for each measured metabolite (n=25). FIG.6D, Quantitative values of control metabolite, N-acetyl serine (N-AS) in urine and plasma samples. Abbreviations: BL, baseline; EOT, end of treatment; HPPA, 3-(4-hydroxyphenyl)propionate; HHA, 3-hydroxyhippurate; CMPF, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate; IPA, imidazolepropionate; 4EPS, 4-ethylphenyl sulfate; pCG, p-cresyl glucuronide; pCS; p-cresyl sulfate; 3IS, 3-indoxyl sulfate; HPHPA, 3-(3-hydroxyphenyl)-3- hydroxypropionate; HPPA, 3- (4-hydroxyphenyl)propionate; HHA, 3-hydroxyhippurate; HPAA, 3-hydroxyphenylacetate; N- AS, N-acetyl serine. Data analysis was conducted on the completers group. Data analysis is exploratory and post hoc in nature, shown as mean and 95% confidence intervals in panels A and C, analyzed by a two-tailed paired t-test or ANOVA with multiple comparisons and false discovery rate correction as appropriate (* p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001) and a Pearson’s correlation in FIG.6B. [0055] FIGs.7A-7E. Altered amygdalar functional connectivity and Vineland Adaptive Behavior Scales (VABS) diagnostic scores. FIG.7A, Functional connectivity between the amygdala and rACC brain regions, assessed by fMRI scans at BL and EOT. VABS test scores at baseline (BL), the end of treatment (EOT), and final visit (FV) timepoints, where a lower score indicates increased severity. Dotted line indicates threshold (≤86) of scores categorized as moderately low and low (n=8). FIGs.7B-7D, Vineland Adaptive Behavior Scales (VABS). FIG. 7B, Composite scores (n=15). FIG.7C, Communication scores (n=15). FIG.7D, Daily living scores (n=15). FIG.7E, Socialization scores (n=15). In each respective left panel, scores of all study participants with valid VABS are shown, with a dotted line marking the threshold of 86 for moderately low and low scoring individuals. Mean increase between BL and EOT timepoints is noted. Abbreviations: rACC, rostral anterior cingulate cortex; BL, baseline; EOT, end of treatment, FV, final visit. Data analysis was conducted on the completers group, but any individual with over 25% estimated answers in any domain was removed. Data analysis is exploratory and post hoc in nature. FIG.7A is a subset of the participants who agreed to fMRI, analyzed by a paired t-test shown, and panels B-E are displayed as mean and 95% confidence intervals with analysis performed by Linear Mixed Effects Analysis with multiple comparisons and false discovery rate correction (* p adj. ≤ 0.05, ** p adj. ≤ 0.01, *** p adj. ≤ 0.001). [0056] FIGs.8A-8J. Extended behavior scores of the social responsiveness scale (SRS) and Aberrant Behavior Checklist (ABC). FIGs.8A-8F, SRS behavior scores (n=24) at baseline (BL), the end of treatment (EOT), and final visit (FV) timepoints for the composite score (FIG.8A), repetitive behavior (FIG.8B), social motivation (FIG.8C), social awareness (FIG.8D), social communication (FIG.8E), and social cognition (FIG.8F) domains. FIGs.8G-8J, ABC behavior scores at BL, EOT, and FV for all individuals for the stereotypic behavior score (BL, EOT, n=26; FV, n=24) (FIG.8G), inappropriate speech (FIG.8H), hyperactivity/noncompliance (FIG. 8I), and social withdrawal (FIG.8J) domains. Dotted lines indicate categorical thresholds for the top quartile among the ASD population. Mean increase between BL and EOT timepoints is noted. Abbreviations: BL, baseline; EOT, end of treatment; FV, final visit. Data analysis was conducted on the completers group minus two subjects who missed assessment due to parental illness. Data analysis is exploratory and post hoc in nature, shown as mean and 95% confidence intervals with statistics for performed by repeated measures one-way ANOVA with multiple comparisons and false discovery rate correction. (* p adj. ≤ 0.05, ** p adj. ≤ 0.01, *** p adj. ≤ 0.001). [0057] FIG.9. Squared Partial Correlation of Change in Score vs. Change in Biomarkers Controlling for Baseline Score ABC-I Assessment. [0058] FIG.10. Squared Partial Correlation of Change in Score vs. Change in Biomarkers Controlling for Baseline Score PARS Assessment. [0059] FIG.11. Models Using Baseline Score + Top (N/3)-1 Specimen/Biomarkers as Covariates Change in Score vs. Change in Biomarkers. [0060] FIG.12. Squared Partial Correlation of Change in Score vs. Baseline Biomarkers Controlling for Baseline Score ABC-I Assessment. [0061] FIG.13. Squared Partial Correlation of Change in Score vs. Baseline Biomarkers Controlling for Baseline Score PARS Assessment. [0062] FIG.14. Models Using Baseline Score + Top (N/3)-1 Specimen/Biomarkers as Covariates Change in Score vs. Baseline Biomarkers. [0063] FIG.15 shows urinary 4-EPS Levels in 4EP+ and 4EP- di-colonized mice. Germfree wild-type C57BL/6 mice were di-colonized at 4 weeks of age by single oral gavage with either the B. ovatus and L. plantarum pair of strains that produces 4-EP or the pair that does not produce 4-EP. High 4-EPS production in vivo with colonization by the 4-EP producing pair (4EP+) and low 4-EPS production with colonization by the 4-EP nonproducing pair (4EP-) were demonstrated via measurement of 4EPS levels in urine at age 5 weeks, prior to providing an AB- 2004 preparation comprising AST-120. [0064] FIG.16 shows that microbiota colonization levels are similar across groups. L. plantarum (left) and B. ovatus (right) achieved similar levels of colonization in mice regardless of whether they produced 4-EP and regardless of whether the mice were provided an AB-2004 preparation. [0065] Figs.17A-17B show that administration of an AB-2004 preparation normalizes repetitive and anxiety-like behaviors. (FIG.17A) Marble burying test of repetitive behavior. (FIG.17B) Elevated plus maze test of exploratory behavior (* indicates p < 0.05, ** indicates p < 0.01. Mean +/- Standard Deviation). [0066] Figs.18A-18C show the results of an Open Field Test. (FIG.18A) Frequency with which mice entered wall area of the open field, as a percentage of total combined entries into the wall area and the center area. (FIG.18B) Total duration in the wall area (seconds). (FIG.18C) Total distance moved during the test (cm). [0067] Figs.19A-19B show the results of a three chamber test of direct social interaction. Time spent in chamber with another mouse by: (FIG.19A) male mice on control diet with microbiota that do not produce 4EP (left bar) and that do produce 4-EP (right bar); and (FIG. 19B) male mice with 4-EP producing microbiota on control diet (left bar) and diet containing an AB-2004 preparation (right bar). (**p<0.01; Mean +/- Standard Error of the Mean shown.) [0068] FIG.20 shows a time course for adsorption of 4-EP by the sequestrants zeolite, bentonite, cellulose (75K), cellulose (15K), and an AB-2004 preparation. At a 1-hour timepoint, the AB-2004 preparation and the cellulose polymers both display >90% sequestration of 4-EP. DETAILED DESCRIPTION [0069] Unusually high intestinal or systemic levels of certain intestinal metabolites, as compared to healthy individuals, can be found in various central nervous system (CNS) diseases and disorders, such as autism spectrum disorder, schizophrenia, an anxiety disorder, depression (also referred to as clinical depression or major depressive disorder), post traumatic stress disorder, Parkinson's Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer’s Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, and/or pure autonomic failure. Reduction of the levels of these intestinal metabolites will lead to alleviation and/or reversal of behavioral and/or other neurological symptoms or conditions, as well as, neurological diseases. Without being bound to any theory, contemplated within the present disclosure are methods and compositions configured to or designed to lower the systemic levels of intestinal metabolites to levels commensurate with (e.g., the same as or lower than) healthy individuals by administering or providing to a subject (e.g., a human, mammal or domestic animal) having such a central nervous system (CNS) disease or disorder associated with raised systemic levels of such intestinal metabolites, a non- absorbable composition, such as a polymer, clay, resin, carbon-based or other chemical moiety, which is capable of or configured to selectively bind intestinal metabolites in the gut thereby alleviating, inhibiting, or mitigating absorption and/or transport of the intestinal metabolites into peripheral tissues. The metabolite-laden composition will then be excreted from the subject in the feces, thereby permanently removing the intestinal metabolites and improving said CNS symptoms, diseases and/or disorders in said subject. Certain intestinal metabolites (e.g., 4- ethylphenol (4-EP) and p-cresol (PC)) have been identified as being correlated with and are believed to be causal of neurodevelopmental and behavioral disorders such as ASD. These metabolites may gain adventitious entry into systemic circulation through the "leaky gut" comorbidity often associated with such disorders. Once in systemic circulation these metabolites may act directly on relevant metabolic and signaling pathways to contribute to disease progression, systems and/or pathology. In addition, metabolites can be further metabolized by normal host processes to create new metabolites (e.g., 4-EPS and PCS) that can have adverse neurological effects, as well. [0070] Thus, as disclosed in the experimental examples below,improvements in multiple exploratory behavioral endpoints, most significantly in post-hoc analysis of anxiety and irritability, as well as gastrointestinal health after 8 weeks of treatment after 8 weeks of treatment with AB-2004 was observed in open-label study (trial registration# ACTRN12618001956291). AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug- related serious adverse events were identified. Moreover, significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement.. [0071] By sequestering these metabolites at the source of their production, e.g., in the gut of the subject, the translocation of the intestinal metabolites into peripheral tissues will be minimized or eliminated. The net effect is the minimization of the impact of these metabolites and their further metabolites on the subject. Using a non-absorbable material, such as a biocompatible polymer or an activated carbon preparation such as an AB-2004 preparation, the target metabolites are permanently removed through normal passage through and excretion from the gut. [0072] Some alternatives of the methods described herein comprise methods of diagnosing, predicting, treating, inhibiting, or ameliorating a neurological disorder associated with an alteration in the intestinal microbiome of a subject, such as a human, mammal, or domestic animal, wherein said methods comprise administering or providing to said subject a composition, which sequesters said intestinal metabolites (and host-generated modifications of these metabolites), wherein said composition having sequestered intestinal metabolites is eliminated from the gastrointestinal tract without being metabolized. In some embodiments, the method further comprises the step of identifying and/or selecting a subject having elevated levels of one or more intestinal metabolites (and host-generated modifications of these metabolites). According to some embodiments, the methods described herein may comprise methods of treating, inhibiting, or ameliorating leaky gut or leaky gut symptoms associated with said one or more neurological disorders. According to some embodiments, the methods described herein may comprise methods of treating, inhibiting, or ameliorating leaky gut or leaky gut symptoms not associated with said one or more neurological disorders. According to some embodiments, the methods described herein may comprise methods of treating, inhibiting, or ameliorating one or more neurological disorders independent of any effect on leaky gut or leaky gut symptoms. DEFINITIONS [0073] All scientific and technical terms used herein, unless otherwise defined below, are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of any conflict, the present specification, including definitions, will control. References to techniques employed herein are intended to refer to the techniques as commonly understood in the art, including variations on those techniques or substitutions of equivalent or later-developed techniques which would be apparent to one of skill in the art. In order to more clearly and concisely describe the subject matter which is the invention, the following definitions are provided for certain terms which are used in the specification and appended claims. [0074] As used herein, “a,” “an,” or “the” can mean one or more than one. For example, “a” symptom or “a” metabolite can mean a single symptom or metabolite or a multiplicity of symptoms or metabolites. [0075] As used herein, the recitation of a numerical range for a variable is intended to convey that the present disclosure may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values ≧0 and ≦2 if the variable is inherently continuous. [0076] As used herein, “gastrointestinal tract” means the part of a subject’s digestive or enteric system that comprises the stomach and intestines. The intestines include the small intestine, which comprises duodenum, jejunum, and ileum, and the large intestine, which comprises the colon, rectum, and anal canal. The colon comprises cecum, ascending colon, transverse colon, descending colon, and sigmoid colon. [0077] As used herein, when referring to the term “intestinal dysbiosis” means an imbalance or maladaptation of the flora or microbiota within the gut or intestines, and particularly the small intestine. Such dysbiosis is characterized by a change in the composition of the intestinal or gut microbiome, in terms of the species/strains which are present and/or the relative abundance or proportion of the species/strains which are present, in which the change has a deleterious effect on the host organism. The deleterious effect on the host organism can result from microbiome- mediated changes in electrolyte balance, biofilm formation, integrity of the barrier formed by the intestinal epithelial lining, or the release from the microbiome of metabolites which are directly (e.g., as toxicity or effectors) or indirectly (e.g., as pre-cursors to toxins or effector) injurious to the health of the host. [0078] As used herein, the term "intestinal hyperpermeability" means abnormal increased permeability of the barrier formed by the intestinal epithelial lining between the intestinal lumen and the surrounding issues. Such hyperpermeability may result from inflammation of the intestinal lining and/or failure of the tight junctions between cells of the intestinal epithelium, which allows the passage of substances from the lumen into the surrounding tissues where some may enter the peritoneal cavity and/or systemic circulation. Because of this leakage of substances from the gut or intestinal lumen, intestinal hyperpermeability may be referred to as "leaky gut" or "leaky gut syndrome." [0079] As used herein, a “intestinal metabolite” refers to a metabolite found in a subject’s gut (that is ingested by a subject, produced by the subject’s gastrointestinal tract, or produced by a microorganism in the subject’s gastrointestinal tract). [0080] As used herein, an “accumulation of an intestinal metabolite” refers to an increased level of one or more intestinal metabolites relative to an accepted standards or relative to levels in a reference group of individuals, e.g., healthy individuals, or individuals that do not suffer from the relevant neurological disease, intestinal hyperpermeability, or intestinal dysbiosis from which the subject suffers. The level of one or more metabolites relative to the level in a reference group may be increased by at least 5% (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% or more) or by at least 1.5-fold (e.g., at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold or more).As used herein with respect to sequestrant compositions, the term “biocompatible” means that the sequestrant composition does not have clinically significant toxic or injurious effects, locally or systemically, when administered orally or otherwise introduced into the gastrointestinal tract. The term “biocompatible” does not exclude the possibility that a sequestrant composition may affect the passage of partially digested food (e.g., chyme, chyle, feces) through the intestines or induce some degree of diarrhea, constipation, flatulence, cramping or discomfort. [0081] As used herein with respect to sequestrant compositions, the term “indigestible” means that the sequestrant composition is substantially resistant to degradation in the environment of the gastrointestinal tract such that at least 50%, and preferably more than 60%, 70%, 80% 90% or 95% of the sequestrant composition by weight is present in bulk (e.g., particulate, granular, fibrous) and not dissolved form when eliminated from the rectum. [0082] As used herein with respect to sequestrant compositions, the term “non-absorbable” means that the sequestrant composition is substantially incapable of being absorbed by the lining of the gastrointestinal epithelium such that less than 25%, and preferably less than 20%, 15%, 10%, 5% or 1% of the sequestrant composition by weight is absorbed by the gastrointestinal epithelium. [0083] As used herein with respect to metabolites and symptoms or disorders, the term “associated” means that the presence or level of a metabolite has been statistically significantly correlated (at least p < 0.05, preferably p < 0.01 or p < 0.001) with the presence or degree of the symptom or disorder, and/or that the metabolite or a reaction product of the metabolite has been causally or mechanistically related to the development, maintenance or degree of the symptom or disorder. [0084] As used herein, the term “autism spectrum disorder” or “ASD” means a neurological and developmental disorder that typically begins early in childhood and has a range of symptoms including: impaired social interactions; a disturbance in the comprehension of language; impaired and delayed verbal and written communication; restricted repetitive and stereotyped patterns of behavior, interests and activities; hyperactivity; short attention span; impulsivity; aggressiveness; self-injurious behaviors, tremors, paralysis, repetitive behaviors, communicative symptoms, cognitive disorders, stereotyped behaviors, attachment to physical objects, aphasia, obsessive behaviors, unusual or inappropriate body language, gestures, and/or facial expressions and/or sensorimotor issues, lack of interest in other people, lack of empathy, difficulty grasping nonverbal cues, touch aversion, difficulty in socialization, lack of social motivation, lack of social awareness, lack of social communication, lack of social cognition, inappropriate speech, hyperactivity/noncompliance, social withdrawal, speech delays, abnormal vocal tone or pitch, vocal repetition, perseveration, conversational difficulty, difficulty communicating needs or desires, inability to understand simple statements or questions, difficulties in processing language subtext, obsessive attachment to unusual objects, preoccupation, intolerance of changes in routine or environment, clumsiness, abnormal posture, odd ways of moving, fascination with particular objects, hyper- or hypo-reactivity to sensory input, and clinical irritability; and, particularly in young children, temper tantrums. ASD, under DSM-IV, was understood to include disorders previously identified as distinct: Autistic Disorder, Asperger’s Disorder and Pervasive Developmental Disorder (Not Otherwise Specified). See, for example, The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Washington, D.C., American Psychiatric Association, 1994 (“DSM-IV”). Disorders related to ASD include Rett Syndrome and Childhood Disintegrative Disorder. ASD is now, under DSM-V, understood exclude Asberger’s syndrome and Rett Syndrome. In any case, compositions and methods disclosed herein can be used to treat Asberger’s syndrome and/or Rett Syndrome. [0085] As used herein, the term “anxiety disorder” means a disorder characterized by an abnormal state of worry or fear, and includes subtypes such as acute stress disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder, selective mutism, or separation anxiety. Symptoms of anxiety vary depending on the type of anxiety experienced. The term “clinical anxiety” means an abnormally intense and disruptive level of anxiety, which is distinctly above normal levels of anxiety associated with a stressful situation. Clinical anxiety can be associated with any of the disorders listed above, or can be secondary to or symptomatic of another neurological disorder such as autism spectrum disorder (ASD) or schizophrenia. See, generally, DSM-IV, pages 393- 444. [0086] As used herein, the term “irritability” or “clinical irritability” means an abnormally intense and disruptive level of irritability, including a tendency to be easily annoyed, upset or provoked to anger, which is distinctly above normal levels of irritability associated with an unpleasant or stressful situation. Clinical irritability can be associated with disorders including, without limitation, generalized anxiety disorder, autism spectrum disorders (ASD), post- traumatic stress disorder, attention-deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), manic disorders, Alzheimer’s Disease, borderline personality disorder, antisocial personality disorder, and schizoaffective disorder, or can be secondary to or symptomatic of another neurological disorder. Irritability can be measured clinically in humans using the Aberrant Behavior Checklist as described in Marcus et al. (2009), J. Am. Acad. Child Adolesc. Psychiatry, 48(11):1110-1119, and in Aman and Singh, Aberrant Behavior Checklist: Manual. East Aurora, NY: Slosson Educational Publications; 1986. In some embodiments, clinical irritability is associated with a neurological disorder associated with intestinal hyperpermeability or intestinal dysbiosis. In some embodiments, clinical irritability is associated with a neurological disease, e.g., irritability associated with ASD. In some embodiments, symptoms of clinical irritability include self-injury, tantrums, overt aggression, inconsolability, and/or need for self-isolation. [0087] As used herein, the term “depression,” “clinical depression,” and “major depressive disorder” are synonymous, and refers to a mood disorder with an abnormal and persistent feeling of sadness and loss of interest. Symptoms of depression may include mental as well as physical manifestations and may be episodic, occurring one more times in a person’s life. An episode of depression may include symptoms that occur most of the day, nearly every day. Mental symptoms may include feelings of sadness, emptiness, guilt, and/or hopelessness, anxiety, tiredness, trouble concentrating, and having suicidal thoughts. Physical symptoms may include unexplained back pain or headaches, reduced appetite and weight loss. [0088] As used herein, the term “ post traumatic stress disorder” (PTSD) refers to abnormal difficulty recovering from a terrifying event, observation, or experience, with symptoms that last more than one month and are sever enough to interfere with relationships or work. In some embodiments, a diagnosis of PTSD includes all of the following for at least one month: at least one re-experiencing symptom (e.g., flashbacks, bad dreads, or frightening thoughts), at least one avoidance symptom (e.g., staying away from places, events or objects that are reminders of the traumatic event/experience, or avoiding thoughts or feelings related to the traumatic event/experience), at least two arousal and reactivity symptom (e.g., being easily startled, feeling tense or on-edge, difficulty sleeping, or having angry outbursts), and at least two cognition and mood symptoms (e.g., trouble remembering key features of the traumatic event, distorted feelings such as guilt or blame, or loss of interest in enjoyable activities). [0089] As used herein, the term “social motivation” refers to a normal need to interact or engage with other people, and in some embodiments, also includes the need to be accepted by them. Social motivation may be manifested by, for example, a preference for being alone than with others. It can be assessed as part of tests such as Social Responsiveness Scale (SRS-2) ⁵⁶. [0090] As used herein, the term “social awareness” refers to a subject’s ability to comprehend what others are thinking or feeling, or broad problems of society and interpersonal struggles. In some embodiments, it also includes a subject’s ability to appropriately react to what others are thinking or feeling, or broad problems of society and interpersonal struggles. It can be assessed as part of tests such as Social Responsiveness Scale (SRS-2) ⁵⁶. [0091] As used herein, the term “social communication” refers to the use of communication skills in a social context. It can include use of verbal skills and/or non-verbal skills. In some embodiments, social communication may be assessed by observing whether a subject abnormally avoids eye contact or has unusual eye contact. It can be assessed as part of tests such as Social Responsiveness Scale (SRS-2) ⁵⁶. [0092] As used herein, the term “social cognition” refers to the ability to process social signals that enable learning of a subject’s environment, e.g., other people around them. Social signals may include facial expressions, such as fear and disgust, and eye gaze direction. See, e.g., Firth CD (2008), “Social Cognition”, (Philos Trans R Soc Lond B Biol Sci.; 363(1499): 2033–2039). Social cognition may be assessed by determining whether a subject is able to recognize when others are trying to take advantage of the subject. It can be assessed as part of tests such as Social Responsiveness Scale (SRS-2) ⁵⁶ [0093] As used herein, the term “inappropriate speech” refers to aberrant speech with respect to one or more of the following qualities: excessive talking, repetitive speech, talking to self aloud, and repeats words or phrases. Inappropriate speech can be assessed, in some embodiments, as part of tests such as Anxiety Rating Scale (ABC) ⁵⁵. See, e.g., Aman and Singh (1985, American Journal of Mental Deficiency; 89:492–502), and Schmidt et al. (2013, “An Evaluation of the Aberrant Behavior Checklist for Children Under Age 5”; Res Dev Disabil.; 34(4): 1190–1197) for methods and assessing inappropriate speech. [0094] As used herein, the term “hyperactivity/noncompliance” refers to abnormal levels of one or more of the following behaviors/qualities: excessively active, boisterous, impulsive, restless, disobedient, disturbs others, uncooperative, does not attend to instructions, and disrupts group activities. See e.g., Aman and Singh (1985, American Journal of Mental Deficiency.; 89:492–502), and Schmidt et al. (2013, “An Evaluation of the Aberrant Behavior Checklist for Children Under Age 5”; Res Dev Disabil.; 34(4): 1190–1197) for methods of assessing hyperactivity/noncompliance. [0095] As used herein, the term “social withdrawal” refers to abnormal levels of one or more of the following behaviors/qualities: listless or sluggish, seeks isolation, preoccupied, withdrawn, fixed facial expressions, sits and watches others, resists physical contact, isolates self, and sits and stands in one position. See e.g., Aman and Singh (American Journal of Mental Deficiency. 1985;89:492–502), and Schmidt et al. (An Evaluation of the Aberrant Behavior Checklist for Children Under Age 5; Res Dev Disabil.2013 Apr; 34(4): 1190–1197) for methods of assessing social withdrawal. [0096] As used herein, the term “repetitive behaviors” refers to abnormal levels of one or more of the following behaviors characterized by repetition and invariance: stereotyped behavior, self-injurious behavior, compulsive behavior, routine behavior, sameness behavior, and restricted behavior. It may be determined using a repetitive behavior tests, e.g., the Repetitive Behavior Scale Revised (RBS-R) test (Lam and Aman, 2007 “The Repetitive Behavior Scale- Revised: independent validation in individuals with autism spectrum disorders”, J Autism Dev Disord.;37(5):855-66.). Such test may be multi-factorial, assessing e.g., five factors: Stereotyped Behaviors, Self-injurious Behavior (SIB), Compulsive Behavior, Ritualistic Sameness Behaviors, and Restricted Behaviors (see, e.g., Hooker et al., (2019), Autism Res.; 12(9): 1399– 1410) or two factors: Compulsive-Ritualistic-Sameness-Restricted Behaviors and Stereotyped- Self-Injurious Behavior (see, e.g., Georgiades et al. (2010), Journal of Autism and Development Disorders, 40, 903–906). Table 4 of Bishop et al. ((2013), J Autism Dev Disord.; 43(6): 1287– 1297)) provides measures of stereotyped behavior, self-injurious behavior, compulsive behavior, routine behavior, sameness behavior, and restricted behavior, and is incorporated herein by reference in its entirety. [0097] As used herein, the term “communicative symptoms” refers to abnormalities in social communication, language (e.g., reduced vocabulary and limited sentence structure, struggle to form complete meaningful sentences, and difficulty grasping grammar), speech and sound (e.g., difficulty with articulation or phonological difficulties), and/or fluency (e.g., stuttering). [0098] As used herein, the term “cognitive symptoms” refers to symptoms typically associated with cognitive disorders, such as confusion, poor motor coordination, loss of short- or long-term memory, identity confusion, and impaired judgement. [0099] As used herein, the term “anxiety” or “clinical anxiety” refers to abnormal emotion characterized by apprehension and somatic symptoms of tension in which an individual anticipates impending danger, catastrophe, or misfortune. Somatic symptoms may include tense muscles, fast breathing, and increase in blood pressure. Anxiety is considered a future-oriented, long-acting response broadly focused on a diffuse threat, and is distinguished from fear or normal emotion that is an appropriate, present-oriented, and short-lived response to a clearly identifiable and specific threat. “Subject” as used herein, refers to a human or a non-human mammal (e.g., a dog or horse) selected or identified for removal or reduction of one or more intestinal or selected or identified for diagnosing or treatment of a neurological disease or neurological disorder, or any symptom thereof, associated with an alteration in the intestinal microbiome, including without limitation autism spectrum disorder (ASD), schizophrenia, an anxiety disorder, depression, Parkinson's Disease, Fragile X, Rett Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, pure autonomic failure, Alzheimer’s Disease, or any combination thereof. “Subject suspected of having” refers to a subject exhibiting one or more clinical indicators of a disease or condition. In certain embodiments, the disease or condition may comprise one or more of autism spectrum disorder, an anxiety disorder, Fragile X, Rett syndrome, tuberous sclerosis, obsessive compulsive disorder, attention deficit disorder, and/or schizophrenia. A subject suspected of having ASD, in some embodiments, meets one or more criteria as presented in Table 2. In some embodiments, a subject is determined to be exhibiting one or more clinical indicators of a disease, disorder, or condition by meeting the requirements for such a determination of one or more of many tests such as Pediatric Anxiety Rating Scale (PARS), Pediatric Anxiety Rating Scale (ABC) ⁵⁵, Social Responsiveness Scale (SRS-2) ⁵⁶, Repetitive Behavior Scale Revised (RBS-R) ⁵⁷, and Vineland Adaptive Behavior Score (VABS-3) ⁵⁸. In some embodiments, a subject a subject is determined to be exhibiting one or more clinical indicators of a disease, disorder, or condition by meeting the requirements for tests that assess gastrointestinal discomfort or abnormalities. Non-limiting tests that assess gastrointestinal discomfort or abnormalities include Bristol Stool Scale (BSS)⁵⁹, and Gastrointestinal Symptom Rating Scale tool (GSRS)⁶⁰. It should be understood that any of the tests for assessment of neurological or behavioral symptoms or gastrointestinal symptoms that are disclosed in the Example section below can be used to assess subject. In some embodiments, functional connectivity, e.g., amygdalar functional connectivity (see Example section) can be used to assess symptoms associated with any one of the neurological diseases as disclosed herein. “Subject in need thereof” refers to a subject selected or identified as one being in need of a composition that removes or sequesters one or more intestinal metabolites (and host-generated modifications of these metabolites) or one in need of a treatment, inhibition, amelioration of a neurological disease or neurological disorder associated with an alteration in the intestinal microbiome such as autism spectrum disorder (ASD), an anxiety disorder, Parkinson's Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer’s Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, pure autonomic failure, or any combination thereof. [0100] As used herein, “to treat” or “treatment” means to reduce, ameliorate, inhibit, or eliminate the frequency or severity of one or more symptoms of a disease or disorder, or to provide a therapeutic effect. “Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as tissue damage). In some embodiments, a subject experiences a therapeutic effect comprising an improvement in one or more behavioral symptoms of a neurological disease associated with intestinal hyperpermeability, intestinal dysbiosis, or accumulation of one or more intestinal metabolites. In some embodiments, the improvement is at least 15% as measured by a test, e.g., PARS, ABS, SRS-2, RBS-R, or VABS-3. In some embodiments, any one of the treatment methods described herein applied to a subject having or suspected of having ASD results in at least 15% (e.g., at least 15%, at least 20%, at least 30%, at least 40%, or at least 50% or more) improvement as measured by PARS. In some embodiments, any one of the treatment methods described herein applied to a subject having or suspected of having ASD results in at least 5-point (e.g., at least 5-point, at least 6-point, at least 7-point, at least 8-point, at least 9- point, at least 10-point) decrease in ABC (e.g., ABC-I). [0101] “Amelioration” refers to a lessening of severity of at least one indicator of a condition or disease. In certain embodiments, amelioration includes a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of indicators can be determined by subjective or objective measures which are described herein or known to those skilled in the art. [0102] “Modulation" refers to a perturbation of function or activity. In certain embodiments, modulation refers to an increase in gene expression. In certain embodiments, modulation refers to a decrease in gene expression. In certain embodiments, modulation refers to an increase or decrease in total serum levels of a specific protein. In certain embodiments, modulation refers to an increase or decrease in free serum levels of a specific protein. In certain embodiments, modulation refers to an increase or decrease in total serum levels of a specific non-protein factor, e.g., a metabolite. In certain embodiments, modulation refers to an increase or decrease in free serum levels of a specific non-protein factor. In certain embodiments, modulation refers to an increase or decrease in total bioavailability of a specific protein. In certain embodiments, modulation refers to an increase or decrease in total bioavailability of a specific non-protein factor. [0103] SEQUESTRANT PREPARATIONS [0104] In some embodiments, the compositions to be administered according to the methods described herein may comprise, consist essentially of, or consist of one or more of activated carbon, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a zeolite, a polymer, or a resin. In some embodiments, a polymer is a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate polymer, a polyglucosamine polymer, a cholestyramine polymer, a tetraethylenepentamine polymer, a boronic acid-presenting polymer, or a catechin-presenting polymer. In some embodiments, a polymer is an antibody, e.g., a plastic antibody. In some embodiments, a polymer is one made via molecular imprinting. See, e.g., Okishima et al. (2019), Biomacromolecules 20(4):1644-1654. In some embodiments, a resin is a phenolic resin or an ion exchange resin. In some embodiments, the compositions to be administered according to the methods described herein may comprise, consist essentially of, or consist of one or more of an adsorbent, polymer, clay or resin, wherein said adsorbent, polymer, clay or resin may further comprise an activated carbon, an apatite or hydroxyapatite, a kaolin, a bentonite, a pectin, a cellulose polymer, an ion exchange resin, a cholestyramine polymer, a tetraethylenepentamine polymer, a phenolic resin, a boronic acid-presenting polymer, a catechin-presenting polymer, a zeolite, and/or a nanoparticle, or any combination thereof. [0105] In some embodiments, according to the methods of the present disclosure, the sequestrant composition to be administered comprises, consists essentially of, or consists of a carbon material or activated carbon material. Said carbon materials or activated carbon materials have average particle sizes of 5-40 nm, 25-100 nm, 50-300 nm, 150-500 nm, 300 nm-1 µm, 0.5 µm-2 µm, 1 µm-5 µm, 2.5-10 µm, 6-20 µm, 15-50 µm, 30-100 µm, 75-150 µm, 100-300 µm, 250-500 µm, 300-750 µm, 600 µm-1 mm, or greater than 1 mm or a size that is within a range defined by any two of the aforementioned sizes. In some embodiments, said carbon materials or activated carbon materials have particle sizes of 300 µm-1 mm, 1-3 mm, 2-5 mm, or greater than 5 mm or a size that is within a range defined by any two of the aforementioned sizes. Said carbon materials or activated carbon materials also comprise a plurality of pores and a specific surface area in the range of from 20 m²/g to 5000 m²/g, such as, e.g., 20, 50, 100, 250, 500, 750, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 m²/g or a specific surface area within a range defined by any two of the aforementioned surface areas. Specific surface area can be determined using known methods, such as, for example, the method of Bruanauer, Emmett and Teller (J. Am. Chem. Soc. (1938), 60:309-311) and/or mercury porosimetry. See, e.g., ASTM Test Methods D3663, D6556, and D4567, each of which is incorporated by reference in its entirety. [0106] Said carbon materials or activated carbon materials may additionally have a specific pore volume (determined on the basis of pores having a diameter of 1.7 nm to 100 nm) that is from 0.1 cm³/g to 1.5 cm³/g, from 0.1 cm³/g to 0.8 cm³/g, from 0.1 cm³/g to 0.7 cm³/g, from 0.1 cm³/g to 0.6 cm³/g, from 0.1 cm³/g to 0.5 cm³/g, from 0.2 cm³/g to 0.8 cm³/g, from 0.2 cm³/g to 0.7 cm³/g, from 0.2 cm³/g to 0.6 cm³/g, from 0.2 cm³/g to 0.5 cm³/g, from 0.3 cm³/g to 1 cm³/g, from 0.3 cm³/g to 0.9 cm³/g, from 0.3 cm³/g to 0.8 cm³/g, from 0.3 cm³/g to 0.7 cm³/g, from 0.3 cm³/g to 0.6 cm³/g, or from 0.3 cm³/g to 0.5 cm³/g or within a range defined by any two of the aforementioned values, as measured by a method for determining pore diameters and specific pore volumes, such as that described in Barrett, Joyner and Halenda (1951), J. Am. Chem. Soc. 73:373-380 and ASTM D4222-03 (2008) (the method referred to herein as the "BJH method"), both of which are expressly incorporated herein by reference in their entireties, and by the method of mercury porosimetry (e.g., using a mercury porosimeter, such as, for example, the Micromeritics Autopore V 9605 Mercury Porosimeter (Micromeritics Instrument Corp., Norcross, GA) in accordance with the manufacturer's instructions). See e.g., ASTM 3663, ASTM D-4284-12 and D6761-07 (2012), all of which are incorporated herein by reference. Said carbon material or activated carbon material may further have a mean pore diameter in the range of from 2 nm to 100 nm, as measured by the BJH method and/or mercury porosimetry. More typically, the carbon material or activated carbon material may have a mean pore diameter in the range of from 2-5 nm, from 3-9 nm, from 6-15 nm, from 10 nm to 90 nm or a size that is within a range defined by any two of the aforementioned sizes, as measured by the BJH method and/or mercury porosimetry. In some embodiments, the mean pore diameter is in the range of from 10 nm to 80 nm, or from 10 nm to 70 nm, or from 10 nm to 60 nm, and often from 10 nm to 50 nm or a size that is within a range defined by any two of the aforementioned sizes, as determined by the BJH method and/or mercury porosimetry. In some embodiments, the mean pore diameter is in the range of from 20 nm to 100 nm or a size that is within a range defined by any two of the aforementioned sizes, as measured by the BJH method and/or mercury porosimetry. In certain of these embodiments, the mean pore diameter is in the range from 20 nm to 90 nm, or from 20 nm to 80 nm, or from 20 nm to 70 nm, or from 20 nm to 60 nm, or from 10 nm to 50 nm or a size that is within a range defined by any two of the aforementioned sizes, as determined by the BJH method and/or mercury porosimetry. [0107] In some embodiments, the methods of the present disclosure contemplate the administration of an adsorbent comprising an AB-2004 preparation. As used herein, the term “AB-2004” or “AB-2004 preparation” refers to a preparation of spherical activated carbon particles (a) having a minimum average specific surface area determined by the Brunauer- Emmett-Teller (BET) method of at least 500 m²/g, at least 600 m²/g, at least 700 m²/g, or at least 800 m²/g and a maximum average specific surface area determined by the Brunauer-Emmett- Teller (BET) method less than 2000 m²/g, less than 3000 m²/g, or less than 4000 m²/g, and/or a minimum average specific surface area determined by Langmuir's adsorption equation of at least 500 m²/g, at least 1000 m²/g or at least 2000 m²/g; and (b) having a minimum average particle diameter of at least 0.005, at least 0.01 mm, at least 0.05 mm, and a maximum average particle diameter of less than 1.5 mm, less than 1 mm, or less than 0.2 mm. In some embodiments, the AB-2004 preparation comprises activated charcoal particles comprising not less than 0.5 wt % nitrogen atoms. Said spherical activated carbon can be prepared using a thermoplastic resin, thermosetting resin, or ion exchange resin containing nitrogen atoms, as a carbon source; where said thermoplastic resin or ion exchange resin may contain a monomer selected from the group consisting of acrylonitrile, ethylacrylonitrile, methylacrylonitrile, diphenylacrylonitrile, and chloroacrylonitrile; and said thermosetting resin may contain a monomer selected from the group consisting of melamine and urea. Said spherical activated carbon may further be surface- unmodified, and may have a total acidic group content from 0.40 to 1.00 meq/g, less than 0.40 meq/g (but not zero), less than 0.30 meq/g (but not zero), and/or a total amount of basic groups from 0.40 to 1.10 meq/g. Alternatively, said spherical activated carbon can be surface modified, for example by oxidation, which can be performed in an atmosphere containing from 0.1 vol % to 50 vol % oxygen, from 1 vol % to 30 vol %, or from 3 vol % to 20 vol %; at a temperature from 300° C to 800° C or from 320° C to 600° C. Said spherical activated carbon can be further modified, or may alternatively be surface modified by other procedures, for example by reduction, which can be performed at a temperature from 800° C to 1200° C or from 800° C to 1000° C. [0108] Exemplary carbon/activated carbon materials, also known as “activated charcoal,” that are useful in the manufacture of non-absorbable spherical particle preparations, including AB- 2004 preparations, are available from numerous manufacturers, including Kureha Corporation (Japan), Aditya Birla Group (India), Orion Engineered Carbons S.A. (Luxembourg), Asbury Graphite Mills, Inc. (Asbury, NJ), Cabot Corporation (Boston, MA), Continental Carbon Company (Houston, TX), Sid Richardson Carbon & Energy Co. (Fort Worth, TX) and Imerys Graphite and Carbon (Switzerland). Various activated carbon/activated carbon products from these and other manufacturers can either be used in AB-2004 preparations, or can be adapted or modified for use in AB-2004 preparations. [0109] Methods for producing a spherical activated carbon, including certain spherical activated carbon AB-2004 preparations of the invention, can be found in U.S. Patent No. 9,877,987, U.S. Patent No.8,309,130, U.S. Patent No.7,651,974, U.S. Patent No.4,761,284 and U.S. Patent No.4,681,764, each of which is hereby expressly incorporated by reference in its entirety, and especially with respect to the disclosure of methods of making spherical activated carbon compositions and the spherical activated carbon compositions made thereby. [0110] In some embodiments, according to the methods of the present disclosure, the sequestrant composition may comprise one or more of activated carbon, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a zeolite, a polymer, or a resin. In some embodiments, a polymer is a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate polymer, a polyglucosamine polymer, a cholestyramine polymer, a tetraethylenepentamine polymer, a boronic acid-presenting polymer, or a catechin-presenting polymer. In some embodiments, a polymer is an antibody, e.g., a plastic antibody. In some embodiments, a polymer is one made via molecular imprinting. See, e.g., Okishima et al. (2019), Biomacromolecules 20(4):1644-1654. In some embodiments, a resin is a phenolic resin or an ion exchange resin. In some embodiments, according to the methods of the present disclosure, the sequestrant composition may comprise one or more of an apatite or hydroxyapatite. Said apatite or hydroxyapatite may have average particle sizes of 5-40 nm, 25- 100 nm, 50-300 nm, 150-500 nm, 300 nm-1 µm, 0.5 µm-2 µm, 1 µm-5 µm, 2.5-10 µm, 6-20 µm, 15-50 µm, 30-100 µm, 75-150 µm, 100-300 µm, 250-500 µm, 300-750 µm, 600 µm-1 mm, or greater than 1 mm or a size that is within a range defined by any two of the aforementioned sizes. In some embodiments, said apatite or hydroxyapatite may have particle sizes of 300 µm-1 mm, 1-3 mm, 2-5 mm, or greater than 5 mm or a size that is within a range defined by any two of the aforementioned sizes. Said apatite or hydroxyapatite may also comprise a plurality of pores and a specific surface area in the range of from 20 m²/g to 500 m²/g, such as, e.g., 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 m²/g or a specific surface area within a range defined by any two of the aforementioned surface areas. Specific surface area can be determined using known methods, such as, for example, the method of Bruanauer, Emmett and Teller and/or mercury porosimetry, as above. [0111] An apatite or hydroxyapatite sequestrant may additionally have a specific pore volume (determined on the basis of pores having a diameter of 1.7 nm to 100 nm) that is from 0.1 cm³/g to 1.5 cm³/g, from 0.1 cm³/g to 0.8 cm³/g, from 0.1 cm³/g to 0.7 cm³/g, from 0.1 cm³/g to 0.6 cm³/g, from 0.1 cm³/g to 0.5 cm³/g, from 0.2 cm³/g to 0.8 cm³/g, from 0.2 cm³/g to 0.7 cm³/g, from 0.2 cm³/g to 0.6 cm³/g, from 0.2 cm³/g to 0.5 cm³/g, from 0.3 cm³/g to 1 cm³/g, from 0.3 cm³/g to 0.9 cm³/g, from 0.3 cm³/g to 0.8 cm³/g, from 0.3 cm³/g to 0.7 cm³/g, from 0.3 cm³/g to 0.6 cm³/g, or from 0.3 cm³/g to 0.5 cm³/g or within a range defined by any two of the aforementioned values, as measured by a method for determining pore diameters and specific pore volumes, such as the BJH method, or by mercury porosimetry, as above. Said apatite or hydroxyapatite sequestrants may further have a mean pore diameter in the range of from 10 nm to 100 nm, as measured by the BJH method and/or mercury porosimetry. More typically, the apatite or hydroxyapatite sequestrant may have a mean pore diameter in the range of from 2 nm to 90 nm, as measured by the BJH method and/or mercury porosimetry. In some embodiments, the mean pore diameter is in the range of from 2-5 nm, from 3-9 nm, from 6-15 nm, from 10 nm to 80 nm, or from 10 nm to 70 nm, or from 10 nm to 60 nm, and often from 10 nm to 50 nm or a size that is within a range defined by any two of the aforementioned sizes, as determined by the BJH method and/or mercury porosimetry. In some embodiments, the mean pore diameter is in the range of from 20 nm to 100 nm, as measured by the BJH method and/or mercury porosimetry. In certain of these embodiments, the mean pore diameter is in the range from 20 nm to 90 nm, or from 20 nm to 80 nm, or from 20 nm to 70 nm, or from 20 nm to 60 nm, or from 10 nm to 50 nm or a size that is within a range defined by any two of the aforementioned sizes, as determined by the BJH method and/or mercury porosimetry. Exemplary forms of apatite or hydroxyapatite sequestrants include milled particles, spray dried particles, spherical nanoparticles, and spherical microparticles. [0112] In some embodiments according to the methods of the present disclosure, the sequestrant compositions may comprise, consist essentially of, or consist of one or more of an ingestible porous silica compound (e.g., calcium silica hydrate), such as the Micro-Cel E^TM product (Imerys Graphite and Carbon, Bironico Switzerland). In some embodiments, according to the methods of the present disclosure, the sequestrant composition comprises an ingestible porous silica compound. Said ingestible porous silica compound may have average particle sizes of 5-40 nm, 25-100 nm, 50-300 nm, 150-500 nm, 300 nm-1 µm, 0.5 µm-2 µm, 1 µm-5 µm, 2.5- 10 µm, 6-20 µm, 15-50 µm, 30-100 µm, 75-150 µm, 100-300 µm, 250-500 µm, 300-750 µm, 600 µm-1 mm, or greater than 1 mm or a size that is within a range defined by any two of the aforementioned sizes. In some embodiments, said ingestible porous silica compound may have particle sizes of 300 µm-1 mm, 1-3 mm, 2-5 mm, or greater than 5 mm or a size that is within a range defined by any two of the aforementioned sizes. Said ingestible porous silica compound may also comprise a plurality of pores and a specific surface area in the range of from 20 m²/g to 500 m²/g, such as, e.g., 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 m²/g or a specific surface area within a range defined by any two of the aforementioned surface areas. Specific surface area can be determined using known methods, such as, for example, the method of Bruanauer, Emmett and Teller and/or mercury porosimetry, as above. [0113] Said ingestible porous silica compound may additionally have a specific pore volume (determined on the basis of pores having a diameter of 1.7 nm to 100 nm) that is from 0.1 cm³/g to 1.5 cm³/g, from 0.1 cm³/g to 0.8 cm³/g, from 0.1 cm³/g to 0.7 cm³/g, from 0.1 cm³/g to 0.6 cm³/g, from 0.1 cm³/g to 0.5 cm³/g, from 0.2 cm³/g to 0.8 cm³/g, from 0.2 cm³/g to 0.7 cm³/g, from 0.2 cm³/g to 0.6 cm³/g, from 0.2 cm³/g to 0.5 cm³/g, from 0.3 cm³/g to 1 cm³/g, from 0.3 cm³/g to 0.9 cm³/g, from 0.3 cm³/g to 0.8 cm³/g, from 0.3 cm³/g to 0.7 cm³/g, from 0.3 cm³/g to 0.6 cm³/g, or from 0.3 cm³/g to 0.5 cm³/g or within a range defined by any two of the aforementioned values, as measured by a method for determining pore diameters and specific pore volumes, such as the BJH method, or by mercury porosimetry, as above. Said ingestible porous silica compound may further have a mean pore diameter in the range of from 2 nm to 100 nm, as measured by the BJH method and/or mercury porosimetry. More typically, the ingestible porous silica compound may have a mean pore diameter in the range of from 2 nm to 90 nm, as measured by the BJH method and/or mercury porosimetry. In some embodiments, the mean pore diameter is in the range of from 2-5 nm, from 3-9 nm, from 6-15 nm, from 10 nm to 80 nm, or from 10 nm to 70 nm, or from 10 nm to 60 nm, or from 10 nm to 50 nm or a size that is within a range defined by any two of the aforementioned sizes, as determined by the BJH method and/or mercury porosimetry. In some embodiments, the mean pore diameter is in the range of from 20 nm to 100 nm, as measured by the BJH method and/or mercury porosimetry. In certain of these embodiments, the mean pore diameter is in the range from 20 nm to 90 nm, or from 20 nm to 80 nm, or from 20 nm to 70 nm, or from 20 nm to 60 nm, or from 10 nm to 50 nm or a size that is within a range defined by any two of the aforementioned sizes, as determined by the BJH method and/or mercury porosimetry. Exemplary ingestible porous silica compounds are described in, for example, U.S. Patent No.6,666,214. [0114] In some embodiments, according to the methods of the present disclosure, the sequestrant compositions may comprise one or more ingestible hydrocarbon or protein polymers. Exemplary ingestible polymers include but are not limited to guars, gums, chondroitin-based polymers, polyethylene-oxide polymers &, polyester, polylactic acid, polylactic-co-glycolic acid, cellulose, nitrocellulose, chitin, chitosan, polyethylene oxide, poly (β-benzyl-L-aspartate), poly (ε-caprolactone), polyglycolide, poly(DL-lactide-co-glycolide), polybutylcyanoacrylate, alginate, poly(adipic anhydride), 1,5-dioxepan-2-one, D,L-dilactide, polyvinyl acetate phthalate, methacrylic acid-methacrylic acid ester copolymers, trimellitate, poly(methacrylic acid), polyurethanes, polysiloxanes, polymethyl methacrylate, polyvinyl alcohol, polyethylene, polyvinyl pyrrolidone, epoxy resins, poly2-hydroxyethylmethacrylate, poly-N-vinyl pyrrolidone, polyvinyl alcohol, polyacrylic acid, polyacrylamide; polyethylene-co-vinyl acetate, polylactides, polyglycolides, polylactide-co-glycolides, polyanhydrides, and polyorthoesters and/or polyfluoroacrylic acid, or others as are known to those of skill in the art, or any combination thereof. These and many other pharmaceutically acceptable polymers are available from DowDuPont, Midland, MI. [0115] In some embodiments according to the methods of the present disclosure, the sequestrant compositions may comprise one or more of a cellulose polymer. Exemplary cellulose polymers include but are not limited to cellulose ethers, ethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxymethylpropylcellulose, carboxymethylcellulose, carboxymethyl ethylcellulose, hydroxypropylcellulose, cellulose esters, cellulose acetate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, and/or cellulose acetate propionate, or others as are known to those of skill in the art, and any combination thereof. Exemplary cellulose polymers may comprise cellulose acetate propionate having an average molecular weight of 10K, 25K, 50K, 100K, 150K, 200K, 250K, 500K, 750K, 1000K or more, or within a range defined by any two of the values disclosed herein, as determined by gel permeation chromatography. [0116] In some embodiments according to the methods of the present disclosure, the compositions may comprise one or more of a weak base amine-containing resin and/or sepiolite. Exemplary amine containing resins include but are not limited to polyacrylamide, chitosan, amine-derivatized poly(methyl acrylate), epoxyamine resins, and/or any amine derivative of any polymer or resin otherwise disclosed herein, or any combination thereof. [0117] In some embodiments according to the methods of the present disclosure, the sequestrant compositions may comprise, consist essentially of, or consist of one or more of an ion exchange resin. Exemplary ion exchange resins may comprise cellulose, polystyrene, acrylic ester, sulfonic acid polymer, sulfonic acid ester, polyethylenimine, polyamide, poly-styrene- divinylbenzene, or poly-phenol-formaldehyde, or other compounds. Commercially available ion exchange resins include but are not limited to Sepharose®, Sephadex®, Amberlite®, Amberlyst®, or Dowex®. [0118] In some embodiments, the sequestrant composition may comprise a clay compound. In some embodiments, the compositions as described herein may comprise bentonite, alumina, or other clay compounds as are known in the art. In some embodiments, the compositions as disclosed herein may comprise a zeolite. In some further embodiments, said compositions may comprise clinoptilolite. In some embodiments, said clinoptilolite may have a general stoichiometry of (Na,K,Ca)_2-3Al₃(Al,Si)₂Si₁₃O₃₆·12H₂O. [0119] It is understood by those of skill in the art that the resins, clays, polymers, cellulose derivatives, etc., disclosed herein or otherwise known in the art can be modified by conventional means such as by crosslinking or amination to be suitable for administration according to the methods of the present disclosure. [0120] In some embodiments, the sequestrant composition can be administered multiple times. In some further embodiments, the same sequestrant composition is administered each time. In some further embodiments, the sequestrant composition to be administered in subsequent administrations can be different from that administered in the initial administration or in any previous administration. In some embodiments, further administrations can be employed at intervals as described herein, for such duration as is necessary to maintain reduced levels of intestinal metabolites relative to the levels identified prior to the first administration of the sequestrant composition. [0121] In some embodiments according to the methods of the present disclosure, the sequestrant compositions and methods may further comprise a probiotic composition or administration of a probiotic composition, e.g., before, during, or after administration of the composition comprising, consisting essentially of, or consisting of the one or more sequestration agents. In some embodiments, the sequestrant compositions and or methods may comprise one or more of Prevotella species, Bifido bacteria species, Parabacteriodes species, (e.g., P. merdae, P. distasonis), Faecalibacterium species, (e.g., F. prausnitzii), Eubacterium species, Coprococcus species, Lactobacillus reuteri, Lactobacillus rhamnosis, Bacteroides caccae, Bacteriodes ovatus, Bacteroides fragilis, Bacteroides vulgatus, and/or Bacteroides thetaiotaomicron, or any combination thereof, which can be administered before, during, or after administration of the composition comprising the one or more sequestration agents. In some embodiments, the methods of the present disclosure further comprise administration of a probiotic composition as a component of a sequestering composition. In some embodiments, the methods of the present disclosure further comprise administration of a probiotic composition in addition to a sequestering composition. [0122] FORMULATIONS AND METHODS OF ADMINISTRATION [0123] “Administering” refers to providing a pharmaceutical agent, dietary supplement, or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administration. Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, intraperitoneally, or rectally. Oral administrations are customary in administering the compositions that are the subject of the preferred embodiments. However in some embodiments, the compositions are administered rectally, such as by enema or suppository. In some embodiments, administration of the compounds may occur outside the body, for example, by apheresis or dialysis. [0124] The term “agent” includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, polymer, resin, organic or inorganic microparticle, organic or inorganic nanoparticle, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. [0125] The compounds useful as described above can be formulated into pharmaceutical compositions and/or dietary supplements for use in treating, inhibiting, or ameliorating a neurological disease or neurological disorder associated with an alteration in the intestinal microbiome such as autism Spectrum Disorder (ASD), schizophrenia, an anxiety disorder, depression, Parkinson's Disease, Fragile X, Rett Syndrome, Tuberous Sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, and/or Alzheimer’s Disease. Standard pharmaceutical and/or dietary supplement formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated herein by reference in its entirety. Accordingly, some embodiments include pharmaceutical and/or dietary supplement compositions comprising, consisting essentially of, or consisting of: (a) a safe and therapeutically effective amount of one or more compounds described herein, or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. [0126] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, diluents, emulsifiers, binders, buffers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like, or any other such compound as is known by those of skill in the art to be useful in preparing pharmaceutical formulations. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art can be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press. [0127] Some examples of substances, which can serve as pharmaceutically-acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such as sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and/or phosphate buffer solutions, or any combination thereof. [0128] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to a subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. A unit dosage form may comprise, consist essentially of, or consist of a single daily dose or a fractional sub-dose wherein several unit dosage forms are to be administered over the course of a day in order to complete a daily dose. According to the present disclosure, a unit dosage form can be given more or less often that once daily, and can be administered more than once during a course of therapy. Such dosage forms can be administered in any manner consistent with their formulation, including orally, rectally, nasally, and/or parenterally. While single administrations are specifically contemplated, the compositions administered according to the methods described herein may also be administered as a continuous infusion or via an implantable infusion pump. [0129] The methods as described herein may utilize any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, or rectal routes of administration. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art can be used. Pharmaceutically- acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surface- active agents, and encapsulating substances. Optional pharmaceutically-active materials can be included, which do not substantially interfere with the activity of the one or more compounds in the formulation. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004). [0130] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and/or bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and/or melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and/or flavoring agents, or any combination thereof. [0131] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and/or cellulose; binders such as starch, gelatin and/or sucrose; disintegrants such as starch, alginic acid and/or croscarmelose; lubricants such as magnesium stearate, stearic acid, microcrystalline cellulose, carboxymethyl cellulose, and/or talc. Tablets may also comprise solubilizers or emulsifiers, such as poloxamers, cremophor/Kolliphor®/Lutrol®, or methylcellulose, hydroxypropylmethyl-cellulose, or others as are known in the art, or any combination thereof. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and/or fruit flavors, or any combination thereof, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which can be readily made by a person skilled in the art. [0132] Peroral (PO) compositions also include liquid solutions, emulsions, or suspensions. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and/or suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and/or water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and/or sodium alginate; typical wetting agents include lecithin and/or polysorbate 80; and typical preservatives include methyl paraben and/or sodium benzoate, or any combination thereof. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and/or colorants, as disclosed above. Peroral compositions can also be in the form of foodstuffs, such as candy, an applesauce, a yogurt, a soft pudding, a gelatin foodstuff, a juice, milk, a soy or nut beverage, a thickened beverage, or a cheese, or any combination thereof. [0133] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject one or more compounds are released in the gastrointestinal tract in the vicinity of the desired application, or at various times to extend the desired action. Exemplary dosage forms for release in the gastrointestinal tract may incorporate one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and/or shellac, or other excipients known to those of skill in the art, or any combination thereof. According to some embodiments, the compositions to be administered according to the methods described herein are formulated for release in the gastrointestinal tract. According to some embodiments, the compositions to be administered according to the methods described herein are formulated for release in the lower gastrointestinal tract. In some embodiments, the compositions are provided as enteric coated capsules, tablets, soft gels; or intrinsically enteric capsules. [0134] The actual unit dose of the compositions described herein depends on the one or more compounds in the formulation. In some embodiments, the amount of each compound in the formulation can be from 5 mg/kg to 500 mg/kg or more of body weight per day, from 10 mg/kg or less to 70 mg/kg, from 50 mg/kg to 80 mg/kg of body weight per day, from 70 mg/kg to 120 mg/kg of body weight per day, from 100 mg/kg to 300 mg/kg of body weight per day, or from 250 mg/kg to 500 mg/kg of body weight per day. In some embodiments, the dose can be less than 100 mg/kg, 500 mg/kg, 300 mg/kg, 200 mg/kg, 150 mg/kg, 100 mg/kg, 50 mg/kg, 40 mg/kg, 30 mg/kg, 25 mg/kg, 20 mg/kg, 10 mg/kg, 7.5 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2.5 mg/kg, or 1 mg/kg of body weight per day or an amount that is within a range defined by any two of the aforementioned amounts. In some embodiments, the actual unit dose is 5, 10, 25, 50, 75, 100, 150, or 200 mg/kg of body weight per day or an amount that is within a range defined by any two of the aforementioned amounts. Thus, for administration to a 70 kg person, for example, the dosage range is from 350 mg to 750 mg, from 500 mg to 1 g, from 750 mg to 2 g, from 1 g to 5 g, from 2.5 g to 6g, from 4g to 10 g, from 8 g to 20 g, from 15 g to 35g, or from 1g or less to 35 g or more, or an amount that is within a range defined by any two of the aforementioned amounts. In some embodiments, the actual unit dose is 6 g. In some embodiments the actual unit dose is 10 g. In some embodiments, the actual unit dose is 35 g. In some embodiments, the actual unit dose is 1 g or less but not zero. In some embodiments, the actual unit dose is 10 g or less but not zero. In some embodiments, the actual unit dose is 35 mg or less but not zero. In some embodiments, a unit dose is 0.1g-10g (e.g., 0.1-10g, 1-5, 1-4, 1-3, 1-2, 0.1-5, or 1-10). In some embodiments, a unit dose is calculated based on the subject’s weight. See the Example section below. In some embodiments, the unit dose administered to a subject is increased or decreased over a period of time (see e.g., Example section). [0135] “Loading dose,” as used herein refers to an initial dose of a compound which is higher than subsequent doses. [0136] “Maintenance dose,” as used herein refers to a subsequent dose that follows a loading dose, and occurs later in time than a loading dose. One of ordinary skill in the art will be aware that the dosage form or mode of administration of a maintenance dose can be different from that used for the loading dose. In any of the embodiments disclosed herein, a maintenance dose may comprise administration of the unit dosage form on any dosing schedule contemplated herein, including but not limited to, monthly or multiple times per month, biweekly or multiple times each two weeks, weekly or multiple times per week, daily or multiple times per day. It is contemplated within the present disclosure that dosing holidays can be incorporated into the dosing period of the maintenance dose. Such dosing holidays may occur immediately after the administration of the loading dose or at any time during the period of administration of the maintenance dose. As used herein, the period of administration of the maintenance dose can be referred to as the “maintenance phase” of the treatment period. [0137] “Mode of administration” as used herein refers to the avenue by which one or more compounds are administered to a subject. As used herein, “mode of administration” comprises the dosage form (for example, a tablet, powder, dissolved liquid, suspension, emulsion, etc.) and mechanism by which the dosage form is applied to the subject (for example, orally, such as by a pill, dissolved liquid, oral suspension). As used herein, “mode of administration” also comprises the dose, dose amount, and dosing schedule by which a compound is administered to a subject. [0138] In some embodiments, the compositions to be administered according to the methods of the present disclosure are provided with, or mixed into, a foodstuff, beverage, or other ingestible item. In some embodiments, said beverage, foodstuff, or other ingestible item may comprise, consist essentially of, or consist of one or more of a candy, an applesauce, a yogurt, a soft pudding, a gelatin foodstuff, a juice, milk, a soy or nut beverage, a thickened beverage, or a cheese, or any combination thereof. One of ordinary skill will readily recognize that the combination of the compositions to be administered according to the methods of the disclosure can be combined with any suitable food or beverage to facilitate ingestion of the compositions. [0139] Because levels of some metabolites will be expected to fluctuate in response to external stimuli, the methods according to the present disclosure contemplate varying or controlling the timing of administration of the compositions described herein, in order to enhance the effectiveness of the treatment, for example, by optimizing the removal of harmful metabolites or limiting the removal of helpful metabolites, in such a manner as to maintain both the somatic and the microbial health of the subject. In some embodiments, the compositions to be administered according to the methods of the present disclosure can be administered with food, such as concurrently with a meal or other ingestion of a foodstuff. In some further embodiments, the compositions to be administered according to the methods of the present disclosure can be administered immediately before or immediately after a meal or other ingestion of a foodstuff. In some further embodiments, the compositions to be administered according to the methods of the present disclosure can be administered within 1-5 minutes, within 3-10 minutes, within 6-15 minutes, within 10-20 minutes, within 15-30 minutes, within 20-45 minutes, or within one hour before or after a meal or other ingestion of a foodstuff. In some embodiments, the compositions to be administered according to the methods of the present disclosure can be administered without food, such as between 1-3 hours, between 2-5 hours, between 4-8 hours, between 6-12 hours, between 9-18 hours, between 12-24 hours, or more than 24 hours before or after a meal or other ingestion of a foodstuff. [0140] As used herein, “duration of the treatment” refers to the time commencing with administration of the first dose and concluding with the administration of the final dose, such length of time being determined by one of ordinary skill in the art of treating neurological disorders or disorders implicating intestinal hyperpermeability (leaky gut), with reference to the symptoms and health of the subject being treated therefor. Such duration can be determined with reference to periodic, sporadic, or ongoing monitoring of the levels of the metabolites as disclosed herein or as known to one of skill in the art of treating neurological disorders and disorders implicating intestinal hyperpermeability (leaky gut). [0141] As used herein, “dosing holiday” refers to a period of 24 hours or more during which either no dose is administered to the subject, or a reduced dose is administered to the subject. As used herein, “reduced dose” refers to a dose that is less than the total daily dose to be administered to a subject. [0142] According to the methods disclosed herein, a reduction in serum metabolites is achieved by modulating the dosing schedule such that subjects experience periodic partial or full reductions in dosing for fixed amounts of time, followed by a resumption of dosing. In some embodiments, dosages are administered daily for between one and thirty days, followed by a dosing holiday lasting for between one and thirty days. In some embodiments, during the dosing holiday, no dose is administered. In some further embodiments, the composition of the present disclosure is allowed to clear completely from the subject’s body prior to administration of the next dose. In some other embodiments, during the dosing holiday, a dose less than the usual daily dose is administered. In some further embodiments, an amount of the administered composition less than the therapeutically effective amount is allowed to remain within the subject during the dosing holiday. In some further embodiments, an amount of the administered composition sufficient to maintain therapeutic levels in the affected tissues is allowed to remain within the subject. [0143] According to the present disclosure, the dosing schedule can be varied so as to attain the desired therapeutic effect. In each of the embodiments as disclosed herein, variations in dosing schedule can be repeated throughout the duration of the therapeutic protocol being administered. In each of the embodiments as disclosed herein, the first dosage can be higher, lower, or the same as the dosages following the first dosage. In each of the embodiments disclosed herein, a loading dose may precede the disclosed dosing regimen, and a dosing holiday may or may not follow the administration of the loading dose. [0144] In some embodiments the methods of the present disclosure comprise administration of the one or more compositions provided herein daily or less frequently than daily, such as every second day, every third day, every fourth day, every fifth day, every sixth day, or every seventh day or for a time period that is within a range defined by any two of the aforementioned times. [0145] The methods of the present disclosure can be used in the treatment, prevention, and/or amelioration of one or more neurological disorders including autism spectrum disorder, schizophrenia, an anxiety disorder, depression, Parkinson's Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer’s Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, pure autonomic failure, or any combination thereof. Said disorders may include behavioral symptoms as are known in the art of clinical diagnosis and treatment of neurological disorders such as communicative symptoms, cognitive disorders, stereotyped behaviors, sensorimotor issues, clinical irritability, social motivation, social awareness, social communication, social cognition, inappropriate speech, hyperactivity/noncompliance, social withdrawal, and/or anxiety-like behaviors in addition to physical symptoms as are known in the art of diagnosis and treatment of neurological disorders such as tremors, paralysis, dyskinesia, and /or gastrointestinal symptoms such as intestinal hyperpermeability (leaky gut). Accordingly, such clinical and/or diagnostic evaluations and determinations can be used to identify and/or select one or more subjects for receiving one or more compounds described herein in accordance with the one or more methods provided in this disclosure. The methods of the present disclosure may, in some embodiments, include monitoring of the behavioral, physical, and/or gastrointestinal symptoms as are known in the art of diagnosis and treatment of neurological disorders. In some embodiments, the methods according to the present disclosure incorporate monitoring changes in the behavior of a subject. In some further embodiments, the methods according to the present disclosure incorporate monitoring the subject for behavioral symptoms as are known to be related to autism spectrum disorder, schizophrenia, an anxiety disorder, depression, Parkinson's Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer’s Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, pure autonomic failure, or any combination thereof. In some embodiments, the monitored behavioral symptoms do not comprise clinical anxiety. In some further embodiments, the methods according to the present disclosure incorporate monitoring the subject for repetitive behaviors, communicative symptoms, cognitive disorders, stereotyped behaviors, attachment to physical objects, aphasia, obsessive behaviors, unusual or inappropriate body language, gestures, and/or facial expressions and/ or sensorimotor issues, lack of interest in other people, lack of empathy, difficulty grasping nonverbal cues, touch aversion, difficulty in socialization, speech delays, abnormal vocal tone or pitch, vocal repetition, perseveration, conversational difficulty, difficulty communicating needs or desires, inability to understand simple statements or questions, difficulties in processing language subtext, obsessive attachment to unusual objects, preoccupation, intolerance of changes in routine or environment, clumsiness, abnormal posture, odd ways of moving, fascination with particular objects, hyper- or hypo-reactivity to sensory input, clinical irritability or any combination thereof. Again, such clinical and/or diagnostic evaluations and determinations can be used to identify and/or select one or more subjects for receiving one or more compounds described herein in accordance with the one or more methods provided in this disclosure. In additional embodiments, the methods may incorporate monitoring the subject for tremors, paralysis, and/or dyskinesia, or other symptoms known to those in the art of diagnosing and treating neurological disorders, or any combination thereof. In some embodiments, the methods of the present disclosure may include monitoring of microbial and/or intestinal metabolites as disclosed herein or as known to those of skill in the art. According to the methods of the present disclosure, said metabolites can be monitored in the gut, feces, urine, blood, saliva, cerebrospinal fluid, and/or synovial fluid of a subject. The methods of the present disclosure contemplate the monitoring of said metabolites in any tissue or fluid obtainable from a subject during the course of treatment. Again, such clinical and/or diagnostic evaluations and determinations can be used to identify and/or select one or more subjects for receiving one or more compounds described herein in accordance with the one or more methods provided in this disclosure. [0146] In some embodiments, the compositions are administered at any time following the onset of one or more of the aforementioned symptoms of a neurological disorder associated with intestinal hyperpermeability (leaky gut) and/or intestinal dysbiosis. In some embodiments, the compositions according to the methods described herein are administered prior to the onset of symptoms of said disorder or disorders. In some embodiments, the compositions according to the methods described herein are administered concurrently with or after the onset of symptoms of said disorder or disorders. [0147] The methods described herein are further illustrated by the following examples. [0148] COMPOSITE BIOMARKERS AND USES THEREOF [0149] In some aspects, provided herein is a composite biomarker that is useful for determining whether a subject will respond to a treatment (e.g., administration of a sequestrant of one or more metabolites as described herein), determining the efficacy of an administered treatment or measuring response to treatment (e.g., administration of a sequestrant of one or more metabolites as described herein), and/or for diagnosis. In some embodiments, a composite biomarker as provided herein is useful as a surrogate measurement for one or more clinical phenotypes or symptoms. [0150] As used herein, a “composite biomarker” is the combination of two or more biomarkers (e.g., levels of two or more metabolites in a biological sample) to produce a single variable, such as an index or score. In some embodiments, a composite biomarker is a combination of a measure (e.g., a level, or change in level) of two, three, four, five, six, seven, eight, nine, or ten or more metabolites. In some embodiments, a composite biomarker is a combination of a measure (e.g., a level or change in level) of 2-3, 2-4, 2-5, 2-6, 2-7, 2-8,2-9, 2-10 or more, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10 or more, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10 or more, 5-6, 5-7, 5-8, 5-9, 5-10 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more metabolites. Non-limiting examples of a composite biomarker includes absolute levels, ratios of levels, ratios of changes, absolute changes, total levels (additive) or total changes (relative or absolute). [0151] In some embodiments, a composite biomarker is a combination of a measure (e.g., a level or change in level) of two metabolites selected from the group consisting of: 4-ethylphenol (4-EP), 4-ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate (3IS), 3-hydroxy indole, coumaric acid, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-(3-hydroxyphenyl)propanoic acid, 3-(4-hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5-propyl-2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4-hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid, p-cresol glucuronide (pCG); 3-hydroxyphenylacetate (HPAA), 3-(3-hydroxyphenyl)-3- hydroxypropionate (HPHPA), 3-(4-hydroxyphenyl)propionate (HPPA), 3-hydroxyhippurate (HHA), and imidazolepropionate (IPA). In some embodiments, a composite biomarker is a combination of a measure (e.g., a level or change in level) of three metabolites selected from the group consisting of: 4-ethylphenol (4-EP), 4-ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate (3IS), 3-hydroxy indole, coumaric acid, 3-(3-hydroxyphenyl)-3- hydroxypropionic acid (HPHPA), 3-(3-hydroxyphenyl)propanoic acid, 3-(4- hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5-propyl- 2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4-hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid, p-cresol glucuronide (pCG); 3- hydroxyphenylacetate (HPAA), 3-(3-hydroxyphenyl)-3-hydroxypropionate (HPHPA), 3-(4- hydroxyphenyl)propionate (HPPA), 3-hydroxyhippurate (HHA), and imidazolepropionate (IPA). In some embodiments, a composite biomarker is a combination of a measure (e.g., a level or change in level) of three metabolites selected from the group consisting of: 4-ethylphenol (4-EP), 4-ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate (3IS), 3- hydroxy indole, coumaric acid, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-(3- hydroxyphenyl)propanoic acid, 3-(4-hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5-propyl-2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4-hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid, p-cresol glucuronide (pCG); 3-hydroxyphenylacetate (HPAA), 3-(3-hydroxyphenyl)-3- hydroxypropionate (HPHPA), 3-(4-hydroxyphenyl)propionate (HPPA), 3-hydroxyhippurate (HHA), and imidazolepropionate (IPA). [0152] In some embodiments, a composite biomarker comprises a measure of a control metabolite, e.g., N-acetyl serine (N-AS). For example, in some embodiments, a composite biomarker is a combination of a measure (e.g., a level or change in level) of two metabolites selected from the group consisting of: N-acetyl serine (N-AS), 4-ethylphenol (4-EP), 4- ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate (3IS), 3- hydroxy indole, coumaric acid, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-(3- hydroxyphenyl)propanoic acid, 3-(4-hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5-propyl-2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4-hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid, p-cresol glucuronide (pCG); 3-hydroxyphenylacetate (HPAA), 3-(3-hydroxyphenyl)-3- hydroxypropionate (HPHPA), 3-(4-hydroxyphenyl)propionate (HPPA), 3-hydroxyhippurate (HHA), and imidazolepropionate (IPA). In some embodiments, a composite biomarker is a combination of a measure (e.g., a level or change in level) of three metabolites selected from the group consisting of: N-acetyl serine (N-AS),4-ethylphenol (4-EP), 4-ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate (3IS), 3-hydroxy indole, coumaric acid, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-(3-hydroxyphenyl)propanoic acid, 3- (4-hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5- propyl-2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4-hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid, p-cresol glucuronide (pCG); 3- hydroxyphenylacetate (HPAA), 3-(3-hydroxyphenyl)-3-hydroxypropionate (HPHPA), 3-(4- hydroxyphenyl)propionate (HPPA), 3-hydroxyhippurate (HHA), and imidazolepropionate (IPA). In some embodiments, a composite biomarker is a combination of a measure (e.g., a level or change in level) of three metabolites selected from the group consisting of: N-acetyl serine (N- AS),4-ethylphenol (4-EP), 4-ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate (3IS), 3-hydroxy indole, coumaric acid, 3-(3-hydroxyphenyl)-3- hydroxypropionic acid (HPHPA), 3-(3-hydroxyphenyl)propanoic acid, 3-(4- hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5-propyl- 2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4-hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid, p-cresol glucuronide (pCG); 3- hydroxyphenylacetate (HPAA), 3-(3-hydroxyphenyl)-3-hydroxypropionate (HPHPA), 3-(4- hydroxyphenyl)propionate (HPPA), 3-hydroxyhippurate (HHA), and imidazolepropionate (IPA). [0153] In some embodiments, a composite biomarker is a combination of levels of two or more metabolite, e.g., as shown or discussed in FIGs.12-14, that correlate with one or more behavioral symptom as disclosed herein. In some embodiments, a composite biomarker is a combination of changes in levels of two or more metabolites relative to a reference condition (e.g., before and after treatment, or at two different times as a measure of disease progression), e.g., as shown or discussed in FIGs.9-11. In some embodiments, a composite biomarker is one that is disclosed in any one of FIGs.9-14. [0154] In some aspects, provided herein is a method of determining whether a subject will respond to a treatment by use of any one of the composite biomarkers disclosed herein. In some embodiments, a method of determining whether a subject will respond to a treatment comprises measuring a level of a composite biomarker before treatment; and determining that the subject is likely to respond to the treatment if the level of the composite marker exceeds a threshold value. In some embodiments, a threshold value is one that is determined by assessing a group of subject to which the treatment is administered and in which the composite marker is evaluated. [0155] In some aspects, provided herein is a method of determining the efficacy of an administered treatment or measuring response to treatment by use of any one of the composite biomarkers disclosed herein. In some embodiments, a method of determining the efficacy of an administered treatment or measuring response to treatment comprises measuring a composite biomarker before treatment, measuring the composite biomarker after treatment, determining the magnitude of change in the composite variable before and after treatment; and determining that the treatment is efficacious if the magnitude of change in the composite biomarker exceeds a threshold value. In some embodiments, a threshold value is one that is determined by assessing a group of subject to which the treatment is administered and in which the composite marker is evaluated. [0156] In some aspects, provided herein is a method of diagnoses of a disease, e.g., a neurological disease, or a behavioral symptom thereof, by use of any one of the composite biomarkers disclosed herein. Such a method is especially useful in diagnosing conditions in pediatric subjects. In some embodiments, a method of diagnosing a neurological disease, or a behavioral symptom thereof, comprises measuring a level of a composite biomarker, or the magnitude of change in levels of a composite biomarker (e.g., before and after a certain time period, or before and after a treatment), and determining that the subject likely suffers from a neurological diseases or will manifest one or more behavioral symptoms of the neurological disorder if the magnitude of level or change in level of the composite biomarker exceeds a threshold value. In some embodiments, a threshold value is one that is determined by assessing a group of subject to which the treatment is administered and in which the composite marker is evaluated. Example 1 Safety and target-engagement of an oral small molecule sequestrant in adolescents with Autism Spectrum Disorder: an open-label phase 1b/2a trial [0157] PRECLINICAL METHODS [0158] Mouse Husbandry [0159] All animal husbandry and experiments were approved by the Caltech Institutional Animal Care and Use Committee. Throughout the study, colonized animals were maintained in autoclaved microisolator cages with autoclaved bedding (Aspen Chip Bedding, Northeastern Products Corp, Warrensburg, NY), water, and chow. Standard chow was provided to the animals (Laboratory Autoclavable Rodent Diet - 5010, LabDiet; St. Louis, MO, USA) until diet was switched to irradiated 5% AB-2004 or control diets (Teklad). This percentage of AB-2004 (AST- 120) in mouse chow was previously used safely in mice. Mice were maintained at an ambient temperature of 71-75F, 30% - 70% humidity, at a cycle of 13 hours light & 11 hours dark. [0160] Experimental Design of Mouse Experiments [0161] Germ-free (GF) C57BL/6J male weanlings (3 weeks of age) from the Mazmanian laboratory colony were colonized by gavage of 100ul of 1:1 mixture of 10⁹ CFU/ml B. ovatus (+/- 4EP pathway genes) and wild type L. plantarum. At 5 weeks of age, mice were switched to the irradiated 5% AB-2004 or control diets (Teklad) for the remainder of the experiment. Mice were weighed weekly beginning at diet switch. Urine was collected at 7 weeks of age prior to behavior testing. Behavior testing began at 7 weeks of age, 3 days after urine collection. [0162] Analysis of metabolites from urine of mice [0163] Urine was passively collected by brief restrain of mouse over aluminum foil.4EPS levels were quantified by LC/MS and normalized to creatinine levels by Charles River Laboratories (Boston, MA). [0164] Behavior Testing [0165] Behavior testing was performed as previously described. All mice were tested using the same battery of behavioral tests, starting at six weeks of age, in the following order: EPM, open-field testing, marble burying, grooming, social behavior, and USV (male-female context). Mice were allowed to settle for at least two days after cage changing before they were tested, and tests were performed 2-3 days apart to allow mice to rest between tests. Mice were acclimated to the behavior testing room for one hour prior to testing. Mice were tested during the light phase of the light/dark cycle. [0166] Elevated Plus Maze (EPM) [0167] EPM was performed in a maze with 25cm by 5cm arms and a 5cm by 5cm center, recorded using an overhead camera, and tracked and analyzed using the EthoVision XT 10 software package (Noldus Information Technology; Leesburg, VA, USA). Prior to testing, the maze was disinfected using Rescue disinfectant (Virox technologies, Oakville, ON, Canada) then allowed to evaporate. Mice were then introduced to the arena and allowed to explore for 5 minutes while being tracked. The number of entries into and the time spent in open and closed arms as well as the outer third of the open arms (the terminus) were analyzed. If a mouse fell or jumped from the apparatus during the test it was removed from the dataset. [0168] Open-field Test [0169] The open-field test was performed in 50 x 50 cm² white Plexiglas arenas, recorded using an overhead camera, and tracked and analyzed using the EthoVision XT 10 software package (Noldus Information Technology; Leesburg, VA, USA). Prior to testing, the arena was disinfected using Rescue disinfectant (Virox technologies, Oakville, ON, Canada) then allowed to evaporate. Mice were then introduced to the arena and allowed to explore for 10 minutes while being tracked. The total distance traveled, and the number of entries and time spent in a 17 x 17 cm² center square were analyzed. Fecal pellets left during the assay were quantified. [0170] Marble Burying [0171] Marble burying was performed in a normal cage bottom (Lab Products; Seaford, DE) filled with 3-4 cm of fresh, autoclaved wood chip bedding (Aspen chip bedding, Northeastern Products Corp; Warrensburg, NY). Mice were first habituated to the cage for 10 minutes, and subsequently transferred to a holding cage while the bedding was leveled, and 20 glass marbles (4 x 5) were placed on top. Mice were then returned to their own cage and removed after 10 minutes. The number of buried marbles (50% or more covered) was then recorded and photographed for reference. A fresh cage was used for each mouse, and marbles were soaked in Rescue disinfectant (Virox technologies, Oakville, ON, Canada) and dried in bedding in between tests. [0172] Grooming [0173] Mice were placed in autoclaved, empty standard cages (Lab Products; Seaford, DE) and video recorded from the side for 15 minutes. The final 10 minutes were scored manually by a blinded, trained researcher for grooming behavior. [0174] CLINICAL METHODS [0175] Clinical study design and ethical approval [0176] The AXL-2004-001 study (ANZCTR (anzctr.org.au/) ACTRN12618001956291) was an open-label, outpatient, multiple ascending dose Phase 1b/2a study in an ASD-diagnosed adolescent (12 - <18 years old) population with confirmed gastrointestinal symptoms (e.g. diarrhea, constipation, abdominal pain, bloating).41 individuals were screened between April 18, 2019 and January 23, 2020.30 participants were enrolled across three sites in Australia and New Zealand, including the Queensland Children’s Hospital in Brisbane (14 subjects), Brain and Mind Centre in Sydney (6 subjects), and Optimal Clinical Trials in Auckland (10 subjects). There was no formal sample size calculation for the phase I study because it focused on safety and tolerability. This approach was common in early-stage exploratory clinical trials. All necessary licenses and permissions to use the behavioral assessments outlined in the study protocol were obtained prior to initiating the study. [0177] The study protocol, investigator brochure, participant information and consent forms, participant facing questionnaires, recruitment documentation and procedures, and documentation regarding the investigators experience and qualifications were submitted to Health and Disability Ethics Committees (New Zealand), Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee, and Bellberry Human Research Ethics Committee for ethical review and approval. The study was conducted in accordance with the Declaration of Helsinki (Fortaleza, October 2013), ICH E6 guidelines, good clinical practices, and local regulations. [0178] Study participation [0179] This open label study consisted of 4 different dosing plans based on the subject’s weight at Visit 1 (V1). Eligible subjects were escalated through three dosing periods during the 8-week treatment period starting with the lowest dose for their dosing plan. See Supplemental Methods for more details. Subjects were requested to consume AB-200490 minutes after any other concomitant medications. Safety and tolerability were confirmed before a subject escalated to the next dosing level. If subjects were unable to tolerate a dosing level, they were returned to previous dosing level for the remainder of the treatment period. Following the last dose of AB- 2004 subjects returned to the clinic 28 days later for a follow-up safety evaluation (Final Visit, FV). The last visit of the study was completed on May 15, 2020. [0180] Study Participants and Study Populations [0181] A total of 41 adolescent subjects, aged 12-17 years inclusive, were screened for eligibility for participation in the study, and the 30 who met the study-specific eligibility criteria were enrolled and received at least one dose of AB-2004 (Safety Population). Of the 41 subjects screened and 30 enrolled, 40 and 29, respectively, were male. A predominantly male cohort was targeted to reduce variability in response in this exploratory study that surveyed a wide range of behavioral assessments. One participant withdrew after the first dose due to the investigator’s decision based on the subject presenting with an unrelated viral infection. Another subject withdrew consent during the low dose period due to anticipated admission to hospital for pre- existing behavioral difficulties. One participant withdrew due to significant study non- compliance, and two did not complete FV assessments due to the caregiver being unwell and unable to accompany the subjects. A total of 27, (26 male and 1 female), completed at least up to the End of Treatment (EOT) visit (Completers Population). One subject, the female participant, was included in the Safety Population, but was not included in the exploratory efficacy analysis. This subject was removed from the exploratory efficacy analysis because their participation in the trial coincided with the initial COVID-19 pandemic outbreak and its associated societal restrictions put into effect in Australia. These restrictions prevented the subject from conducting normal routines and accessing normal services. As determined by the site Principal Investigator, these abrupt changes in routine had an impact on the behavior of the participant; therefore, this subject was excluded from the efficacy analysis. [0182] Safety assessments [0183] The primary endpoint of the study was the safety and tolerability of AB-2004 as assessed by physical exams, vital signs, clinical laboratory measurements (hematology, serum chemistry, urinalysis), and Adverse Events. [0184] Blood collection [0185] Blood was obtained using uniform collection kits from Sonic Clinical Trials (SCT)(Australia) sent to each facility. Blood was drawn from study participants on visits 1, 4, and 5 and aliquoted for health monitoring by Sonic Clinical Trials (SCT) (Australia) and metabolite analysis by Metabolon, Inc (Durham, NC). Blood chemistry panels performed by SCT included albumin, alkaline phosphatase, alanine amino transferase, aspartate amino transferase, blood urea nitrogen, urea, corrected calcium, bicarbonate, chloride, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, total bilirubin, conjugated bilirubin, unconjugated bilirubin, and total protein. Haematology panels included measurement of platelets, haematocrit, red blood cells, haemoglobin, reticulocytes, total white blood cell count and absolute and percentages of neutrophils, lymphocytes, monocytes, eosinophils, and basophils. [0186] Urine collection [0187] Each participant was provided with a urine home collection kit and instructions to collect all of the first morning void a maximum of 2 days before clinic visit and place in refrigerator to bring to their visit or to be picked up by courier. Urinalysis samples were collected during the in-clinic visit. Aliquoting for metabolite analysis and health monitoring urinalysis were performed by SCT and included measurements of pH, specific gravity, ketones, protein, glucose, nitrite, urobilinogen, leukocyte esterase, and blood. [0188] Human Plasma Metabolite Quantification [0189] Human plasma was analyzed by Metabolon, Inc (Durham, NC). Briefly, plasma was spiked with internal standards (4-ethylphenyl sulfate-d₄, p-cresol sulfate-d₇, 3-hydroxyhippurate- ¹³C₂,¹⁵N, 3-hydroxyphenylacetate-d₃, 3-(3-hydroxyphenyl)-3-hydroxypropionate-d₃, 3-indoxyl sulfate-¹³C₆, 3-(4-hydroxyphenyl)propionate-d₄, p-cresol glucuronide-d₇, N-acetylserine-d₃,), protein precipitated, and analyzed on an Agilent 1290/AB Sciex 5500 QTrap LC-MS/MS system equipped with a UHPLC C18 column. Quantitation was performed using a weighted linear least squares regression analysis with a weighting of 1/x or 1/x² generated from fortified calibration standards prepared immediately prior to each run. [0190] Human Urine Metabolite Quantification [0191] Human urine was analyzed by Metabolon, Inc (Durham, NC). Briefly, urine was diluted 10-fold and spiked with internal standards (p-cresol sulfate-d₇, 3-hydroxyhippurate- ¹³C₂,¹⁵N, 3-hydroxyphenylacetate-d₃, 3-(3-hydroxyphenyl)-3-hydroxypropionate-d₃, 3-indoxyl sulfate-¹³C₆, 3-(4-hydroxyphenyl)propionate-d₄, and p-cresol glucuronide-d₇, N-acetylserine-d₃,), then an aliquot was subjected to either a solvent crash (for p-cresol sulfate, 3-indoxyl sulfate, and p-cresol glucuronide) or derivatization (for 3-hydroxyhippurate, 3-hydroxyphenylacetate, 3-(3- hydroxyphenyl)-3-hydroxypropionate, N-acetylserine, and 3-(4-hydroxyphenyl)propionate) and analyzed on an Agilent 1290/AB Sciex 5500 QTrap LC-MS/MS system equipped with a UHPLC C18 column in negative mode. Quantification of 4-ethylphenyl sulfate was performed by the same method with a solvent crash (using the internal standard, 4-ethylphenyl sulfate-d₄), but without sample dilution. Quantitation was performed using a weighted linear least squares regression analysis with a weighting of 1/x generated from fortified calibration standards prepared immediately prior to each run. All urine metabolites were normalized to creatinine levels. [0192] Exploratory efficacy assessments [0193] Exploratory efficacy outcomes included changes from BL at EOT and FV on the GSI- 6, NRS, GSRS, BSS, RBS-R VABS, CASI-5, SRS, CGI-S and CGI-I, ABC, or PARS diagnostics. Efficacy assessments were administered on site at the respective clinics during visits. VABS, PARS, and CGI-S and CGI-I were conducted by the PI or qualified designee. The GSI-6, NRS, GSRS, RBS-R, BSS, CASI-5 SRS, and ABC questionnaires were completed by the designated caregivers of the participants. In the VABS assessment, 10 participants did not pass the under 25% estimated answers criterion of any domain during assessment, and thus had to be removed from this analysis, according to the VABS manual, p.47.⁵ [0194] AB-2004 Treatment Dosage For subjects weighing ≥ 60 kgs, three daily doses each of: • Period 1: 0.75g Days 1 – 14 (2 weeks) • Period 2: 1.5 gm Days 15 – 28 (2 weeks) • Period 3: 2 g Days 29 – 56 (4 weeks) For subjects weighing 50- < 60 kgs, three daily doses each of: • Period 1: 0.75 g Days 1 – 14 (2 weeks) • Period 2: 1.0 g Days 15 – 28 (2 weeks) • Period 3: 1.75 g Days 29 – 56 (4 weeks) For subjects weighing 40- < 50 kgs, three daily doses each of: • Period 1: 0.5 g Days 1 – 14 (2 weeks) • Period 2: 0.75g Days 15 – 28 (2 weeks) • Period 3: 1.5 g Days 29 – 56 (4 weeks) For subjects weighing 30- < 40 kgs, three daily doses each of: • Period 1: 0.5 g Days 1 – 14 (2 weeks) • Period 2: 0.75 g Days 15 – 28 (2 weeks) • Period 3: 1.0 g Days 29 – 56 (4 weeks) Magnetic Resonance [0195] MR scan protocol [0196] The imaging protocol was designed with a number of competing requirements. To meet the goals of the study, the protocol was designed first, to obtain anatomic, resting state, and diffusion weighted image data of high quality, second, to be well tolerated by the target subjects, and third, to be comparable between the three imaging sites. The study design used each subject as their own control, to mitigate effects between sites and scanners. Prior to design the imaging sites were consulted, both to ascertain their system capabilities, and to draw on their extensive experience imaging subjects with ASD, before designing a protocol. The major design criteria were therefore: 1) The protocol must acquire high resolution anatomic images, rs-fMRI, and DTI data. 2) EPI based scans (rs-fMRI and DTI) would need to be distortion corrected. 3) Total scan time needed to be 45 minutes or less, and individual scans should be kept as close to 5 minute duration as possible, due to subject tolerance. 4) It was expected that any given scan might be corrupted by motion, so scans were designed to be partially redundant. 5) The scan parameters needed to be as consistent as possible between sites, despite different scanner manufacturers and models (Site 1: GE Discovery 750, software level DV26.0, Site 2: Siemens Skyra, software level VE11, Site 3: Siemens Prisma Fit, software level VE11). [0197] Scan parameters [0198] All scans were collected using phased array receive only head coils (32 channels at Sites 1 and 2, 64 channels at Site 3). High resolution anatomic images (T1w and T2w) were acquired with 1mm isotropic resolution. T1w images (2@4:01 each, for sites 1 and 2, 1@4:00 for site 3) were sagittally oriented using a 3D MPRAGE sequence. A single resolution matched T2w image (4:28) was acquired (the T2_CUBE sequence at Site 1, T2_SPACE at Sites 2 and 3). Two gradient echo multiband EPI rs-FMRI acquisitions (300 volumes each) were performed with 2.5mm isotropic resolution, 1 second repetition time, multiband factor 3.51 slices were acquired obliquely with the bottom slice oriented on the line between the bottom of the cerebellum and the bottom of the orbitofrontal cortex. The phase encode was reversed between the first and second scan (AP for the first scan, PA for the second) to allow for distortion correction. Two diffusion scans were also acquired as part of the protocol (5:56 each), but they were not used for this analysis. [0199] Data processing [0200] Prior to processing, all data were named and organized following the BIDS 1.2.1 specification. Anatomical and fMRI data used in this manuscript were preprocessed using fMRIPrep 20.0.489,90 (RRID:SCR_016216), which is based on Nipype 1.4.291 (RRID:SCR_002502). [0201] Anatomical data preprocessing [0202] A total of 2 T1-weighted (T1w) images were found within each BIDS dataset. All of them were corrected for intensity non-uniformity (INU) with N4BiasFieldCorrection, distributed with ANTs 2.2.0 (RRID:SCR_004757). The T1w-reference was then skull-stripped with a Nipype implementation of the antsBrainExtraction.shworkflow (from ANTs), using OASIS30ANTs as target template. Brain tissue segmentation of cerebrospinal fluid (CSF), white-matter (WM) and gray-matter (GM) was performed on the brain-extracted T1w using fast (FSL 5.0.9, RRID:SCR_002823). A T1w-reference map was computed after registration of 4 T1w images (after INU-correction) using mri_robust_template (FreeSurfer 6.0.1). Brain surfaces were reconstructed using recon-all (FreeSurfer 6.0.1, RRID:SCR_001847), and the brain mask estimated previously was refined with a custom variation of the method to reconcile ANTs- derived and FreeSurfer-derived segmentations of the cortical gray-matter of Mindboggle (RRID:SCR_002438). Volume-based spatial normalization to two standard spaces (MNI152NLin6Asym, MNI152NLin2009cAsym) was performed through nonlinear registration with antsRegistration (ANTs 2.2.0), using brain-extracted versions of both T1w reference and the T1w template. The following templates were selected for spatial normalization: FSL’s MNI ICBM 152 non-linear 6th Generation Asymmetric Average Brain Stereotaxic Registration Model [RRID:SCR_002823; TemplateFlow ID: MNI152NLin6Asym], ICBM 152 Nonlinear Asymmetrical template version 2009c [RRID:SCR_008796; TemplateFlow ID: MNI152NLin2009cAsym]. [0203] Functional data preprocessing [0204] For each of the 4 BOLD runs found per subject (across all tasks and sessions), the following preprocessing was performed. First, a reference volume and its skull-stripped version were generated using a custom methodology of fMRIPrep. A deformation field to correct for susceptibility distortions was estimated based on fMRIPrep’s fieldmap-less approach. The deformation field was that resulting from co-registering the BOLD reference to the same-subject T1w-reference with its intensity inverted. Registration was performed with antsRegistration (ANTs 2.2.0), and the process regularized by constraining deformation to be nonzero only along the phase-encoding direction, and modulated with an average fieldmap template. Based on the estimated susceptibility distortion, a corrected EPI (echo-planar imaging) reference was calculated for a more accurate co-registration with the anatomical reference. The BOLD reference was then co-registered to the T1w reference using bbregister (FreeSurfer) which implements boundary-based registration. Co-registration was configured with six degrees of freedom. Head-motion parameters with respect to the BOLD reference (transformation matrices, and six corresponding rotation and translation parameters) are estimated before any spatiotemporal filtering using mcflirt (FSL 5.0.9). BOLD runs were slice-time corrected using 3dTshift from AFNI 20160207 (RRID:SCR_005927). The BOLD time-series (including slice- timing correction when applied) were resampled onto their original, native space by applying a single, composite transform to correct for head-motion and susceptibility distortions. These resampled BOLD time-series were referred to as preprocessed BOLD in original space, or just preprocessed BOLD. The BOLD time-series were resampled into standard space, which generated a preprocessed BOLD run in MNI152NLin6Asym space. First, a reference volume and its skull-stripped version were generated using a custom methodology of fMRIPrep. Automatic removal of motion artifacts using independent component analysis (ICA-AROMA) was performed on the preprocessed BOLD on MNI space time-series after removal of non-steady state volumes and spatial smoothing with an isotropic, Gaussian kernel of 6mm FWHM (full- width half-maximum). Corresponding “non-aggressively” denoised runs were produced after such smoothing. Additionally, the “aggressive” noise-regressors were collected and placed in the corresponding confounds file. Several confounding time-series were calculated based on the preprocessed BOLD: framewise displacement (FD), DVARS and three region-wise global signals. FD and DVARS were calculated for each functional run, both using their implementations in Nipype (following the definitions by Power et al.2014). The three global signals were extracted within the CSF, the WM, and the whole-brain masks. Additionally, a set of physiological regressors were extracted to allow for component-based noise correction (CompCor). Principal components were estimated after high-pass filtering the preprocessed BOLD time-series (using a discrete cosine filter with 128s cut-off) for the two CompCor variants: temporal (tCompCor) and anatomical (aCompCor). tCompCor components were then calculated from the top 5% variable voxels within a mask covering the subcortical regions. This subcortical mask was obtained by heavily eroding the brain mask, which ensured it did not include cortical GM regions. For aCompCor, components were calculated within the intersection of the aforementioned mask and the union of CSF and WM masks calculated in T1w space, after their projection to the native space of each functional run (using the inverse BOLD-to-T1w transformation). Components were also calculated separately within the WM and CSF masks. For each CompCor decomposition, the k components with the largest singular values were retained, such that the retained components’ time series were sufficient to explain 50 percent of variance across the nuisance mask (CSF, WM, combined, or temporal). The remaining components were dropped from consideration. The head-motion estimates calculated in the correction step were also placed within the corresponding confounds file. The confound time series derived from head motion estimates and global signals were expanded with the inclusion of temporal derivatives and quadratic terms for each. Frames that exceeded a threshold of 0.5 mm FD or 1.5 standardised DVARS were annotated as motion outliers. All resamplings were performed with a single interpolation step by composing all the pertinent transformations (i.e. head-motion transform matrices, susceptibility distortion correction when available, and co- registrations to anatomical and output spaces). Gridded (volumetric) resamplings were performed using antsApplyTransforms (ANTs), configured with Lanczos interpolation to minimize the smoothing effects of other kernels. Non-gridded (surface) resamplings were performed using mri_vol2surf (FreeSurfer). Many internal operations of fMRIPrep use Nilearn 0.6.2 (RRID:SCR_001362), mostly within the functional processing workflow. [0205] fMRI data analysis [0206] To quantify connectivity between the bilateral amygdala and rostral anterior cingulate cortex (rACC), a region of interest (ROI) approach was used employing methods from prior work. The bilateral amygdala was defined using the Harvard-Oxford atlas. The rACC ROI was just anterior to the genu of the corpus callosum and had been used in prior work. This ROI was defined by a 5 mm sphere located at Montreal Neurological Institute (MNI) coordinates x = 0, y = 38, z -4. Average time courses for each ROI were extracted, demeaned, detrended, Hamming windowed, and correlated to generate a single correlation value (r) for each participant both before and after treatment. Baseline and end of treatment values for amygdala-rACC coupling were compared using a paired t-test. The treatment-induced change in bilateral amygdala-rACC coupling was then correlated with baseline anxiety score. [0207] Statistical Information [0208] Results presented here were from post hoc analyses of the data from the clinical trial using Graphpad Prism 9. Here, bar graphs representing the preclinical data by mean ± SEM analyzed by ordinary two-way ANOVA test with FDR correction using the Benjamini Krieger and Yekutieli method, with individual variances computed for each comparison were presented. Clinical data was presented as mean and 95% confidence intervals analyzed by Repeated Measures ANOVA, or linear mixed effects model, with Geisser-Greenhouse correction tests and false discovery rate correction by the Benjamini, Krieger and Yekutieli method. Metabolite data was presented as individual graphs but was statistically analyzed across all metabolites and samples. Clinical behavioral metrics were analyzed within each test. Pearson’s correlations were performed comparing change in metabolite levels to change in behavioral scores for the PARS and ABC-I tests. fMRI values were analyzed using a two-tailed paired t-test. Study participants were studied as a single group, and all comparisons, especially those within the subgroup of individuals in the top quartile of ASD severity were post hoc and exploratory in nature. Missing data were not imputed, and data were analyzed for subjects who withdrew from the study, for any reason prior to study completion, regardless of treatment duration, up to the point of discontinuation. [0209] Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction, as well as repetitive activities and restricted interests. ASD represents a broad spectrum from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression, and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, which complemented findings of differences in intestinal metabolites in feces and circulation. However, a role for the gastrointestinal tract or microbiome in ASD remained controversial. Herein, an oral gastrointestinal-restricted adsorbent (AB-2004) was reported, that had affinity for small aromatic or phenolic molecules, relieved anxiety-like behaviors that were driven by a gut intestinal metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single cohort, multiple ascending dose clinical trial that enrolled 30 adolescents with ASD and gastrointestinal symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, improvements were observed in multiple exploratory behavioral endpoints, most significantly in post-hoc analysis of anxiety and irritability, as well as gastrointestinal health after 8 weeks of treatment. These results from an open-label study (trial registration# ACTRN12618001956291) suggested that targeting intestinal metabolites with an oral adsorbent was a safe and well- tolerated approach to improving symptoms associated with ASD and thereby emboldened larger placebo-controlled trials. [0210] AB-2004, known otherwise as AST-120, is a high surface-area spherical carbon adsorbent that has affinity for uremic toxins including those of gut bacterial origin, such as the simple phenols, 4EPS, p-cresyl sulfate (pCS), and p-cresyl glucuronide (pCG), as well as the indole derivative, 3-indoxyl sulfate (3IS) and hippuric acid, based on evidence from rodent models and patients with chronic kidney disease and IBS. It was found that, taken orally, it binds and sequesters related aromatic metabolites as it passes through the gastrointestinal tract without being absorbed and was ultimately excreted, effectively lowering systemic metabolite exposure. It was hypothesized that AB-2004 would also reduce the structurally related 3-hydroxyhippurate (HHA) and phenylpropanoic acids, or other related small-molecule metabolites such as 3-(3- hydroxyphenyl)-3-hydroxypropionate (HPHPA), 3-(4-hydroxyphenyl)propionate (HPPA), 3- hydroxyphenylacetate (HPAA), 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), and imidazolepropionate (IPA). There was accumulating evidence that increased levels of this chemical class of intestinal metabolites was associated with ASD. For instance, 4EPS, pCS, 3IS, hippuric acid, and hydroxyphenylacetic acid metabolite levels were found to be elevated in children with ASD, and levels of some of these metabolites also correlated with gastrointestinal and behavioral symptoms. These findings go beyond simple associations between intestinal metabolites and behavioral endpoints; namely production of 4EPS by gut bacteria resulted in changes in brain cell function and increased anxiety-like and ASD-like behaviors in mice pCS administered to mice lead to deficits in social communication and repetitive behaviors, and both pCS and 3IS promoted anxiety-like and depression-like features in rodents. To date, no studies have attempted to modify the production or concentrations of this class of compound in human neuropsychiatric disorders. [0211] Results [0212] AB-2004 reduces 4EPS and anxiety-like behavior in mice. It was reported that 4EPS was elevated in the plasma of individuals with ASD, though bacterial sources for production of the metabolite remained unknown. The gut microbiome is predicted to harbor genes that convert tyrosine, the precursor of several mammalian neurotransmitters, to 4- ethylphenol (4EP), which could then be sulfated to 4EPS. Sulfation in the liver or other organs is a common detoxifying activity in mice and humans for structurally related phenolic molecules. [0213] Several bacterial species were systematically tested for the enzymatic activity required for biosynthesis of 4EP from tyrosine. Next, genes that showed predicted activity were cloned into genetically tractable strains of gut bacteria. Subsequently, gnotobiotic mice were colonized with isogenic bacterial strains that were engineered to convert tyrosine to 4-ethylphenol (4EP+ group), or mutants of the same strains that lack genes encoding enzymes that mediate this conversion (4EP- group). It was verified that gut microbial production of 4EP, followed by efficient host sulfation, lead to the presence of 4EPS in urine of 4EP+ mice (FIGs.4A-4C; control).4EPS promoted anxiety-like behavior in several testing paradigms: first, open-field exploration where mice ventured less into the more exposed zone of the arena, second, the elevated plus maze (EPM) where 4EP+ mice spent less time in the terminus of the open arms, and third, the marble burying test (FIGs.4F-I). This experimental paradigm enabled effective testing of drugs that neutralized 4EPS. [0214] Following colonization, both groups of mice were placed on a diet consisting of 5% AB-2004 by weight of chow or matched control diet two weeks prior to behavior testing (FIG. 4B). As expected, systemic levels of 4EPS measured in urine were lowered by oral AB-2004 administration (FIG.4C). There were no differences in bacterial colonization levels and weight gain was not significantly influenced (FIGs.4D, 4E), and no signs of distress, illness or other differences were observed among the mouse groups. Behavioral analysis revealed that treatment with AB-2004 ameliorated behavioral deficits in the open field and elevated plus maze tests for anxiety (FIGs.4F-4H). Specifically, 4EP+ mice given AB-2004 spent more time exploring the exposed (i.e., riskier) areas of the tests compared to 4EP+ mice on the control diet. AB-2004 treatment also stabilized performance in the anxiety/repetitive behavior-related marble burying test (FIG.4I). These results were accompanied by trending improvements in the grooming test for repetitive behavior (FIG.4J). Results from this simplified mouse model indicated that AB- 2004 was effective in reducing systemic levels of 4EPS and prevented 4EPS-induced anxiety- like behaviors. [0215] Phase I clinical trial design. An open-label, phase 1b/2a clinical trial was designed and conducted at three sites in New Zealand and Australia with primary endpoints for safety and tolerability as determined by reported/observed adverse effects and laboratory results. Secondary endpoints included target engagement, which was assessed objectively by measuring microbially-derived metabolites in plasma and urine. Behavioral endpoints were exploratory. At screening, ASD diagnosis was confirmed using the Autism Diagnostic Observational Schedule, Second Edition (ADOS-2) and the presence of gastrointestinal symptoms was verified through the Gastrointestinal Severity Index (6-GSI) and a 14-day bowel habit diary.30 adolescents (29 male, 1 female) previously diagnosed with ASD (FIG.1A, FIG.6A) met the inclusion criteria as outlined in Table 2. After enrollment, each participant was administered baseline behavioral assessments using the Pediatric Anxiety Rating Scale (PARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS-2), Repetitive Behavior Scale Revised (RBS-R), and Vineland Adaptive Behavior Score (VABS-3) and several gastrointestinal symptom metrics were measured, including the 6-GSI53, Bristol Stool Scale (BSS), and Gastrointestinal Symptom Rating Scale tool (GSRS). All inclusion and exclusion criteria can be found in Table 2. Study participants were asked to take three daily, weight-adjusted (see Methods for details), ascending oral doses of AB-2004 totaling ≤2.25g/day, escalating to ≤4.5g/day at 2 weeks and ≤6g/day daily at 4 weeks until the end of treatment on Week 8, with a final visit 4 weeks after end of treatment (FIG.1B). Urine, blood and stool samples were collected, and behavioral assessment performed, at baseline (BL), end of treatment (EOT), and final visit (FV), with continuous health monitoring throughout (FIG.1B, Table 3).27 of 30 enrolled participants completed to the EOT, but one was removed due to COVID schedule interruptions, resulting in a completers group of 26.24 participants completed to the FV. [0216] AB-2004 is safe and well tolerated in adolescents with ASD. Assessment of overall health, including gastrointestinal symptoms, was determined by the clinical global impressions scale for severity and improvement (CGI-S and CGI-I, respectively).76.9% of participants (20 out of 26) improved at least one point on the CGI-I scale from BL to EOT (FIG.5B). While gastrointestinal symptoms were an inclusion criterion based on 6-GSI and a 14-day bowel habit e-diary assessment during screening, 19.2% of participants presented with no clinical gastrointestinal disorder based on the CGI at the time of assessment (including normal and borderline scores). Importantly, the number of participants with no measurable gastrointestinal symptoms doubled from BL to EOT (19.2% to 38.5%) (FIG.5C). [0217] Median adherence to dosing was 97.5% and no laboratory concerns arose, showing AB-2004 was well tolerated. Importantly, overall safety metrics showed that no serious adverse events related to the drug or any deaths occurred during the reporting period of the study. The majority of mild or moderate adverse effects were in the gastrointestinal category, including abdominal pain and nausea (Table 1). The study therefore met its primary endpoints for safety and tolerability, extending the safety record of this drug to an adolescent ASD population for the first time. [0218] Microbial metabolite levels are lowered by AB-2004. Based on the known pharmacology of binding phenolic compounds, and its practically complete lack of systemic absorption, it was hypothesized that oral AB-2004 would diminish levels of specific intestinal metabolites in circulation by facilitating their excretion in the feces. As predicted, AB-2004 treatment resulted in reduced levels of 4EPS, pCG, pCS, 3IS, HPHPA, and HPAA in urine from the BL to EOT timepoints (FIGs.2A-2G, FIG.6A), with similar profiles in plasma (FIG.6B). Concentrations between urine and plasma were highly correlated for many metabolites (FIG. 6C). Urine metabolites largely rebounded to pre-drug (BL) levels at the FV timepoint 4 weeks after treatment had concluded, which supported the conclusion that metabolite levels were influenced directly by AB-2004 administration (FIGs.2A-2G). N-acetyl serine levels, which were measured as a control metabolite not bound by AB-2004, did not change in urine or plasma between BL and EOT (FIG.6D). These data indicated that target engagement of gut-derived intestinal metabolites by AB-2004 could effectively reduce their systemic levels. [0219] Oral AB-2004 may alter brain connectivity. As a measure of brain activity patterns, resting state functional magnetic resonance imaging (fMRI) were performed on a small subset of ten study participants to estimate connectivity between brain regions. Two 5-minute scans were conducted at BL and EOT timepoints that focused on changes in regions associated with emotional behavior responses. This included regions such as the amygdala, which was crucial for emotional processing networks such as those involving anxiety, and the anterior cingulate cortex (ACC), which was involved in emotional and cognitive networks. Atypical activity in one or both of these regions was observed in preclinical studies and in ASD cohorts. A decrease in coupling between the amygdala and the rostral anterior cingulate cortex (rACC2) was observed (FIG.7A), an encouraging outcome since higher amygdala-rACC connectivity was associated with higher anxiety. This pilot finding suggested that further study of functional connectivity in the amygdala and ACC may provide insights into mechanisms-of-action of AB-2004 and the metabolites it binds. [0220] Exploratory efficacy outcomes show improvement of core ASD behavior. Several domains of behavioral data for all study participants were captured as exploratory endpoints. The VABS5 was administered at BL, EOT, and FV, and overall scores as well as communication and socialization scores were significantly increased by EOT (FIGs.7B-7E). Although ten participants were removed from this analysis due to incomplete data, thereby limiting the sample size of this comparison, a mean increase of 7.8 points from BL to EOT in the Adaptive Behavior Composite score was above the minimal clinically relevant cutoff of 3.75 points (FIG.7B). Modest indications of improved social communication and repetitive behavior of study participants was also detected in other behavioral assessments, including the SRS (FIGs.8A-8F) and to a lesser extent in the ABC (FIGs.8G-8J). Importantly, both assessment tools had been used to evaluate the efficacy of ASD therapeutics. [0221] AB-2004 reduces anxiety and irritability. The most striking behavioral outcomes of AB-2004 treatment in two highly prevalent non-core domains of ASD, namely anxiety and irritability were reported. In particular, study participants with elevated BL anxiety scores ≥10, as measured by the PARS test, showed marked improvements in anxiety between initial (BL) and last (EOT) dose, a positive effect that persisted 1 month after withdrawal of drug (FV) (FIGs.3A, 3B). These results indicated that AB-2004 may be effective in treating elevated anxiety in individuals with ASD, as the minimum clinically important change in the PARS score was 15%. The results described herein showed an average improvement of 30% among the group with anxiety at BL, with 9 out of 15 individuals with elevated anxiety resulting in a diagnostic score that qualified as remission (score of 10 or below). [0222] Irritability is also frequent in the ASD population and can be assessed as part of the ABC scale. A significant overall decrease in irritability as measured by the ABC-I subscale between BL and EOT was observed (FIG.3C). In particular, individuals with high BL irritability (scores ≥ 15), which represented the top quartile of severity within the ASD population as a whole, displayed a remarkable 9.1 point decrease in ABC-I (FIG.3D). The improvements at EOT were largely mitigated after drug washout (FV) in most participants (FIG.3D). Correlations between a single metabolite and behavioral scores were not clear (Table 4). These data revealed that almost all study participants with elevated anxiety or irritability showed significant behavioral improvements following 8 weeks of treatment with AB-2004. [0223] Discussion [0224] Based on data from the completed open-label trial described herein, AB-2004 is safe and well-tolerated for use in an adolescent ASD population, with no serious adverse events related to the drug. This study also suggested target engagement by AB-2004, as evidenced by reduced levels of intestinal metabolites in plasma and urine following 8 weeks of treatment, and a general rebound to baseline levels after 4 weeks of drug washout. Further, AB-2004 decreased the number participants presenting with gastrointestinal symptoms; however, it was unclear whether intestinal issues were linked to other endpoints. Though this study was powered for safety and tolerability, surprisingly, indicators of improvements in ASD-associated behaviors, namely anxiety and irritability, were observed. Decreased anxiety persisted after drug removal, whereas improvements in irritability largely returned to baseline levels by the final visit. A contribution for metabolites bound by AB-2004 that were not measured here, either of host, dietary, or microbial origin, could not be excluded. Also, this study did not resolve indirect effects of drug through potential changes in nutrition, immune status, and gastrointestinal function, for example, and further proof-of-mechanism will require additional work. However, this was the first interventional study that linked phenolic metabolites in the gut with clinical features of ASD. While the preliminary evidence for improvements in behavior within this small ASD cohort were encouraging, the absence of a control arm necessitated double-blinded placebo-controlled trials to confirm efficacy of AB-2004. [0225] There are currently no approved pharmacological therapies for the treatment of the core symptoms of ASD. Two drugs, risperidone and aripiprazole, are approved by the U.S. Food and Drug Association (FDA) for treatment of irritability in ASD individuals. Irritability behaviors are common in pediatric ASD and have major implications in child development, receptivity to behavioral therapy, and child/caregiver health-related quality of life. Both drugs are atypical antipsychotic medications and are associated with a range of side effects such as somnolence, metabolic changes, weight gain, leukopenia, and tardive dyskinesia. In a phase 3 study of aripiprazole with inclusion criteria based on high irritability levels (ABC-I ≥ 18), the response rate, or percentage of individuals with 25% improvement in ABC-I scores and a CGI-I ≤ 2, was 49-56% in the drug arms, with a 34.7% response rate in the placebo arm. In the present study, a post-hoc analysis showed a 75% and 82% response rate in subgroups meeting somewhat similar criteria (ABC-I 18 or 15, respectively). [0226] A placebo-controlled randomized trial is performed to test the effects of AB-2004 in an ASD cohort powered to report changes in irritability. Table 1. Treatment Emergent Adverse Events. n=number of subjects with events; %=percent of subjects with events; E=number of events.

Table 2. Exclusion Criteria

Table 3. Schedule of Assessments

Key: X: Mandatory, O: Optional. Footnotes for Schedule of Assessments: a) Vital signs included body weight, pulse rate (beats per minute), blood pressure (systolic and diastolic blood pressure, mm Hg), and respiratory rate (respirations per minute) after at least 2 minutes at rest in a supine position. Height was only to be recorded at Visit 1 . b) Physical Examination (PE) - full PE including at least general appearance, head (eyes, ears, nose, mouth, throat), skin, neurological, musculoskeletal, cardiovascular, respiratory, abdomen and extremities; abbreviated PE was symptom-directed. c) An e-diary was used to assess GI symptoms, including pain, additional electronic patient reported outcomes (BSS and NRS), and IP dosing. A paper diary was provided to subjects to use if there were technical issues with the-diary application or if subjects were unable to complete the details in the e-diary for any reason. d) Home collection samples. First sample was to be collected within 1 week of Visit 1 and subsequent samples were to be collected 2 to 3 days before the next scheduled visit. e) Biomarker assessments performed in samples from blood (plasma or serum), urine, and feces. Blood: intestinal permeability (eg, zonulin, fatty acid-binding protein 2, ct-1 antitrypsin, lipopolysaccharide binding protein) and systemic inflammation (eg, TNF-a, IL-2, IL-2R, IL-2Ra, IFN-y, IL-4, IL-5, IL- 12, IL-10, IL- 13, IL- 17, IL- 1 P, IL-6, and/or IL-8). Urine: microbial and host metabolites (eg, 4-EPS, p-CS, 5HIAA). Feces: intestinal inflammation (fecal calprotectin) and metagenomics. f) Laboratory tests to establish eligibility were to be completed within 28 days prior to enrollment and results reviewed by the Investigator or authorized delegate before enrollment. g) Drug of Abuse Screen - dipstick urine drug tests were screened for non-prescribed cannabis, cocaine, amphetamines, benzodiazepines, and barbiturates to ensure subjects were not self-medicating during the study. A separate urine alcohol test was performed by the central laboratory. h) Pregnancy testing was applicable to female subjects only. The test was to be conducted on either a urine or serum sample. i) BSS and NRS were captured in the e-diary/paper diary on a daily basis. j) MRIs were performed on a subset of subjects (—10). All subjects were to be offered an MRI at sites where MRIs were available. k) Screening visit was to be conducted over 2 to 3 visits. Consent/assent, assessments to confirm eligibility, and initiation of the e-diary/paper diary were to be completed at the first part of Visit 1, whereas other tests were to be performed over a period of up to 28 days.

Abbreviations: 4-EPS = 4-Ethylphenyl Sulfate; 5HIAA = 5-Hydroxyindoleacetic acid; 6-GSI = Gastrointestinal Severity Index; ABC = Aberrant Behavior Checklist; ADOS-2 = Autism Diagnostic Observational Schedule, Second Edition; BSS = Bristol Stool Scale; CASI-5 = Child and Adolescent Symptom Inventory 5; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-Severity; EOT = End of Treatment; GI = gastrointestinal; GSRS = Gastrointestinal Symptom Rating Scale; IP = Investigational Product; MRI = magnetic resonance imaging; NRS = Numeric Rating Scale; PARS = Pediatric Anxiety Rating Scale; p- CS = p-Cresol sulfate; RBS-R = Repetitive Behaviors Scale - Revised; SRS-2 = Social Responsiveness Scale-2; V = Visit.

Table 4. Metabolite and Behavior Correlations

Table 5. Demographics (completers)

Table 6. ABC Subscales

Table 7. PARS

Table 8. VABS

Table 9. SRS

Example 2

Exploratory Analysis of Metabolite Biomarkers or Composite Biomarkers

An exploratory analysis was conducted to determine the nature of the relationship between change in metabolites from Baseline to Week 8 and change in assessment scores over that period, for subjects who participated in AXL- 1224-2004-001. This was an open-label, single-arm, multiple ascending dose study.

Objectives:

1. To determine which biomarker changes from Baseline to Week 8 were most strongly related to change in assessment score for Aberrant Behavior Checklist - Irritability (ABC- I) and Pediatric Anxiety Rating Scale (PARS), within three overlapping subject populations.

2. To measure evidence that changes in biomarkers are generally related to changes in assessment score.

Population analysis was conducted among subjects who met the following conditions: all subjects who completed the study through week 8 (N=26), subjects who had a screening ABC-I score of 15 (N=l 1) or higher or a screening PARS score of 10 or higher (N=15), and subjects who had a Screening ABC-I score of 15 or higher and a screening PARS score of 10 or higher (N=8).

The response variables included: Change in assessment score, calculated as raw change (Week 8 score - Screening score) in ABC-I score and PARS score. The covariate was the baseline score (ABC-I or PARS). The predictor variable was calculated as follows: Change in biomarker = Iog2-Fold Change (log2(Week 8 value / Baseline value)) for 12 biomarkers measured in two specimen types (Serum and Urine) - 22 total combinations. The baseline value was the average of the screening and day 1 values, when both were available.

Analysis for Objective 1

The squared partial correlation between each response variable and each predictor variable, adjusting for baseline assessment score, was calculated to measure the strength of the relationships between the change in assessment scores and the change in biomarkers, for each analysis population. The theoretical range for these values was between 0 (little to no relationship) and 1 (a perfect linear relationship). Higher values represented a stronger relationship.

The relationship between assessment and biomarker varied depending on the assessment, biomarker, and analysis population. Biomarkers 4-EPS, INDPYR, N-AS generally showed the strongest relationship with ABC-I across analysis populations. Biomarkers HPAA, N-AS, and p- CS generally showed the strongest relationship with PARS across analysis populations.

Analysis for Objective 2

Following Objective 1, The top k biomarkers for each assessment, in terms of squared partial correlation, were selected for a multiple regression analysis. For each analysis population, k was chosen to be N/3, rounded down, to mitigate the risk overfitting. These biomarkers, along with baseline score, were used to predict the change in assessment score.

Across analysis populations and assessments, the biomarker + baseline-score models outperformed the baseline-score-only models by between 10-50 percentage points in multiple-R² This implied that changes in several of the exploratory biomarkers contain important, unique, and potentially predictive information about changes in assessment scores.

ASD Metabolomics assays and sample analysis

Samples from the AB-2004 Phase lb/2a study was analyzed. Targeted analysis was conducted in urine (11 analytes; IP A removed) and plasma (12 analytes).

A quantitative assay for 4-EPS and pCS was developed. Quantitative LC-MS assay were developed for 4-EPS and pCS for human urine and plasma to provide relatively quick and cost- effective generation of “fast turnaround” data.

Urine and plasma samples for 4-EPS and pCS were analyzed.

Targeted analysis was carried out in urine (11 analytes) and plasma (12 analytes)

ASD targeted metabolite panel history The original panel targeted 14 metabolites that were selected based on: structural similarity to 4-EPS and putative role in or correlation with behavioral phenotypes (ASD, anxiety, executive function, etc.). The metabolites were 4-EP: 4-ethyl phenol, 4-EPS: 4- ethylphenyl sulfate, pC: para-cresol, pCS: para-cresyl sulfate, pCG: p-cresyl glucuronide, 3-IS

(3-indoxyl sulfate), NAS: N-acetylserine, Indole pyruvate, IPA: Imidazole propionate, CMPF:

3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid, 3-HHA: 3 -hydroxy hippuric acid or 3- hydroxyhippurate, 3-HPHPA: 3-(3-hydroxyphenyl)-3-hydroxyproprionic acid, HPPA: 4- hydroxyphenylpropionic acid, and HPAA: 3-hydroxyphenylacetic acid or 3- hydroxyphenylacetate.

In the revised targeted panel, a down-selected targeted panel based on lack or prevalence in ASD samples or inability to validate technically in 11 urine and 12 plasma samples. The metabolites 4-EP and pC were excluded. Indole pyruvate was removed from both the urine and plasma panel and Imidazole propionate (IPA) was removed from the plasma panel. The metabolites that were included were 4-EPS, pCS, pCG: p-cresol glucuronide, 3-IS, NAS: N-acetylserine, CMPF: 3-Carboxy-4-methyl-5-propyl-2- furanpropionic acid, 3-HHA: 3 -hydroxy hippuric acid or 3-hydroxyhippurate, 3-HPHPA: 3-(3- hydroxyphenyl)-3-hydroxyproprionic acid, HPPA: 4-hydroxyphenylpropionic acid, and

HPAA: 3-hydroxyphenylacetic acid or 3-hydroxyphenylacetate.

Table 10. Autism metabolite panel - Urine

Indole pyruvate was not included in final urine assay. A quantitative assay was unable to be developed either with or without derivatization. Furthermore, it was shown that the compound was unstable in the analysis solution while in the autosampler. See validation report for more context and detail. All urine samples were diluted 10-x as part of the method. Observed ranges shown were what assay result showed. The actual original concentration in urine sample was 10-x higher. Quantitation ranges (100 or 400-fold) were established based on the analysis of 6 male and 6 female plasma and urine samples. In some embodiments, quantification ranges were established by the lower limits of assay sensitivity.

Table 11. Autism metabolite panel -- PLASMA

Indole pyruvate was omitted from the plasma panel due to observed run-to-run (lot-to-lot) performance issues observed in analysis of AXL- 1224-2004-001 study samples. IPA was omitted from the plasma panel due to low hit-rate (only 2/139 samples were positive in CHARGE quantitative analysis). Quantitation ranges (100 or 400-fold) were established based on the analysis of 6 male and 6 female plasma and urine samples. In some embodiments, quantification ranges were established by the lower limits of assay sensitivity. Table 12. Autism metabolite panels - validation overview

Autism metabolite panels - Assay details

Urine Methods

For Assay 1, samples were prepared by diluting human urine 10-fold [10 pL urine

+ 90 pL PBS]. Samples were spiked with an Internal Standard [+40 ul Internal Standard

Working Solution (WIS8)]. A solvent crash was performed using ACN/MeOH extraction. An aliquot was removed for Method 1 [150 μL]. An aliquot was derivatized for Method 2 using

100 pL of the ACN/MeOH extracted sample.

In method 1, LCMS was conducted by injecting aliquot onto Agilent 1290/AB

Sciex 5500 QTrap LC-MS/MS with UHPLC C18 column. pCS, 3-IS, and pCG were measured in Negative Mode. In method 2, LCMS was conducted by injecting aliquot onto

Agilent 1290/AB Sciex 5500 QTrap LC-MS/MS with UHPLC CIS column. N-AS, HPA,

HPAA, HPHPA, and HPAA were measured in Negative mode.

For Assay 2, samples were prepared using undiluted urine [50 pL], The samples were spiked with an Internal Standard [+20 pl Internal Standard Working Solution (WIS3)].

A solvent crash was performed using ACN/MeOH extraction. An aliquot was removed for 2 native LC/MS methods [3 and 4; 150 pL|.

In method 3, LCMS was conducted by injecting aliquot onto Agilent 1290/AB

Sciex 5500 QTrap LC-MS/MS with UHPLC C18 column. 4-EPS and CMPF were measured in Negative Mode. In method 4, LCMS was conducted by injecting aliquot onto Agilent 1290/AB Sciex 5500 QTrap LC-MS/MS with a second UHPLC C18 column. Imidaxol epropionate (IP A) was measured in Positive Mode.

PLASMA METHODS

All 3 samples were prepared using undiluted plasma [50μL] and spiked with Internal Standard [+20 μL WIS], Protein was precipitated using ACN/MeOH extraction and spun. 100 μL of aliquot was removed for 2 native LC/MS methods, methods 1 and 2. An aliquot was derivatized for Method 3 using 100 μL of the ACN/MeOH extracted sample.

In method 2, LCMS was conducted by injecting aliquot onto Agilent 1290/AB Sciex 5500 QTrap LC-MS/MS with UHPLC C18 column. pCS, 3-IS, pCG, 4-EPS, and CMPF were measured in Negative Mode. In method 3, LCMS was conducted by injecting aliquot onto Agilent 1290/AB Sciex 5500 QTrap LC-MS/MS with UHPLC C18 column. N-AS, HP A, HPAA, HPHPA, and HPAA were measured in Negative mode.

Results

1. Composite Biomarkers for patient identification (likelihood of responding to treatment)

See FIGs. 12-14. FIGs. 12 and 13 show the correlation of individual metabolite levels at baseline (pre-treatment) with changes in irritability (ABC-I) score (FIG. 12), changes in anxiety (PARS) score (FIG. 13). As can be seen, some of these metabolites show good correlations to these score changes on an individual metabolite basis. For example, FIGs. 12 and 13 show high correlation of levels of serum and urine 4-EPS in subjects with high baseline irritability (ABC-I) and both high baseline irritability (ABC-I) and anxiety (PARS). FIG. 14 shows the correlations of different combinations of metabolites with these different subsets of subjects (all subjects, high baseline irritability, high baseline irritability and anxiety). For example, FIG. 14 shows several combinations of metabolites have r-squared correlation values > 75%, which indicates a high correlation in this data set.

2. Composite Biomarkers of change (e.g., measuring treatment response) See FIGs. 9-11. FIGs. 9 and 10 shows show the correlation of change of individual metabolite levels after treatment with changes in irritability (ABC-I) score (page 1), changes in anxiety (PARS) score (page 2). Some of these metabolites show good correlations to these score changes on an individual metabolite basis. For example, FIG. 9 shows changes in serum and urine 4-EPS correlate strongly with changes in irritability (ABC-I) score. FIG. 11 shows the correlations of changes in different combinations of metabolites with changes in scores within these different subsets of subjects (all subjects, high baseline irritability, high baseline irritability and anxiety). For example, FIG. 11 shows changes in several combinations of metabolites have r-squared correlation values > 70%, again, which indicates a high correlation in this data set.

3. Composite Biomarkers for diagnosis

See FIGs. 12-14. This data can be used to make diagnoses. For example, those subjects with certain baseline levels of metabolites (e.g., 4-EPS in serum and urine, or HHA in serum) may be predicted to have high irritability given the high correlation value of change (improvement) in irritability. It could be inferred that those subjects must have measurable irritability, and hence could be diagnosed with irritability, in order to see an improvement in irritability.

4. Composite Biomarkers for risk of different clinical phenotypes (and/or symptoms)

See FIGs. 9-14. This data can be used to predict risk of different clinical phenotypes or symptoms in a way that is explained under paragraph 3 above.

Example 3

Exploratory Analysis of Metabolite Biomarkers or Composite Biomarkers

An exploratory analysis was conducted to determine the nature of the relationship between change in metabolites from Baseline to Week 8 and change in assessment scores over that period, for subjects who participated in a placebo-controlled Phase 2b clinical trial in which AB2004 is tested. The wet methods and the statistical analysis described in Example 2 is used to analyze the Phase 2b data, and is adaptable to data sets of any size, and the predictive power should increase with larger data sets. Example 4

Establishment of 4EP -producing microbiota and administration of AB-2004

The effect of 4EP production by the gastrointestinal microbiota was investigated using gnotobiotic mice that were di -colonized with strains engineered to differ solely in their capacity to produce 4EP, which is converted to 4EPS by the host. The effect of an AB-2004 preparation that sequesters 4-EP, its derivative 4-EPS and other toxic microbial metabolites, was investigated by formulating the AB-2004 into mouse food and administering it in parallel with a control diet that did not contain AB-2004 but was otherwise identical. Impact of 4EP production by the microbiota and AB-2004 administration was determined via assessments of repetitive, social and anxiety-like behaviors that represent core and non-core symptoms of autism spectrum disorders (ASD).

To produce the engineered strains, the Bacteroides ovatus gene for p-coumaric acid production was cloned in tandem with the Bacillus subtilis gene for phenolic acid decarboxylase into the B. ovatus chromosome to produce 4-vinylphenol. Lactobacillus plantarum converts 4- vinylphenol produced by the engineered B. ovatus strain to 4-EP. To produce a pair of otherwise identical strains that is incapable of 4EP production, a loss-of-function mutation was introduced into the B. ovatus strain, resulting in elimination of 4-vinylphenol production and consequently 4- EP production by L. plantarum.

At the age of 5 weeks, mice were placed on a diet that contained 8% w/w of an AB-2004 preparation (AST-120, Kureha Corporation, Japan), or an otherwise identical diet that did not contain AB-2004. Colonization of mice was quantified by plating dilutions of fecal homogenates on solid media, and the two pairs of strains were confirmed to colonize mice to similar levels, as similar levels of colony forming units per mL fecal homogenate were produced in the assay (Figure 16). Table 13 describes the identifiers used for groups of mice in figure labels in this section.

Table 13. Descriptions of Mouse Group Labels in Figures

Marble Burying

A marble burying test was used to assess repetitive behavior, which is a core symptom of ASD. In the assay as described by Malkova et al. (Behav Immun. 26(4):607-16 (2012)), marbles are placed on top of bedding in a cage, a test mouse is placed in the cage, and the number of marbles buried by the mouse during the test period is measured. As shown in Figure 17(a), in the assay, mice on control diet that were di-colonized with 4-EP producing microbes buried significantly more marbles than mice on control diet that had been di-colonized with microbes that did not produce 4-EP, thereby demonstrating repetitive behavior due to 4EP production by the gut microbiota. Administration of AB-2004 normalized this repetitive behavior in the assay: mice with 4-EP producing microbiota on the AB-2004 diet burying significantly fewer marbles than mice with 4-EP producing microbiota on control diet. The data indicate that administration of materials that sequester 4-EP, 4-EPS and/or other toxic microbial metabolites can be beneficial for reducing repetitive behaviors, one of the core symptoms of ASD.

Elevated Plus Maze

The elevated plus maze (EPM) test of exploratory behavior was used to assess general locomotion and anxiety-like behavior. Mice were allowed 5 minutes to explore an elevated plus maze comprised of two open arms and two closed arms that extend from a common central platform. A small raised lip around the edges of the open arms helped prevent mice from slipping off. An overhead video camera was used to record the session, and Ethovision software (Noldus Information Technology, Sacramento, CA) was used to analyze mouse movements. Time spent in closed, relatively protected portions of the maze versus time spent exploring open, relatively exposed portions of the maze is interpreted as a measurement of anxiety. As shown in Figure 17(b), in the assay, mice with 4-EP producing microbiota on control diet spent less time than mice on control diet with microbiota that does not produce 4-EP in open portions of the EPM versus closed portions of the EPM, thereby demonstrating anxiety-like behavior due to production of 4EP by the intestinal microbiota. Administration of an AB-2004 preparation normalized these anxietylike behaviors in the assay, as mice with 4-EP producing microbiota on AB-2004 diet spent significantly more time in open versus closed portions of the EPM than mice with 4-EP producing microbiota mice on control diet that lacks AB-2004. Anxiety is a common non-core symptom of ASD, and these indicate that administration of sequestrants of 4-EP, 4-EPS and/or other toxic microbial metabolites can be beneficial in reducing anxiety symptoms in some ASD patients.

Open Field

The open field test of exploratory behavior was used to assess general locomotion and anxiety-like behavior. For open-field testing, mice were allowed to explore a 50 x 50-cm white Plexiglas box for 10 minutes. An overhead video camera was used to record the session, and Ethovision software (Noldus Information Technology, Sacramento, CA) was used to analyze the distance traveled, and the number of entries and duration of time spent in the center arena (central square, 17 x 17 cm) versus the wall area of the box. Mice on control diet that had been colonized with 4-EP producing microbiota exhibited an anxiety -like phenotype in the assay, entering the wall area with greater frequency and spending more time in the wall area compared to mice on the control diet that had been colonized with microbiota that did not produce 4-EP. In the assay, the amount of time that mice that had been colonized with 4-EP producing microbiota on AB-2004 diet spent in the wall area (Figure 18(B)) and the frequency with which they entered the wall area (Figure 18(A)) were similar to mice that had been colonized with microbiota that do not produce 4-EP, suggesting normalization of this behavior by AB-2004. Total distance moved (Figure 18(C)) in the open field test was similar for all groups, suggesting that differences in exploration of open versus closed parts of the field are not due to differences in the distance that the mice moved during the test. Consistent with the EPM data, these data provide additional evidence that administration of materials that sequester 4-EP, its derivative 4-EPS and/or other toxic microbial metabolites can be beneficial in alleviating symptoms of anxiety in ASD patients who suffer from them. Direct Social Interaction

A three-chambered social approach test was used to measure direct social interaction. The test mouse was placed in the center chamber of three adjacent chambers, with a novel object in an adjacent terminal chamber and an unfamiliar mouse in the other adjacent terminal chamber. The test mouse was habituated in the apparatus for 10 minutes prior to initiation of scoring. The test mouse was able to pass through openings from the center chamber into each of the adjacent chambers. The test was recorded by video, and the time spent by the test mouse in the chamber with the unfamiliar mouse was scored manually. A higher amount of time spent with the unfamiliar mouse is an indicator of increased sociability, while a lower amount of time spent with the unfamiliar mouse is an indicator of decreased sociability, consistent with the social deficits that are a core symptom of Autism Spectrum Disorders.

As shown in Figure 19, in the three-chamber test of social interaction, male mice dicolonized with 4EP -producing microbiota spent significantly less time in the chamber with another mouse than male mice di-colonized with microbes that do not produce 4EP. In the assay, there was a trend for improvement of this social deficit by treatment with an AB-2004 preparation (p=0.1071). These data indicate that administration of materials such as AB-2004 that sequester 4EP, its derivative, 4EPS, and other toxic microbially-derived metabolites to patients with ASD can be beneficial to improve core symptoms of ASD, such as social deficits.

Example 5

Removal of microbial metabolites by sequestrant materials

A 50 mg/mL stock solution of a single microbial metabolite was prepared in dimethylsulfoxide (DMSO) and serially diluted (2: 1) in DMSO to create standard solutions of 50, 25, 12.5, 6.25, 3.125, 1.56 and 0.78 mg/mL. Each DMSO standard solution (10 μL) was diluted into deionized water (990 μL) to create standard calibration samples of 0.5, 0.25, 0.125, 0.06, 0.03, 0.015, 0.078 mg/mL aqueous solutions (1% DMSO). A blank sample was prepared by adding 10 μL DMSO to 990 μL distilled water and the UV-absorbance of each aqueous standard solution was measured at a single wavelength using a Thermo Scientific NanoDrop™ spectrophotometer to identify the linear range of absorbance and generate a calibration curve.

A 0.5 mg/mL solution of a single microbial metabolite was prepared in deionized water by adding 100 μL of 50 mg/mL DMSO stock solution to 9.9 mL deionized water. Next, 50 mg/mL of one of a series of sequestrant material being tested was added and the solution was stirred at room temperature. The resulting mixture was sampled over a time course from 0 to <4 hours. At each time point, approximately 1 mL of sequestrant mixture was taken up by syringe and passed through a nylon syringe filter (0.2μm). Each sample was appropriately diluted with deionized water and either transferred to a cuvette for analysis using a Thermo Scientific™ NanoDrop (Fisher Scientific, Waltham, MA) or transferred to a 96-well clear bottom plate for analysis using a Spectramax i3x (Molecular Devices, San Jose, CA).

The absorbance of 4-EP by various representative sequestrant materials was conducted according to the general protocol. The UV-absorbance of each sample was measured at 270 nm by spectrophotometry. The % remaining of 4-EP following treatment with representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 14.

The following meanings apply: “++++” refers to <10% remaining; “+++” refers to 10-30% remaining; “++” refers to 31-70% remaining; “+” refers to 71-90% remaining; NA refers >90% remaining or no absorption observed. The zeolite used was clinoptilolite, with the general stoichiometry of (Na,K,Ca)_2-3AI₃(Al,Si)₂Si₁₃O₃₆. ₁₂H₂O; bentonite preparation was produced from Bentonite B.P. (Hal ewood Chemicals, UK); activated charcoal preparation was produced from 260 mg Activated Charcoal Dietary Supplement capsules (Nature’s Way, Green Bay, WI), and the AB- 2004 preparation was produced from AST-120 (Kureha Corporation, Japan).

Table 14: Absorption of 4-EP

Example 6

The removal of 4-EPS from test solutions by various representative sequestrant materials was conducted according to the general protocol given in Example 5 with the UV-absorbance of each sample measured at 265 nm using spectrophotometry. The % remaining of 4-EPS following provision of representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 15.

Table 15: Absorption of 4-etl

Example 7

The removal of p-cresol from test solutions by various representative sequestrant materials was conducted according to the general protocol given in Example 5 with the UV-absorbance of each sample measured at 260 nm using spectrophotometry. The % remaining of p-cresol following provision of representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 16.

Table 16: Absorption of p-cresol

Example 8

The removal of p-cresyl sulfate from test solutions by various representative sequestrant materials was conducted according to the general protocol given in Example 5 with the UV- absorbance of each sample measured at 260 nm using spectrophotometry. The % remaining of p- cresyl sulfate following treatment with representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 17. Table 17: Absorption of p-cresyl sulfate

Example 9

The removal of indole from test solutions by various representative sequestrant materials was conducted according to the general protocol given in Example 5 with the UV-absorbance of each sample measured at 278 nm using spectrophotometry. The % remaining of indole following provision of representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 18.

Table 18: Absorption of indole

Example 10

The removal of 3 -indoxyl sulfate from test solutions by various representative sequestrant materials was conducted according to the general protocol given in Example 5 with the UV- absorbance of each sample measured at 260 nm using spectrophotometry. The % remaining of 3- indoxyl sulfate following treatment with representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 19. Table 19: Absorption of 3-indoxyl sulfate

Example 11

The removal of 4-hydroxyphenylacetic acid from test solutions by various representative sequestrant materials was conducted according to the general protocol given in Example 5 with the UV-absorbance of each sample measured at 278 nm using spectrophotometry. The % remaining of tyrosine following treatment with representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 20.

Table 20: Absorption of 4-hydroxyphenylacetic acid

Example 12

The removal of 2-hydroxy-2(4-hydroxyphenyl)acetic acid from test solutions by various representative sequestrant materials was conducted according to the general protocol given in Example 5 with the UV-absorbance of each sample measured at 278 nm using spectrophotometry. The % remaining of 2-hydroxy-2(4-hydroxyphenyl)acetic acid following treatment with representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 21. Table 21 : Absorption of 2-hydroxy-2(4-hydroxyphenyl)acetic acid

Example 13

The removal of L-homocitrulline from test solutions by various representative sequestrant materials was conducted according to the general protocol given in Example 5 with the UV- absorbance of each sample measured at 274 nm using spectrophotometry. The % remaining of L- homocitrulline following treatment with representative adsorbent materials at 50 mg/mL for 2 hours is reported in Table 21.

Table 21: Absorption of L-homocitrulline

Example 14

Indoxyl sulfate, p-cresyl sulfate, and 4-ethylphenyl sulfate, respectively, were separately dissolved in phosphate buffer at pH 6.8 and exposed to AB-2004 with stirring for various lengths of time. At various time points, samples were withdrawn and assayed for the presence of the respective compound (labeled “toxins” below), and the amount of each compound removed from solution was calculated. Results are shown below in Table 22, where “Activated Charcoal” refers to an AB-2004 preparation. Table 22

These results indicate that maximal absorption occurs in less than four hours of exposure for each compound when exposed to an AB-2004 preparation.

Example 15

Indoxyl sulfate, p-cresyl sulfate, and 4-EP, were simultaneously dissolved in phosphate buffer at pH 6.8 to create a simulated metabolite mixture and exposed to AB -2004 with stirring for various lengths of time. At various time points, samples were withdrawn and assayed for the presence of the respective compound (labeled “toxins” below), and the amount of each compound removed from solution was calculated. Results are shown below in Table 23, where “Activated Charcoal” refers to an AB-2004 preparation.

Table 23

These results indicate that maximal absorption occurs in less than four hours of exposure even for compounds in mixed solutions when exposed to an AB-2004 preparation.

Example 16

4-ethylphenyl sulfate, was dissolved in phosphate buffer at pH 6.8 and exposed to AB- 2004, cellulose acetate propionate (MW 15K and 75K), bentonite, and clinoptilolite zeolite with stirring for various lengths of time. At various time points, samples were withdrawn and assayed for the presence of the respective compound, and the percentage of each compound removed from solution was calculated. Results are shown in Figure 20.

These results provide evidence that cellulose based polymeric materials are effective sequestrants of the metabolite 4-EP.

Example 17

Removal of microbial metabolites in fecal slurry supernatant by sequestrant

To determine the capacity of AB-2004, bentonite, zeolite, cellulose acetate propionate (Mn -15,000) and activated charcoal to adsorb the toxins 4-ethylphenol, p-cresol and 3-indoxyl sulfate from a complex mixture of metabolites similar to those found in the lumen of the human colon, an ex vivo assay was performed using human stool. A freshly collected stool was maintained at or below 4° C In an anaerobic chamber (AS-580, Anaerobe Systems, Morgan Hill, CA) with an atmosphere of 5% carbon dioxide, 5% hydrogen and balance nitrogen, the stool was suspended in ice-cold phosphate buffered saline by pipetting to achieve 20% w/v fecal slurry, solids were allowed to settle, and the supernatant was transferred to conical tubes on ice prior to transfer to an aerobic atmosphere and -80°C. All subsequent steps were performed aerobically. Frozen aliquots were thawed on ice, centrifuged at 21,000 x g for 3 minutes, and supernatant was transferred to fresh tubes and diluted with an equal volume of ice cold phosphate buffered saline. 4-ethylphenol, p-cresol and 3-indoxyl sulfate were prepared in dimethyl sulfoxide at 25 mg/mL and added to separate aliquots of the fecal slurry supernatant to a final concentration of 2 mg/mL. Spiked fecal slurry supernatants were added to the sequestrant materials consisting of an AB-2004 preparation, bentonite, zeolite, cellulose acetate propionate (Mn~15,000) and activated charcoal for 35-59 mg/mL final of the sequestrant materials, with the exception that activated charcoal was tested at 98 mg/mL versus p-cresol. The mixtures were incubated with vigorous mixing in conical tubes at 750 rpm at 10° C for 4 hours and centrifuged at 21,000 x g for 3 minutes. The supernatant was transferred to a 96-well plate and diluted 10-fold in phosphate buffered saline prior to determining the concentration of the metabolites by measuring absorption at 278 nm with a spectrophotometer (Spectramax i3x, Molecular Devices, San Jose, CA).

A standard curve was generated for each of the toxins by adding them to the fecal slurry supernatant at 4, 2, 1, 0.5 and 0.25 mg/mL final, diluting them 10-fold in phosphate buffered saline, and measuring absorption at 278 nm. The concentration of spiked 4-ethylphenol, p-cresol and 3- indoxyl sulfate in samples was determined by interpolation from the standard curves using GraphPad Prism 7 (GraphPad, La Jolla, CA). The percentage of spiked toxin that was removed by sequestrant was calculated by dividing the interpolated value by the interpolated value of a spiked control sample that was not treated with a sequestrant material and multiplying by 100. The percentage of spiked toxin removed by each sequestrant is shown in Table 24.

Table 24. Percentage spiked toxin remaining in fecal slurry supernatant after 4 hours incubation with the indicated concentration of adsorbent material.

Percentage Spiked Toxin Remaining

As seen in Table 24, the number of toxins adsorbed and the extent of adsorption of each toxin varied across materials tested in the assay. AB-2004 and activated charcoal each adsorbed >90% of the spiked 4-ethylphenol, 3 -indoxyl sulfate and p-cresol in the assay, while cellulose acetate propionate adsorbed 65-90% of spiked 4-ethylphenol and to a 35-65% of p-cresol, but less than 10% of spiked 3-indoxyl sulfate. Bentonite adsorbed 35-65% of spiked 4-ethylphenol and 10-35% of spiked p-cresol in the assay, and <10% of spiked 3-indoxyl sulfate. Zeolite adsorbed 10-35% of spiked 4-ethylphenol in the assay, and less than 10% of spiked p-cresol and 3-indoxyl sulfate. Thus, different materials have different affinities for various toxins within the ex vivo assay, which recapitulates some of the diversity and composition of metabolites found in the human gut.

To determine the capacity of AB-2004, bentonite, zeolite and cellulose acetate propionate (Mn -15,000) to adsorb the toxins 4-ethylphenyl sulfate and p-cresyl sulfate from a complex mixture of metabolites similar to those found in the lumen of the human colon, an ex vivo assay was performed using human stool. A freshly collected stool was maintained at or below 4° C in an anaerobic chamber (AS-580, Anaerobe Systems, Morgan Hill, CA) with an atmosphere of 5% carbon dioxide, 5% hydrogen and balance nitrogen, the stool was suspended in ice-cold phosphate buffered saline by pipetting to achieve 20% w/v fecal slurry, solids were allowed to settle, and the supernatant was transferred to conical tubes on ice prior to transfer to an aerobic atmosphere and -80°C. All subsequent steps were performed aerobically. Frozen aliquots were thawed on ice, centrifuged at 21,000 x g for 3 minutes, and supernatant was transferred to fresh tubes. 4- ethylphenyl sulfate and p-cresyl sulfate were prepared in dimethyl sulfoxide at 25 mg/mL and added to separate aliquots of the fecal slurry supernatant to a final concentration of 0.75 mg/mL, in triplicate. The spiked fecal slurry supernatants were added to the sequestrant materials consisting of an AB-2004 preparation, bentonite, zeolite, and cellulose acetate propionate (Mn~75,000) to achieve 12 mg/mL final of the sequestrant materials. The mixtures were incubated with vigorous mixing in conical tubes at 1700 rpm at room temperature for 1 hour and centrifuged at 12,000 x g for 1 minute. The supernatant was transferred to fresh conical tubes and frozen at - 80°C prior to quantification of 4-ethylphenyl sulfate and p-cresyl sulfate by LC-MS/MS analysis against a surrogate matrix curve (Charles River, Worcester, MA). Results are shown in Table 25.

Table 25. Percent 4-ethylphenyl sulfate and p-cresyl sulfate remaining following 1 hour incubation with various materials

As seen in Table 25, AB-2004 demonstrated the greatest affinity for 4-ethylphenyl sulfate and p-cresyl sulfate of any of the tested materials. Cellulose Acetate Propionate adsorbed 7-35% of p-cresyl sulfate but less than 7% of 4-ethyl phenyl sulfate in the assay. Bentonite and Zeolite adsorbed less than 7% of 4-ethylphenyl sulfate and p-cresyl sulfate in the assay. Thus, the tested materials demonstrated a range of affinities for 4-ethylphenyl sulfate and p-cresyl sulfate within the ex vivo assay, which recapitulates some of the diversity and composition of metabolites found in the human gut.

Example 18

Modeling MIA in mice by injecting pregnant dams with the viral double-stranded RNA mimic poly(I:C) yields offspring that exhibit the core communicative, social, and stereotyped impairments relevant to ASD. Pregnant C57BL/6N mice are injected intraperitoneally on day E12.5 with saline or 20 mg/kg poly(I:C) according to methods described in Smith et al. (2007), J. Neurosci., 27: 10695-10702, which is hereby incorporated by reference in its entirety. MIA offspring and control offspring are either treated with an effective amount of an AB -2004 preparation daily for 10 days, or are left untreated for 10 days. Offspring are monitored for levels of 4-EP, 4-EPS, PC, PCS, 4-hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate in blood, urine and feces. Levels of 4-EP, 4-EPS, PC, PCS, 4-hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate are observed to be reduced in AB-2004 treated MIA offspring relative to untreated MIA offspring. The treated offspring are observed to have levels of 4-EP, 4-EPS, PC, PCS, 3 -4-hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate similar to, equivalent to, or reduced as compared to untreated offspring and/or healthy subjects.

MIA offspring and control offspring are also observed for behavioral symptoms of ASD as follows. Open field exploration involves mapping an animal’s movement in an open arena to measure locomotion and anxiety. Untreated MIA offspring display decreased entries and time spent in the center of the arena, which is indicative of anxiety-like behavior. Treated MIA offspring and untreated control offspring show commensurate or equivalent amounts of entries and time spent in the center of the arena.

Prepulse inhibition (PPI) measures the ability of an animal to inhibit its startle in response to an acoustic tone when it is preceded by a lower-intensity stimulus. Deficiencies in PPI are a measure of impaired sensorimotor gating and are observed in several neurodevelopmental disorders, including autism. Untreated MIA offspring exhibit decreased PPI. Treated MIA offspring and untreated control offspring show normal PPI.

The marble burying test measures the propensity of mice to engage repetitively in a natural digging behavior that is not confounded by anxiety. Untreated MIA offspring display increased stereotyped marble burying compared to controls. Treated MIA offspring and untreated control offspring, show normal digging behavior.

Ultrasonic vocalizations are used to measure communication by mice, wherein calls of varying types and motifs are produced in different social paradigms. Untreated MIA offspring exhibit deficits in communication, as indicated by reduced number and duration of ultrasonic vocalizations produced in response to a social encounter. Treated MIA offspring and untreated control offspring show a normal number and duration of ultrasonic vocalizations produced in response to a social encounter.

The three-chamber social test is used to measure ASD-related impairments in social interaction. Untreated MIA offspring exhibit deficits in both sociability, or preference to interact with a novel mouse over a novel object, and social preference, or preference to interact with an unfamiliar versus a familiar mouse. Treated MIA offspring and untreated control offspring show normal social interaction.

In some experiments, an inoculant of bacteria comprising one or more of Prevotella species, Bifido bacteria species, Parabacteriodes species, (e.g., P. merdae, P. dislasonis). Faecalibacterium species, (e.g., F. prausnitzii), Eubacterium species, Coprococcus species, Lactobacillus reuteri, Lactobacillus rhamnosis, Bacteroides caccae, Bacteriodes ovatus, Bacteroides fragilis, Bacteroides vulgatus, and/or Bacteroides thetaiotaomicron, or any combination thereof, is administered before, during, or after administration of the sequestrant composition, and the effect of the added bacteria is determined.

Example 19

Fecal samples are obtained from human patients undergoing treatment with an AB-2004 preparation or cholestyramine. For each sample, the AB-2004 preparation or cholestyramine is recovered and compounds eluted from the AB-2004 or cholestyramine are assayed by GC-MS or MALDI-TOF mass spectrometry for the presence of any of the microbial metabolites (and hostgenerated modifications of these metabolites) listed herein. One or more of the microbial metabolites (and/or host-generated modifications of these metabolites) described herein is then recovered from the AB-2004 or cholestyramine, demonstrating that said microbial metabolites (and/or host-generated modifications of these metabolites) are bound or sequestered by AB-2004 or cholestyramine in humans in vivo. These results will also demonstrate the therapeutic efficacy of the methods described herein.

Example 20

MIA offspring are generated as described above in Example 18. MIA offspring and control offspring are either treated with AB-2004 daily for 10 days or left untreated for 10 days. Offspring are monitored for levels of 4-EP, 4-EPS, PC, PCS, 4-hydroxyphenylacetate, 2-hydroxy-2(4- hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate in blood, urine and feces. Levels of 4-EP, 4-EPS, PC, PCS, 4-hydroxyphenylacetate, 2-hydroxy-2(4- hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate are observed to be reduced in AB-2004 treated MIA offspring relative to untreated MIA offspring. The treated offspring are observed to have levels of 4-EP, 4-EPS, PC, PCS, 4-hydroxyphenylacetate, 2- hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate similar to, equivalent to, or reduced as compared to untreated offspring and/or healthy subjects.

MIA offspring and control offspring are also tested for leaky gut symptoms by orally administering oligosaccharides of large size, such as lactulose or high MW-PEGs (1500 or 4000 kD), and/or small sugars such as mannitol, L-rhamnose, or low MW-PEG (400 kD), and/or other indigestible probes such as ⁵¹Cr-EDTA. Administration of said compounds occurs separately from administration of AB-2004 or other sequestering agent. Urine is collected and monitored for the presence of such molecules, where the presence of the test molecule in the urine is symptomatic of leaky gut. Untreated MIA offspring show significant amounts of lactulose, high MW-PEGs (1500 or 4000 kD), small sugars, mannitol, L-rhamnose, low MW-PEG (400 kD), ⁵¹Cr-EDTA and/or other indigestible probes in their urine after oral administration. Treated MIA offspring and untreated control offspring show little or no lactulose, high MW-PEGs (1500 or 4000 kD), small sugars, mannitol, L-rhamnose, low MW-PEG (400 kD), ⁵¹Cr-EDTA and/or other indigestible probes in their urine after oral administration.

In some experiments, an inoculant of bacteria comprising one or more of Prevotella species, Bifido bacteria species, Parabacteriodes species, (e.g., P. merdae, P. dislasonis). Faecalibacterium species, (e.g., F. praiisnilzii), Eubacterium species, Coprococcus species, Lactobacillus reuteri, Lactobacillus rhamnosis, Bacteroides caccae, Bacteriodes ovatus, Bacteroides fragilis, Bacteroides vulgatus, and/or Bacteroides thetaiotaomicron, or any combination thereof, is administered before, during, or after administration of the sequestrant composition, and the effect of the added bacteria is determined.

Example 21

CNTNAP2^-/" or Shank3^-/" mice provide genetic models of autism-like behaviors. See, e.g., Welberg et al. (2011), Nature Rev. Neurosci., 12:615 and Silverman et al. (2010), Nature Rev. Neurosci. 11 :490-502, each of which is hereby incorporated by reference in its entirety. CNTNAP2^-/", Shank3^-/" or genetically unaltered (control) mice are either treated with AB-2004 or other sequestering agent daily for 10 days or left untreated for 10 days. Mice are monitored for levels of 4-EP, 4-EPS, PC, PCS, 4-hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate in blood and feces. Levels of 4-EP, 4- EPS, PC, PCS, 4-hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate are observed to be reduced in AB-2004 treated CNTNAP2"^Z" or Shank3-/- mice relative to untreated CNTNAP2"^Z" or Shank3"^z" mice. The treated mice are observed to have levels of 4-EP, 4-EPS, PC, PCS, 4-hydroxyphenylacetate, 2-hydroxy- 2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate similar to, equivalent to, or reduced as compared to untreated mice and/or healthy subjects. CNTNAP2"^Z" or Shank3"^z" mice and control mice are also observed for behavioral symptoms of ASD as in Example

15.

In the open field exploration assay, untreated CNTNAP2"^Z" oorr SShhaannkk33"^z" mice display decreased entries and time spent in the center of the arena, which is indicative of anxiety-like behavior. Treated CNTNAP2"^Z" or Shank3"^z" mice and untreated control mice show commensurate or equivalent amounts of entries and time spent in the center of the arena.

In the prepulse inhibition (PPI) assay, untreated CNTNAP2"^Z" or Shank3 mice exhibit decreased PPI. Treated CNTNAP2 or Shank3 mice and untreated control mice show normal

PPI.

In the marble burying assay, untreated CNTNAP2"^Z" or Shank3"' mice display increased stereotyped marble burying compared to controls. Treated CNTNAP2 or Shank3"^z" mice and untreated control offspring, show normal digging behavior.

In the ultrasonic vocalization assay, treated CNTNAP2"^Z" or Shank3"^z" mice and untreated control mice show a normal number and duration of ultrasonic vocalizations produced in response to a social encounter.

In the three-chamber social test, untreated CNTNAP2 or Shank3 mice exhibit deficits in both sociability and social preference. Treated CNTNAP2 or Shank3 mice and untreated control mice show normal social interaction.

In some experiments, an inoculant of bacteria comprising one or more of Prevotella species, Bifido bacteria species, Parabacteriodes species, (e.g., P. merdae, P. dislasonis). Faecalibacterium species, (e.g., F. praiisnilzii), Eubacterium species, Coprococcus species, Lactobacillus reuteri, Lactobacillus rhamnosis, Bacteroides caccae, Bacteriodes ovatus, Bacteroides fragilis, Bacteroides vulgatus, and/or Bacteroides thetaiotaomicron, or any combination thereof, is administered before, during, or after administration of the sequestrant composition, and the effect of the added bacteria is determined. Example 22

Mecp2"^z" or an equivalent mouse model of Rett Syndrome are evaluated for improvement in behavioral and/or gastrointestinal symptoms following treatment with an AB-2004 preparation or other sequestering agents. See, e.g., Shahbazian et al. (2002), Neuron 35:243-254, which is hereby incorporated by reference in its entirety. Mecp2"^z" or equivalent mice, and genetically unaltered (control) mice are either treated with AB-2004 or other sequestering agent daily for 10 days or left untreated for 10 days. Mice are monitored for levels of 4-EP, 4-EPS, PC, PCS, 4- hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate in blood, urine and feces. Levels of 4-EP, 4-EPS, PC, PCS, 4- hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate are observed to be reduced in AB-2004 treated Mecp2"^z" or an equivalent mice relative to untreated Mecp2"^z" or equivalent mice. The treated mice are observed to have levels of 4-EP, 4-EPS, PC, PCS, 4-hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, hydroxy indole and/or 3-indoxyl sulfate similar to, equivalent to, or reduced as compared to untreated mice and/or healthy subjects. Mecp2"^z" or equivalent mice and control mice are also observed for behavioral symptoms of ASD as in Example 18.

In the open field exploration assay, untreated Mecp2"^z" or equivalent mice display decreased entries and time spent in the center of the arena, though fecal bolus counts, grooming times, and time spent in different areas of the field may not be affected. Treated Mecp2-/- or an equivalent mice and untreated control mice show commensurate or equivalent amounts of entries and time spent in the center of the arena. Untreated Mecp2"^z" or equivalent mice also show inertia, breathing irregularities, and hind limb clasping phenotypes not present in treated Mecp2"^z" or equivalent mice or in control mice.

Mecp2"^z" or equivalent mice and control mice are also tested for leaky gut symptoms by orally administering oligosaccharides of large size, such as lactulose or high MW-PEGs (1500 or 4000 kD), and/or small sugars such as mannitol, L-rhamnose, or low MW -PEG (400 kD), and/or other indigestible probes such as ⁵¹Cr-EDTA. Administration of said compounds occurs separately from administration of AB-2004 or other sequestering agent. Urine is collected and monitored for the presence of such molecules, where the presence of the test molecule in the urine is symptomatic of leaky gut. Untreated Mecp2-/- or equivalent mice show significant amounts of lactulose, high MW-PEGs (1500 or 4000 kD), small sugars, mannitol, L-rhamnose, lowMW-PEG(400 kD), ⁵¹Cr- EDTA and/or other indigestible probes in their urine after oral administration. Treated Mecp2-/- or equivalent mice and untreated control mice show little or no lactulose, high MW-PEGs (1500 or 4000 kD), small sugars, mannitol, L-rhamnose, low MW -PEG (400 kD), ⁵¹Cr-EDTA and/or other indigestible probes in their urine after oral administration.

In some experiments, an inoculant of bacteria comprising one or more of Prevotella species, Bifido bacteria species, Parabacteriodes species, (e.g., P. merdae, P. dislasonis). Faecalibacterium species, (e.g., F. prausnilzii), Eubacterium species, Coprococcus species, Lactobacillus reuteri, Lactobacillus rhamnosis, Bacteroides caccae, Bacteriodes ovatus, Bacteroides fragilis, Bacteroides vulgatus, and/or Bacteroides thetaiotaomicron, or any combination thereof, is administered before, during, or after administration of the sequestrant composition, and the effect of the added bacteria is determined.

Example 23

We have previously generated bacterial strains that produce 4-ethylphenol (4-EP) (the precursor to 4-EPS) and colonized mice with these strains, and have shown that intestinal production of a specific microbial metabolite is sufficient to promote anxiety and related behaviors in mice. Anxiety can also be induced by injection of 4-EPS.

Animals and Dosing

In the present study, 3 -week-old microbiologically sterile (germ-free) and normally colonized specific pathogen free (SPF), C57B1/6 mice are obtained (Jackson Labs, Bar Harbor, ME). Mice are initially divided into 4 groups: 1) specific pathogen free; 2) germ-free; 3) germ- free colonized with engineered bacterial strains that produce 4-EP or, alternatively, germ-free injected intravenously with 4-EPS; 4) germ-free colonized with engineered bacterial strains that do not produce 4-EP. Each group is further divided into groups that are administered an AB-2004 preparation, saline (negative control), B. fragilis (positive control), and no treatment. Each test article is administered orally, once per day or at each feeding. The test articles are administered for five weeks, followed by behavioral testing. In some groups, dosing is discontinued prior to behavioral testing, and in some groups dosing continues throughout the testing period.

An AB-2004 preparation (AST-120, Kureha Corporation, Japan) is given in food or by gavage, B. fragilis at IO¹⁰ cfu in 1.5% sodium bicarbonate solution is administered in apple sauce plugs or by gavage, and saline is administered in food or by gavage. The AB-2004 preparation is initially dosed at a level of 8 - 100 mg/mouse/dose and dosing is adjusted as necessary.

Behavioral testing

In the elevated “plus” maze test, animals are placed on an apparatus having two crossed elements in the shape of a plus-sign, with one element enclosed and one element exposed. Animals having symptoms of anxiety spend more time in the enclosed regions of the maze relative to animals without anxiety. In the present study, mice colonized with 4-EP producing bacteria and treated with AB-2004, mice colonized with 4-EP producing bacteria and treated with B. fragilis, and mice that are not colonized by 4-EP producing bacteria (specific pathogen free, germ-free, and germ-free colonized with engineered bacterial strains that do not produce 4-EP), spend less time in the enclosed regions of the maze relative to untreated mice or mice colonized with 4-EP producing bacteria that are mock-treated with saline, indicating a reduction in anxiety symptoms due to the AB -2004 or B. fragilis treatment.

In the light/dark box test, animals are placed in a box, most of which is lit, with a smaller separate dark compartment accessible to the animal. Mice showing symptoms of anxiety spend less time in the lit areas of the box relative to animals without anxiety. In the present study, mice colonized with 4-EP producing bacteria and treated with AB-2004, mice colonized with 4-EP producing bacteria and treated with B. fragilis, and mice that are not colonized by 4-EP producing bacteria (specific pathogen free, germ-free, and germ-free colonized with engineered bacterial strains that do not produce 4-EP), spend less time in the enclosed regions relative to untreated mice or mice colonized with 4-EP producing bacteria that are mock-treated with saline, indicating a reduction in anxiety symptoms due to the AB-2004 or B. fragilis treatment.

The open field exploration assay is described in Example 18. In the present study, mice colonized with 4-EP producing bacteria and treated with AB-2004, mice colonized with 4-EP producing bacteria and treated with B. fragilis, and mice that are not colonized by 4-EP producing bacteria (specific pathogen free, germ-free, and germ-free colonized with engineered bacterial strains that do not produce 4-EP), show more entries into the center of the arena and spend more time in the center of the arena relative to untreated mice or mice colonized with 4-EP producing bacteria that are mock-treated with saline, indicating a reduction in anxiety symptoms due to the AB -2004 or B. fragilis treatment.

Non-Behavioral testing Levels of pro-inflammatory markers, including IL-6, TNF-a, etc., are evaluated in tissue after sacrifice. Elevated levels of pro-inflammatory markers are seen in mice colonized with 4-EP producing bacteria and treated with an AB-2004 preparation, mice colonized with 4-EP producing bacteria and treated with B. fragilis, and mice that are not colonized by 4-EP producing bacteria (specific pathogen free, germ-free, and germ-free colonized with engineered bacterial strains that do not produce 4-EP) relative to untreated mice or mice colonized with 4-EP producing bacteria that are mock-treated with saline, indicating a reduction in inflammatory responses due to the AB- 2004 or B. fragilis treatment.

Serum and urine levels of key microbial metabolites including 4-EP, 4-EPS, PC, PCS, 4- hydroxyphenylacetate, 2-hydroxy-2(4-hydroxyphenyl)acetate, homocitrulline, indole pyruvate, serotonin, 3-hydroxy indole and indoxyl sulfate will be monitored during dosing and before behavior tests as early indicator of sequestration. Dosing can be adjusted in order to provide additional reductions in metabolite levels. Reduced levels of anxiety-associated metabolites are seen in mice colonized with 4-EP producing bacteria and treated with an AB-2004 preparation, mice colonized with 4-EP producing bacteria and treated with B. fragilis, and mice that are not colonized by 4-EP producing bacteria (specific pathogen free, germ-free, and germ-free colonized with engineered bacterial strains that do not produce 4-EP) relative to untreated mice or mice colonized with 4-EP producing bacteria that are mock-treated with saline, indicating a reduction in metabolite levels due to the AB-2004 or B. fragilis treatment.

In some experiments, an inoculant of bacteria comprising one or more of Prevotella species, Bifido bacteria species, Parabacteriodes species, (e.g., P. merdae, P. dislasonis), Faecalibacterium species, (e.g., F. prausnilzii), Eubacterium species, Coprococcus species, Lactobacillus reuteri, Lactobacillus rhamnosis, Bacteroides caccae, Bacteriodes ovatus, Bacteroides vulgatus, and/or Bacteroides thetaiotaomicron, or any combination thereof, is administered rather than B. fragilis.

Example 24

The effect of AB-2004 was studied in gnotobiotic mice that had been colonized with one or more specific bacterial strains, or with human fecal matter, that had previously been characterized to produce one or more intestinal metabolites associated with the microbially produced metabolites (or host-modifications thereof) described herein, including 4-ethylphenol (4- EP), p-cresol (PC), 3-hydroxy indole, 4-ethylphenyl sulfate (4-EPS), p-cresyl sulfate (PCS), and 3-indoxyl sulfate. The effect of AB-2004, a material that sequesters one or more intestinal metabolites associated with the microbially produced metabolites (or host-modifications thereof) described herein, including 4-ethylphenol (4-EP), p-cresol (PC), 3-hydroxy indole, 4-ethylphenyl sulfate (4-EPS), p-cresyl sulfate (PCS), and 3-indoxyl sulfate, was investigated by formulating AB-2004 into mouse food and administering it in parallel with a control diet that did not contain AB-2004 but was otherwise identical. Impact of toxic microbial metabolite production by the microbiota and AB-2004 administration was determined via assessments of the levels of the toxic bacterial metabolites in samples of serum, feces and/or urine obtained from the host, impact on repetitive, social, sensory and anxiety-like behaviors that represent core and non-core symptoms of autism spectrum disorders (ASD), and impact on the integrity of gastrointestinal barrier as a measure of leaky gut.

At 4 weeks of age and after weaning gnotobiotic mice were colonized with either specific bacterial strains or with human fecal matter. At the age of 5 weeks, mice were placed on a diet that contained 8% w/w AB-2004, or an otherwise identical diet that did not contain AB-2004. Colonization of mice was confirmed by plating dilutions of fecal homogenates on solid media and assessment of bacterial strain specific markers.

Marble Burying

A marble burying test was used to assess repetitive behavior, which is a core symptom of ASD. In the assay as described by Malkova et al. (Behav Immun. 26(4):607-16 (2012)), marbles are placed on top of bedding in a cage, a test mouse is placed in the cage, and the number of marbles buried by the mouse during the test period is measured. Mice given control diet that were colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites buried significantly more marbles than germ free gnotobiotic mice, thereby demonstrating repetitive behavior due to toxic bacterial metabolite production by the gut microbiota. Administration of AB-2004 to mice colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites normalized this repetitive behavior in the assay. The data indicate that administration of materials that sequester 4-EP, PC, 3-hydroxy indole, 4-EPS, PCS, and 3-indoxyl sulfate, can be beneficial for reducing repetitive behaviors, one of the core symptoms of ASD, in some ASD patients.

Elevated Plus Maze The elevated plus maze (EPM) test of exploratory behavior was used to assess general locomotion and anxiety-like behavior. Mice were allowed 5 minutes to explore an elevated plus maze comprised of two open arms and two closed arms that extend from a common central platform. A small raised lip around the edges of the open arms helped prevent mice from slipping off. An overhead video camera was used to record the session, and Ethovision software (Noldus Information Technology, Sacramento, CA) was used to analyze mouse movements. Time spent in closed, relatively protected portions of the maze versus time spent exploring open, relatively exposed portions of the maze is interpreted as a measurement of anxiety. Mice given control diet that were colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites spent significantly less time in the open portions of the EPM versus closed portions of the EPM than germ free gnotobiotic mice. Thereby demonstrating anxiety-like behavior due to production of toxic metabolites by the intestinal microbiota. Administration of AB-2004 normalized these anxiety -like behaviors in the assay. Anxiety is a common non-core symptom of ASD, and these data indicate that administration of sequestrants of 4-EP, PC, 3-hydroxy indole, 4-EPS, PCS, and 3-indoxyl sulfate can be beneficial in reducing anxiety in some ASD patients.

Open Field

The open field test of exploratory behavior was used to assess general locomotion and anxiety-like behavior. For open-field testing, mice were allowed to explore a 50 x 50-cm white Plexiglas box for 10 min. An overhead video camera was used to record the session, and Ethovision software (Noldus Information Technology, Sacramento, CA) was used to analyze the distance traveled, and the number of entries and duration of time spent in the center arena (central square, 17 x 17 cm) versus the wall area of the box. Mice given control diet that were colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites exhibited an anxiety-like phenotype in this assay, spending less time within and crossing the center of the test arena, entering the wall area with greater frequency and spending more time in the wall area when compared with germ free gnotobiotic mice. Administration of AB-2004 normalized these anxietylike behaviors in the assay. Importantly, total distance moved in the open field test was similar for all groups, suggesting that differences in exploration of open versus closed parts of the field are not due to differences in the distance that the mice moved during the test. Consistent with the EPM data, these data provide additional evidence that administration of materials that sequester 4- EP, PC, 3-hydroxy indole, 4-EPS, PCS, and 3-indoxyl sulfate can be beneficial in alleviating symptoms of anxiety in ASD patients who suffer from them.

Direct Social Interaction

In this test of social interaction, male mice colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites spent significantly less time in the chamber with another mouse than male germ free gnotobiotic mice. Administration of AB-2004 normalized the deficits in social behavior observed in the assay. These data indicate that administration of materials such as AB-2004 that sequester 4-EP, PC, 3-hydroxy indole, 4-EPS, PCS, and 3-indoxyl sulfate can be beneficial to improve core symptoms of ASD, such as social deficits.

Sensory Gating

Prepulse inhibition (PPI) measures the ability of an animal to inhibit its startle in response to an acoustic tone when it is preceded by a lower-intensity stimulus. Deficiencies in PPI are a measure of impaired sensorimotor gating and are observed in several neurodevelopmental disorders, including autism. Mice colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites exhibit decreased PPI response in comparison to that observed in germ free gnotobiotic mice. Administration of AB-2004 normalized the deficits in sensory gating observed in the assay.

Social Communication Behavior

Ultrasonic vocalizations are used to measure social communication by mice, wherein calls of varying types and motifs are produced in different social paradigms. Mice colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites exhibit deficits in communication, as indicated by reduced number and duration of ultrasonic vocalizations produced in response to a social encounter. Administration of AB-2004 normalized the deficits in social communication behavior observed in the assay.

Social Interaction Behavior

The three-chamber social test is used to measure ASD-related impairments in social interaction. Mice colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites exhibit deficits in both sociability, or preference to interact with a novel mouse over a novel object, and social preference, or preference to interact with an unfamiliar versus a familiar mouse. Administration of AB-2004 normalized the deficits in social interaction behavior observed in the assay

Gastrointestinal barrier integrity

Mice colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites were also tested for leaky gut symptoms by orally administering oligosaccharides of large size, such as lactulose or high MW-PEGs (1500 or 4000 kD), and/or small sugars such as mannitol, L-rhamnose, or low MW-PEG (400 kD), and/or other indigestible probes such as 51Cr- EDTA. Urine, blood and/or fecal samples are collected and monitored for the presence of such molecules, where the presence of the test molecule in the urine is symptomatic of leaky gut. Mice colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites show significant amounts of lactulose, high MW-PEGs (1500 or 4000 kD), small sugars, mannitol, L-rhamnose, low MW-PEG (400 kD), 51Cr-EDTA and/or other indigestible probes in their urine after oral administration. Administration of AB-2004 normalized one or more of the elevated urine levels lactulose, high MW-PEGs (1500 or 4000 kD), small sugars, mannitol, L-rhamnose, low MW -PEG (400 kD), 5 ICr-EDTA and/or other indigestible probes, indicating a correction of leaky gut.

Serum, urine and feces

Levels of key microbial metabolites including 4-ethylphenol (4-EP), p-cresol (PC), 3- hydroxy indole, 4-ethylphenyl sulfate (4-EPS), p-cresyl sulfate (PCS), 3-indoxyl sulfate, indole pyruvate and/or serotonin were monitored as an indicator of sequestration. Dosing may be adjusted in order to provide additional reductions in metabolite levels. In mice colonized with specific bacterial strains, or with human fecal matter, that produce toxic metabolites, treatment with AB- 2004 reduced levels of one or more of these target metabolites. REFERENCES

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[0227] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (for example, bodies of the appended claims) are generally intended as “open” terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims can contain usage of the introductory phrases “at least one” and “ to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “ aa”” oorr “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (for example, “a” and/or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” [0228] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. [0229] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0230] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

WHAT IS CLAIMED IS: 1. A method of treating a subject having a behavioral symptom of a neurological disorder, comprising: administering to said subject a sequestrant composition which binds to at least a fraction of at least one intestinal metabolite present in the gastrointestinal tract of the subject to form a sequestrant-metabolite complex, such that the sequestrant-metabolite complex is eliminated from the gastrointestinal tract; and wherein the sequestrant composition comprises a multiplicity of biocompatible particles which are non-absorbable by the gastrointestinal tract of the subject.

2. The method of claim 1 wherein: the neurological disorder is selected from the group consisting of: autism spectrum disorder, an anxiety disorder, major depressive disorder, post traumatic stress disorder, Parkinson's Disease, Rett Syndrome, Fragile X Syndrome, Tuberous Sclerosis, Multiple Sclerosis, Alzheimer’s Disease, Angelman Syndrome, Williams Syndrome, amyotrophic lateral sclerosis, leukodystrophies including Alexander Syndrome, alpha-synucleinopathies including Lewy Body Dementia, incidental Lewy body disease, Lewy body variant of Alzheimer’s disease, multiple system atrophy, pure autonomic failure, or any combination thereof.

3. The method of claim 1wherein: the behavioral symptom is selected from the group consisting of: tremors, paralysis, dyskinesia, repetitive behaviors, communicative symptoms, cognitive symptoms, stereotyped behaviors, attachment to physical objects, aphasia, obsessive behaviors, unusual or inappropriate body language, gestures, and/or facial expressions and/or sensorimotor issues, lack of interest in other people, lack of empathy, difficulty grasping nonverbal cues, touch aversion, difficulty in socialization, lack of social motivation, lack of social awareness, lack of social communication, lack of social cognition, inappropriate speech, hyperactivity/noncompliance, social withdrawal, speech delays, abnormal vocal tone or pitch, vocal repetition, perseveration, conversational difficulty, difficulty communicating needs or desires, inability to understand simple statements or questions, difficulties in processing language subtext, obsessive attachment to unusual objects, preoccupation, intolerance of changes in routine or environment, clumsiness, abnormal posture, odd ways of moving, fascination with particular objects, hyper- or hypo-reactivity to sensory input, and clinical irritability.

4. The method of claim 1 wherein: the neurological disorder is autism spectrum disorder and the behavioral symptom is selected from the group consisting of repetitive behaviors, lack of social motivation, lack of social awareness, lack of social communication, lack of social cognition, inappropriate speech, hyperactivity/noncompliance, social withdrawal, communicative symptoms, stereotyped behaviors, anxiety, and clinical irritability.

5. The method of any one of claims 1-4 wherein: the subject has a neurological disorder according to an anxiety rating scale, optionally Pediatric Anxiety Rating Scale (PARS), an aberrant behavior test, optionally Pediatric Anxiety Rating Scale (ABC), a social behavior test, optionally Social Responsiveness Scale (SRS-2), a repetitive behavior test, optionally, Repetitive Behavior Scale Revised (RBS-R), or an adaptive behavior test, optionally Vineland Adaptive Behavior Score (VABS-3).

6. The method of any one of claim 1-5 wherein: the subject does not have chronic kidney disease.

7. The method of claim 1 wherein: the intestinal metabolite is selected from the group consisting of: 4-ethylphenol (4-EP), 4- ethylphenylsulfate (4-EPS), p-cresol (PC), p-cresyl sulfate (PCS), 3-indoxyl sulfate (3IS), 3- hydroxy indole, coumaric acid, 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-(3- hydroxyphenyl)propanoic acid, 3-(4-hydroxyphenyl)propanoic acid, 3-hydroxy hippuric acid (3HHA), 3-carboxy-4-methyl-5-propyl-2-furanoic acid (CMPF), 3-hydroxyphenyl acetic acid (3HPA), 4-hydroxyphenyl acetic acid, and 2-hydroxy-2-(4-hydroxyphenyl)acetic acid, p-cresol glucuronide (pCG), 3-hydroxyphenylacetate (HPAA), 3-(3-hydroxyphenyl)-3-hydroxypropionate (HPHPA), 3-(4-hydroxyphenyl)propionate (HPPA), 3-hydroxyhippurate (HHA), and imidazolepropionate (IPA).

8. The method of claim 1 wherein: the intestinal metabolite is selected from the group consisting of: 4-ethylphenol (4-EP), 4- ethylphenylsulfate (4-EPS), p-cresyl (PC), p-cresyl sulfate (PCS), 3-hydroxy indole, and 3-indoxyl sulfate (3IS), p-cresyl glucuronide (pCG), and 3-hydroxyphenylacetate (HPAA).

9. The method of claim 1 wherein: the sequestrant composition comprises activated carbon, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a zeolite, a polymer, or a resin; wherein the polymer is a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate polymer, a polyglucosamine polymer, a cholestyramine polymer, a tetraethylenepentamine polymer, a boronic acid-presenting polymer, or a catechin-presenting polymer; and the resin is a phenolic resin or an ion exchange resin.

10. The method of claim 1 wherein: the sequestrant composition comprises an AB-2004 preparation comprising spherical activated carbon particles having a minimum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method of at least 500 m²/g and a maximum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method less than 4000 m²/g.

11. The method of any one of claims 1 or 10 wherein: the sequestrant composition comprises an AB-2004 preparation comprising spherical activated carbon particles having a minimum average particle diameter of at least 0.005 and a maximum average particle diameter of less than 1.5 mm.

12. The method of any of claims 1-11, further comprising monitoring intestinal metabolite levels of said subject during the course of treatment.

13. A method of reducing the amount of one or more intestinal metabolites from a subject having a behavioral symptom of a neurological disorder, comprising: administering to said subject a sequestrant composition which binds to at least a fraction of at least one intestinal metabolite present in the gastrointestinal tract of the subject to form a sequestrant-metabolite complex, such that the sequestrant-metabolite complex is eliminated from the gastrointestinal tract; wherein the intestinal metabolite is associated with the development or presence of the behavioral symptom, and wherein the sequestrant composition comprises a multiplicity of biocompatible particles which are non-absorbable by the gastrointestinal tract of the subject.

14. A sequestrant composition for use in the treatment of a subject having a behavioral symptom of a neurological disorder, comprising: a multiplicity of biocompatible particles which are non-absorbable by the gastrointestinal tract of the subject, wherein the sequestrant composition binds to at least a fraction of at least one intestinal metabolite present in the gastrointestinal tract of the subject to form a sequestrant-metabolite complex, such that the sequestrant-metabolite complex is eliminated from the gastrointestinal tract.

15. The sequestrant composition of claim 14 wherein: the biocompatible particles comprise activated carbon, a clay, an apatite or hydroxyapatite, a bentonite, a kaolin, a pectin, a zeolite, a polymer, or a resin; wherein the polymer is a cellulose polymer, a cellulose acetate polymer, a cellulose acetate propionate polymer, a polyglucosamine polymer, a cholestyramine polymer, a tetraethylenepentamine polymer, a boronic acid-presenting polymer, or a catechin-presenting polymer; and the resin is a phenolic resin or an ion exchange resin.

16. The sequestrant composition of claim 14 comprising: spherical activated carbon particles having a minimum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method of at least 500 m²/g and a maximum average specific surface area determined by the Brunauer-Emmett-Teller (BET) method less than 4000 m²/g.

17. The sequestrant composition of any one of claims 14 or 16 comprising: spherical activated carbon particles having a minimum average particle diameter of at least 0.005 and a maximum average particle diameter of less than 1.5 mm.

18. The sequestrant composition of any one of claims 14-17 wherein: the sequestrant composition is formulated for controlled release in the lower gastrointestinal tract.