US20140335131A1 - Probiotic prevention and treatment of colon cancer - Google Patents

Probiotic prevention and treatment of colon cancer Download PDF

Info

Publication number
US20140335131A1
US20140335131A1 US14/274,607 US201414274607A US2014335131A1 US 20140335131 A1 US20140335131 A1 US 20140335131A1 US 201414274607 A US201414274607 A US 201414274607A US 2014335131 A1 US2014335131 A1 US 2014335131A1
Authority
US
United States
Prior art keywords
subject
composition
colorectal
fragilis
administered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/274,607
Other languages
English (en)
Inventor
Sarkis K. Mazmanian
YunKyung Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
California Institute of Technology CalTech
Original Assignee
California Institute of Technology CalTech
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by California Institute of Technology CalTech filed Critical California Institute of Technology CalTech
Priority to US14/274,607 priority Critical patent/US20140335131A1/en
Assigned to CALIFORNIA INSTITUE OF TECHNOLOGY reassignment CALIFORNIA INSTITUE OF TECHNOLOGY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEE, YUNKYUNG, MAZMANIAN, SARKIS K
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: CALIFORNIA INSTITUTE OF TECHNOLOGY
Publication of US20140335131A1 publication Critical patent/US20140335131A1/en
Priority to US16/514,796 priority patent/US10772918B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present application relates generally to the field of prevention and treatment of colorectal cancer.
  • Colorectal cancer is the third most common malignancy in the world and inflammatory bowel diseases (IBD) increase the risk of colorectal cancer in humans.
  • IBD inflammatory bowel diseases
  • B. fragilis and polysaccharide A (PSA) of B. fragilis can be used to protect a subject from the development of colitis-associated colon cancer, for example by suppressing the expression of proinflammatory cytokines, chemokines and inducible nitric oxide synthase (iNOS).
  • methods of preventing and treating colorectal tumorigenesis are provided using a probiotic approach.
  • methods for preventing, delaying the onset of or reducing the progression of colorectal tumorigenesis in a subject identified as at risk of colorectal tumorigenesis, comprising adjusting the composition of gut microbiota in the subject via administering to the subject a composition comprising Bacteroides bacteria.
  • the Bacteroides is one or more of B. fragilis, B. thetaiotaomicron, B. vulgatus , or a mixture thereof.
  • the composition is a probiotic composition, a neutraceutical composition, a pharmaceutical composition, or a mixture thereof.
  • the composition comprises one or more zwitterionic polysaccharides (ZPS), Vitamin D, or a combination thereof.
  • ZPS zwitterionic polysaccharides
  • Vitamin D or a combination thereof.
  • the composition is administered via fecal transplantation.
  • the composition is administered via oral administration.
  • the composition is administered intermittently, periodically, continuously, or chronically.
  • the methods comprise measuring the expression level of a pro-inflammatory cytokine, a chemokine, and/or inducible nitric oxide synthase (iNOS) in the subject before and/or after the composition of gut microbiota is adjusted in the subject.
  • the pro-inflammatory cytokine is selected from the group consisting of TNF ⁇ , IL-6, IL-17A, and IL-23.
  • the chemokine is selected from the group consisting of monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and chemokine ligand (KC).
  • the methods comprise diagnosing a subject with a colorectal condition.
  • the colorectal condition is an intestinal inflammatory condition.
  • the intestinal inflammatory condition is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC).
  • the intestinal inflammatory condition is UC.
  • the methods comprise assessing the risk of colorectal tumorigenesis of a subject.
  • assessing the risk of colorectal tumorigenesis of the subject comprises looking for a family history of colorectal cancer of the subject, identifying a genetic mutation associated with colorectal cancer in the subject, testing for dysbiosis in the subject, or a combination thereof.
  • the dysbiosis comprises an over-representation of Proteus mirabilis and/or Klebsiella Pneumonia.
  • the tumor-free time of the subject in which the composition of gut microbiota has been adjusted is increased in comparison to a reference tumor-free time in one or more subjects in which the composition of gut microbiota has not been adjusted.
  • the total size of one or more tumors in the subject in which the composition of gut microbiota has been adjusted is decreased in comparison to a reference total tumor size in one or more subjects in which the composition of gut microbiota has not been adjusted.
  • the total number of the tumors in the subject in which the composition of gut microbiota has been adjusted is decreased in comparison to a reference total tumor number in one or more subjects in which the composition of gut microbiota has not been adjusted.
  • the total size of one or more tumors in the subject in which the composition of gut microbiota has been adjusted is unchanged or changed at a slower pace in comparison to prior to treatment. In some embodiments, the total number of the tumors in the subject in which the composition of gut microbiota has been adjusted is unchanged or decreased in comparison to prior to treatment.
  • zwitterionic polysaccharide ZPS
  • the ZPS is derived from bacteria. In some embodiments, the ZPS is derived from intestinal bacteria. In some embodiments, the ZPS is derived from Bacteroides bacteria. In some embodiments, the Bacteroides bacteria is B. fragilis, B. thetaiotaomicron , or B. vulgatus . In some embodiments, the ZPS is polysaccharide A (PSA). In some embodiments, the pharmaceutical composition comprises Bacteroides bacteria, Vitamin D, or a combination thereof.
  • the methods comprise diagnosing the subject with a colorectal condition.
  • the colorectal condition is an intestinal inflammatory condition.
  • the intestinal inflammatory condition is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC).
  • the intestinal inflammatory condition is UC.
  • the methods comprise assessing the risk of colorectal tumorigenesis of the subject.
  • assessing the risk of colorectal tumorigenesis of the subject comprises looking for a family history of colorectal cancer of the subject, identifying a genetic mutation associated with colorectal cancer in the subject, testing for dysbiosis in the subject, or a combination thereof.
  • the dysbiosis comprises an over-representation of Proteus mirabilis and/or Klebsiella Pneumonia.
  • the pharmaceutical composition is administered orally to the subject.
  • the methods comprise measuring the expression level of a pro-inflammatory cytokine, a chemokine, and/or inducible nitric oxide synthase (iNOS) in the subject after the pharmaceutical composition has been administered to the subject.
  • the pro-inflammatory cytokine is selected from the group consisting of TNF ⁇ , IL-6, IL-17A, and IL-23.
  • the chemokine is selected from the group consisting of monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and chemokine ligand (KC).
  • the tumor-free time of the subject to which the pharmaceutical composition has been administered is increased in comparison to a reference tumor-free time in subjects to which the pharmaceutical composition has not been administered.
  • the total size of one or more tumors in the subject to which the pharmaceutical composition has been administered is decreased in comparison to a reference total tumor size in one or more subjects to which the pharmaceutical composition has not been administered.
  • the total number of one or more tumors in the subject to which the pharmaceutical composition has been administered is decreased in comparison to a reference total tumor number in one or more subjects to which the pharmaceutical composition has not been administered.
  • the total size of one or more tumors in the subject to which the pharmaceutical composition has been administered is unchanged or changed at a slower pace in comparison to prior to treatment.
  • the total number of the tumors in the subject to which the pharmaceutical composition has been administered is unchanged or decreased in comparison to prior to treatment.
  • methods for treating or ameliorating a colorectal cancer in a subject, comprising adjusting the composition of gut microbiota in the subject having the colorectal cancer.
  • the methods comprise diagnosing the subject with a colorectal cancer.
  • the colorectal cancer is a colitis-associated colorectal cancer.
  • the colorectal cancer is a complication of inflammatory bowel disease (IBD).
  • adjusting the composition of gut microbiota of the subject comprises administering to the subject a composition comprising Bacteroides bacteria.
  • Bacteroides bacteria is B. fragilis, B. thetaiotaomicron, B. vulgatus , or a mixture thereof.
  • the composition is a probiotic composition, a neutraceutical composition, a pharmaceutical composition, or a mixture thereof.
  • the composition comprises ZPS, Vitamin D, or a combination thereof.
  • the composition is administered via fecal transplantation. In some embodiments, the composition is administered via oral administration.
  • GI gastrointestinal
  • methods for relieving gastrointestinal (GI) distress of a subject having a colorectal condition, comprising: determining the colorectal condition of the subject; and relieving GI distress in the subject by adjusting the composition of gut microbiota in the subject.
  • the colorectal condition is a colorectal cancer.
  • the colorectal cancer is a colitis-associated colorectal cancer.
  • the colorectal cancer is a complication of inflammatory bowel disease (IBD).
  • the colorectal condition is an intestinal inflammatory condition.
  • the intestinal inflammatory condition is selected from the group consisting of IBD, Crohn's disease (CD), and ulcerative colitis (UC).
  • the intestinal inflammatory condition is IBD.
  • FIG. 1 shows colonization of azoxymethane (AOM)/dextran sulfate sodium (DSS) treated mice with B. fragilis protects from the development of colon cancer, compared to mice colonized with B. fragilis ⁇ PSA (a mutant in B. fragilis only of the genes required to produce PSA) or control group.
  • A B. fragilis or B. fragilis ⁇ PSA was orally administered to mice and monitored for weight loss during DSS water treatment. Mice with PBS or B. fragilis ⁇ PSA colonization showed significantly increased weight loss during the third DSS treatment period compared to mice with B. fragilis colonization.
  • B, C The number of tumors and the sum of tumor size in B. fragilis colonized mice were also significantly decreased compared to control and B. fragilis ⁇ PSA colonized groups.
  • FIG. 2 shows the effect of B. fragilis colonization on the expression of pro-inflammatory cytokines and signature genes during colon cancer development.
  • A Comparison of TNF- ⁇ level among control, mice colonized with B. fragilis and mice colonized with B. fragilis ⁇ PSA.
  • B Comparison of IL-6 level among control, mice colonized with B. fragilis and mice colonized with B. fragilis ⁇ PSA.
  • C Comparison of IL-17A level among control, mice colonized with B. fragilis and mice colonized with B. fragilis ⁇ PSA.
  • D Comparison of MCP-1 level among control, mice colonized with B. fragilis and mice colonized with B. fragilis ⁇ PSA.
  • E Comparison of MIP-2 level among control, mice colonized with B.
  • FIG. 3 shows TLR2 signaling is responsible for the protection by B. fragilis from the development of colon cancer in mice.
  • A WT mice colonized with B. fragilis showed significantly decreased weight loss compared to WT mice treated PBS, whereas TLR2 ⁇ / ⁇ mice showed similar degree of weight loss regardless of B. fragilis colonization.
  • B The number of tumors in distal colon was significantly decreased in WT mice colonized with B. fragilis compared to WT mice treated with PBS, whereas TLR2 ⁇ / ⁇ mice developed similar number of tumors in distal colon regardless of B. fragilis colonization.
  • C More tumors were found in proximal colon of TLR2 ⁇ / ⁇ mice with or without B. fragilis colonization in comparison to WT.
  • the term “subject” is a vertebrate, such as a mammal.
  • the term “mammal” is defined as an individual belonging to the class Mammalia and includes, without limitation, humans, domestic and farm animals, and zoo, sports, or pet animals, such as sheep, dogs, horses, cats or cows. In preferred embodiments, the subject is human.
  • treatment refers to a clinical intervention made in response to a disease, disorder or physiological condition manifested by a patient.
  • the aim of treatment may include, but is not limited to, one or more of the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and the remission of the disease, disorder or condition.
  • treatment may refer to a clinical intervention made to a cancer patient, particularly a patient suffering from colorectal cancer.
  • “treatment” refers to both therapeutic treatment and prophylactic or preventative measures.
  • treatment may prevent, delay the onset of or reduce the progression of colorectal tumorigenesis of the subject, including subjects having an intestinal inflammatory condition such as IBD.
  • prevention refers to any activity that avoids, delays the onset of or reduces the progression of colorectal cancer.
  • the term “neutraceutical” refers to a food stuff (as a fortified food or a dietary supplement) that provides health benefits.
  • probiotic refers to live microorganisms, which, when administered in adequate amounts, may confer a health benefit on the host.
  • the probiotics may be available in foods and dietary supplements (for example, but not limited to capsules, tablets, and powders).
  • foods containing probiotics include dairy products such as yogurt, fermented and unfermented milk, smoothies, butter, cream, hummus, kombucha, salad dressing, miso, tempeh, nutrition bars, and some juices and soy beverages.
  • the probiotics may be present naturally.
  • ZPS zwitterionic polysaccharide
  • a zwitterionic polysaccharide can include repeating units wherein each repeating unit includes from two to ten monosaccharides, a positively charged moiety (e.g., an free positively charged amino moiety) and a negatively charged moiety (such as sulfonate, sulfate, phosphate and phosphonate).
  • the ZPS can have a molecular weight from about 500 Da to about 2,000,000 Da. In some embodiments, the ZPS can have a molecular weight from about 200 to about 2500.
  • ZPSs can be isolated from natural sources, and in particular from bacterial sources, e.g., by purification. Exemplary ZPSs include but are not limited to PSA and PSB from B.
  • ZPSs can also be produced by chemical or biochemical methods, as well as by recombinant microorganism technologies all identifiable by a skilled person. Thus, those methods and technologies will not be further described herein in detail.
  • polysaccharide A indicates a molecule produced by the PSA locus of B. fragilis and derivatives thereof which include but are not limited to polymers of the repeating unit ⁇ 3) ⁇ -d-AAT Galp(1 ⁇ 4)-[ ⁇ -d-Galf(1 ⁇ 3)] ⁇ -d-GalpNAc(1 ⁇ 3)-[4,6-pyruvate]- ⁇ -d-Galp(1 ⁇ , where AATGal is acetamido-amino-2,4,6-trideoxygalactose, and the galactopyranosyl residue is modified by a pyruvate substituent spanning O-4 and O-6.
  • a derivative polysaccharide indicates a second polysaccharide that is structurally related to the first polysaccharide and is derivable from the first polysaccharide by a modification that introduces a feature that is not present in the first polysaccharide while retaining chemical properties, biological properties, or both, of the first polysaccharide.
  • a derivative polysaccharide of PSA usually differs from the original polysaccharide by modification of the repeating units or of the saccharidic component of one or more of the repeating units that might or might not be associated with an additional function not present in the original polysaccharide.
  • a derivative polysaccharide of PSA retains however one or more functional activities that are herein described in connection with the anti-inflammatory activity of PSA.
  • Vitamin D as used herein includes any one or a combination of a group of fat-soluble prohormones (D1-D5: 25 D, 1,25 D see below), which encourages the absorption and metabolism of calcium and phosphorous.
  • D1-D5 25 D, 1,25 D see below
  • Five forms of vitamin D have been discovered, vitamin D 1 , D 2 , D 3 , D 4 , D 5 .
  • the two forms that seem to matter to humans the most are vitamins D 2 (ergocalciferol) and D 3 (cholecalciferol).
  • Vitamin D for humans is obtained from sun exposure, food and supplements. It is biologically inert and has to undergo two hydroxylation reactions to become active in the body.
  • 1,25-D 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin
  • 1,25-D 1,25-dihydroxyvitamin
  • 1,25 D is derived from its precursor 25-hydroxyvitamin-D(D-25) by the enzyme 1 ⁇ -hydroxylase (“CYP27B1”) encoded by the CYP27B1 gene, (NG — 007076.1 Homo Sapiens ) CYP27B1.
  • cytokine refers to a secreted protein or active fragment or mutant thereof that modulates the activity of cells of the immune system.
  • cytokines include, without limitation, interleukins, interferons, chemokines, tumor necrosis factors, colony-stimulating factors for immune cell precursors, and the like.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • mice colonized with B. fragilis developed significantly less colorectal tumors than mice with B. fragilis ⁇ PSA or control mice using an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer model.
  • AOM azoxymethane
  • DSS distaln sulfate sodium
  • Proinflammatory cytokines and signature genes of colon homogenates were down-regulated by B. fragilis colonization during the development of colon cancer. Without being held to any particular theory, it is believed that toll-like receptor (TLR) 2 signaling is responsible to protect B. fragilis colonized mice from tumor development.
  • TLR toll-like receptor
  • the present invention provides methods for preventing, delaying the onset of or reducing the progression of colorectal tumorigenesis in a subject.
  • the methods comprise adjusting the composition of gut microbiota in the subject.
  • the subject is a human.
  • the colorectal tumorigenesis may be associated with an intestinal inflammatory condition. In some embodiments, the colorectal tumorigenesis may be associated with colitis or IBD.
  • Chronic inflammation is a known risk factor for tumorigenesis, and epidemiological data suggest that up to 15% of human cancer incidence is associated with inflammation (Mantovani et al., Nature 454: 436-444 (2008)); Kuper et al., J. Intern. Med. 248: 171-183 (2000)). Inflammation-induced colorectal cancer develops in patients with chronic IBD (Jawad et al, Recent Results Cancer Rec. 185: 99-115 (2011)), which has been shown to be regulated by caspase-1 and NLRC4 (Hu et al., Proc. Natl.
  • a number of intestinal inflammatory conditions are known to one of ordinary skill in the art, including but not limited to, colitis, IBD, Chron's disease, ulcerative colitis and pancolitis. Severity of the inflammation and the longer time of the inflammation have been linked to an increased risk of colorectal cancer tumorigenesis (Xie & Itzkowitz, World J. Gastroenterol. 14: 378-89 (2008); Triantafillidis et al., Anticancer Res. 29: 2727-37 (2009)).
  • risk factors that increase the likelihood of colorectal tumorigenesis may be used to evaluate the suitability of a subject for the preventative methods disclosed herein.
  • risk factors include, but are not limited to, duration of colitis, extent of colitis, a family history of colorectal cancer, and, according to some studies, early disease onset and more severely active inflammation, greater extent of colonic involvement, primary sclerosing cholangitis, young age of IBD onset, backwash ileitis, history of dysplasia, etc.
  • Raised dysplastic lesions also known as dysplasia associated lesion or mass (DALM), or flat dysplastic lesions may significantly increase the likelihood of a subject to develop colitis-associated colorectal cancer.
  • DALM dysplasia associated lesion or mass
  • HNPCC hereditary nonpolyposis colorectal cancer
  • Gardner syndrome Gardner syndrome
  • FAP familial adenomatous polyposis
  • Severity of inflammation or diagnosis/staging of dysplasia or cancer in subjects may be assessed using a number of techniques, including but not limited to, histology, endoscopy, colonoscopy, chromoendoscopy, biopsy, etc.
  • multiple biopsy specimens may be required. In some embodiments, at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30 or more biopsy specimens are taken from the subject.
  • Another risk factor that may increase a subject's susceptibility to colorectal tumorigenesis is the composition of gut microbiota. Shifts in the intestinal microenvironment may lead to changes in the microbiota known as dysbiosis, which in turn may increase susceptibility to intestinal inflammation and colorectal tumorigenesis (Mazmanian et al., Nature 453: 620-625 (2008); Garrett et al., Cancer Cell 16: 208-19 (2009)). Proteus mirabilis and/or Klebsiella Pneumonia were found to be over-represented in mice that spontaneously develop dysbiosis and colitis (Garrett et al., Cell Host Microbe 8: 292-300 (2010)).
  • dysbiosis conditions that may contribute to colorectal cancer tumorigenesis include, but are not limited to, increased colonization of segmented filamentous bacteria (SFB), Helicobacter hepaticus, Helicobacter pylori, Actinobacteria or Ptoteobacteria , and/or decreased colonization of Firmicutes or Bacteroides bacteria.
  • Dysbiosis conditions that may contribute to colorectal tumorigenesis may also include a genetic mutation in commensal bacteria. For example, deletion of the commensal colonization factor (ccf) gene in B. fragilis has been shown to result in colonization defects in mice (Lee et al., Nature 501: 426-29 (2013)).
  • a combination of risk factors may be combined to evaluate a subject's susceptibility to colorectal tumorigenesis.
  • a subject identified as at an increased risk of colorectal tumorigenesis may be treated with the preventative methods disclosed herein.
  • a subject with an intestinal inflammatory condition such as IBD
  • a subject with ulcerative colitis may be treated with the preventative methods disclosed herein.
  • a subject with chronic IBD i.e., which has had IBD for 7, 8, 9, 10, 20, 30, 40 or more years, may be treated with the preventative methods disclosed herein.
  • known molecular biomarkers of colorectal tumorigenesis may be used to identify a subject that is at an increased risk of colorectal tumorigenesis to be treated with the preventative methods disclosed herein.
  • a number of biomarkers are well known in the art that may contribute to colorectal tumorigenesis, including but not limited to, APC, ⁇ -catenin, TP53, TGF- ⁇ , DCC (Deleted in Colorectal Cancer), SMAD, AXIN1, AXIN2, TCF7L2, or NKD1, KRAS, RAF, and PI3K, PTEN, CTNNB1, FAM123B, SOX9, ATM, and ARID1A, ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF, MYC, etc.
  • the molecular biomarkers may be used to monitor the progression (or lack thereof) of colorectal cancer in a subject under treatment.
  • preventing, delaying or reducing colorectal tumorigenesis may include, but not limited to, delaying the onset of dysplasia or colorectal cancer, slowing the progression of colorectal cancer from an early stage to a more advanced stage, delaying or preventing the transformation of a benign tumor to a malignant tumor, delay or preventing the metastasis of the tumor, etc.
  • Colorectal tumorigenesis may also refer to recurrence of colorectal cancer after remission induced by surgery, chemotherapy, radiation therapy, etc.
  • the presently disclosed methods may be used to prevent or delay the development of precancers, such as tubular adenoma, colorectal villous adenoma, or colonic polyp.
  • precancers such as tubular adenoma, colorectal villous adenoma, or colonic polyp.
  • the subject treated with the methods disclosed herein is tested for the development of tubular adenoma, colorectal villous adenoma, or colonic polyp.
  • Onset of colorectal cancer may refer to tumor budding.
  • Biopsy specimens are graded pathologically as negative, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, or invasive cancer.
  • the subject treated with the methods disclosed herein is graded pathologically for stage of colorectal cancer.
  • the preventative effect may be characterized as the tumor-free period for the treated subject, the total number of tumors in the treated subject, the total weight of tumors in the treated subject, or a combination thereof.
  • the subject treated with the methods disclosed herein is assessed for the tumor-free period, the total number of tumors, the total weight of tumors in the treated subject, or a combination thereof.
  • the tumors may be tumors of distal colon, proximal colon, or both.
  • a reference value may be established based on one or more control subjects that are not treated with the methods disclosed herein.
  • the treated subject may show an increase of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500% or more in the tumor-free period in comparison to the reference value.
  • the treated subject may show a decrease of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or about 100%, or a range between any two of these values in the total number of tumors in comparison to the reference value.
  • the treated subject may show a decrease of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or about 100%, or a range between any two of these values in the total weight of tumors in comparison to prior to treatment.
  • the treated subject may show a decrease of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or about 100%, or a range between any two of these values in the total number of tumors in comparison to prior to the treatment.
  • the treated subject may show a decrease of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or about 100%, or a range between any two of these values in the total weight of tumors in comparison to prior to the treatment.
  • cancers or cancer-like diseases such as small intestinal adenocarcinoma, Squamous cell carcinoma of the anus, cholangiocarcinoma, hepatobiliary cancers, and hematologic malignancies such as leukemia, hematopoietic cancer, lymphoma, myeloid leukemia may also be prevented, delayed, reduced or treated by the methods disclosed herein.
  • colorectal tumorigenesis may be prevented, delayed, or reduced through the adjustment of the composition of gut microbiota in a subject susceptible to developing colorectal cancer.
  • Adjustment of composition of gut microbiota refers to changing the composition of the bacteria in the gut.
  • Adjustment of the composition of gut microbiota in the subject can be achieved by, for example, fecal transplantation (also known as fecal microbiota transplantation (FMT), fecal bacteriotherapy or stool transplant).
  • Fecal transplantation can include a process of transplantation of fecal bacteria from a healthy donor, for example a subject without IBD, to a recipient (e.g., a subject suffering from IBD).
  • the procedure of fecal transplantation can include single or multiple infusions (e.g., by enema) of bacterial fecal flora from the donor to the recipient.
  • methods disclosed herein consist essentially of adjusting the composition of gut microbiota in a subject susceptible to colorectal cancer.
  • methods disclosed herein consist of adjusting the composition of gut microbiota in a subject susceptible to colorectal cancer.
  • methods disclosed herein are not combined with other pharmaceutical(s), e.g., antibiotics, anti-inflammatory drug(s) or chemotherapeutics, e.g., 5-Fluorouracil, Capecitabine, oxaliplatin, Irinotecan, etc.
  • adjusting the composition of gut microbiota in the subject includes administering the subject a composition comprising bacteria, for example, a composition comprising Bacteroides bacteria.
  • Bacteroides bacteria comprise B. fragilis, B. thetaiotaomicron, B. vulgatus , or a mixture thereof.
  • the composition may comprise B. fragilis and B. thetaiotaomicron .
  • the composition may comprise B. fragilis and B. vulgatus .
  • the composition may comprise B. thetaiotaomicron and B. vulgatus .
  • the Bacteroides bacteria can be B. fragilis .
  • the composition comprising bacteria for example a composition comprising Bacteroides bacteria
  • the composition can be administered to the subject via oral administration, rectal administration, transdermal administration, intranasal administration or inhalation.
  • the composition is administered to the subject orally.
  • the composition comprising bacteria, such as Bacteroides bacteria can also be in various forms.
  • the composition can be a probiotic composition, a neutraceutical, a pharmaceutical composition, or a mixture thereof.
  • the composition is a probiotic composition.
  • Each dosage for human and animal subjects preferably contains a predetermined quantity of the bacteria calculated in an amount sufficient to produce the desired effect.
  • the actual dosage forms will depend on the particular bacteria employed and the effect to be achieved.
  • the composition comprising bacteria for example, a composition comprising Bacteroides bacteria, can be administered alone or in combination with one or more additional probiotic, neutraceutical, or therapeutic agents.
  • Administration “in combination with” one or more further additional probiotic, neutraceutical, or therapeutic agents includes both simultaneous (at the same time) and consecutive administration in any order.
  • Administration can be chronic or intermittent, as deemed appropriate by the supervising practitioner, particularly in view of any change in the disease state or any undesirable side effects. “Chronic” administration refers to administration of the composition in a continuous manner while “intermittent” administration refers to treatment that is done with interruption.
  • the composition of gut microbiota of the treated subject may be monitored before, during, or after the treatment period.
  • a variety of monitoring techniques are known to one of ordinary skill in the art. For example, sequencing, PCR or microarray analysis may be used to identify the species and amount of bacteria present in the gut microbiota. ELISA assays using antibodies that specifically bind to bacterial antigens may also be used to identify and quantify the bacteria species in the gut microbiota.
  • administrating the composition comprising bacteria for example, a composition comprising Bacteroides bacteria, may also be adjusted according to the results from monitoring the composition of gut microbiota. For example, if the administered bacteria composition fully restores the normal colonization state of the bacteria, further administration of the composition may be suspended in view of further monitoring results.
  • administrating the composition comprising bacteria may also be adjusted according to the subject's intestinal inflammatory condition.
  • Administration of the bacteria composition may be suspended if the intestinal inflammatory condition, such as IBD, Crohn's disease, ulcerative colitis, etc., has been cured permanently or has gone into remission.
  • the subject's intestinal inflammatory condition may be assessed using a number of techniques, including but not limited to, histology, endoscopy, colonoscopy, chromoendoscopy, biopsy, etc.
  • multiple biopsy specimens may be required. In some embodiments, at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30 or more biopsy specimens are taken from the subject.
  • the amount of bacteria for example Bacteroides bacteria (e.g., B. fragilis ), administered to the subject in need of treatment can be determined according to various parameters such as the age, body weight, response of the subject, condition of the subject to be treated; the type and severity of intestinal inflammatory condition, IBD, or the pathological conditions with one or more symptoms of IBD; the form of the composition in which the bacteria is included; the route of administration; and the required regimen.
  • the severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods.
  • the amount of bacteria can be titrated to determine the effective amount for administering to the subject in need of treatment.
  • the bacteria may be administered at a dose of at least 10 3 CFU, optionally at least 10 4 CFU, optionally at least 10 5 CFU, optionally at least 10 6 CFU, optionally at least 10 7 CFU, optionally at least 10 8 CFU, or optionally at least 10 9 CFU.
  • the bacteria may be administered at a dose of 10 3 to 10 12 CFU, optionally at a dose of 10 4 to 10 11 CFU, optionally at a dose of 10 5 to 10 10 CFU, optionally at a dose of 10 6 to 10 10 CFU, or optionally at a dose of 10 7 to 10 10 CFU.
  • the bacteria may be administered at optionally at a dose of 10 7 to 10 10 CFU.
  • the bacteria may be administered at optionally at a dose of 5 ⁇ 10 9 to 7 ⁇ 10 10 CFU.
  • the subject being treated may be a human. In some embodiments, the subject being treated may be a non-human mammal. A program comparable to that discussed above may be used in veterinary medicine.
  • the methods can include: determining the level of a B. fragilis -responsive metabolite in the subject; and comparing the level of the B. fragilis -responsive metabolite in the subject to a reference level of the metabolite in subjects suffering from an intestinal inflammatory condition, wherein substantial identity between the blood level of the metabolites in the subject and the reference level indicates that the subject is susceptible to the probiotic treatment, for example B. fragilis probiotic treatment.
  • the methods include determining the level of two or more B. fragilis -responsive metabolites in the subject; and comparing the level of each of the two or more B.
  • fragilis -responsive metabolites in the subject to the reference level of each of the two or more B. fragilis -responsive metabolites, wherein substantial identity between the blood levels of the metabolites in the subject and the reference levels indicates an increased susceptibility of the subject to the probiotic treatment.
  • the level of the metabolite can be the level of the metabolite in circulation of the subject.
  • the level of the metabolite is the level of the metabolite in blood or other body fluids (e.g., cerebrospinal fluid, pleural fluid, amniotic fluid, semen, or saliva) of the subject.
  • the level of the metabolite is the blood level of the metabolite in the subject.
  • the blood level of the metabolite can be, for example, serum level or plasma level of the metabolite.
  • the level of the metabolite is the urine level of the metabolite in the subject.
  • B. fragilis -responsive metabolite refers to a metabolite whose level has been determined to be altered by B. fragilis treatment.
  • the level of the metabolite may be altered in circulation of the subject after B. fragilis treatment.
  • the level of the metabolite is altered in blood, serum, plasma, body fluids (e.g., cerebrospinal fluid, pleural fluid, amniotic fluid, semen, or saliva), urine, and/or feces of the subject after B. fragilis treatment.
  • the B. fragilis -responsive metabolite can be increased or decreased in level after B. fragilis treatment.
  • B. fragilis -responsive metabolite can be determined by comparing the pre-treatment level of a metabolite in a subject, for example a subject suffering from an intestinal inflammatory condition, with the level of a metabolite in the subject after B. fragilis treatment.
  • a subject for example a subject suffering from an intestinal inflammatory condition
  • B. fragilis treatment One of ordinary skill in the art will appreciate that variability in the level of metabolites may exist between individuals, and a reference level for a B. fragilis -responsive metabolite can be established as a value representative of the level of the metabolites in a population of subjects suffering from an intestinal inflammatory condition for the comparison.
  • Non-limiting examples of B. fragilis -responsive metabolites are provided in Table 1.
  • the methods of adjusting the composition of gut microbiota disclosed herein may be combined with other medications and/or dietary supplements that have anti-inflammatory effects, such as aspirin or other NSAID, 5-aminosalicylates (5-ASA), systemic steroids, topical steroids, 6-mercaptopurine or azathioprine.
  • Folate supplement, ursodiol and other anti-oxidants, statins may also be used in combination with the methods of adjusting the composition of gut microbiota disclosed herein.
  • the methods of adjusting the composition of gut microbiota disclosed herein may be combined with Vitamin D. Vitamin D has been known to enhance the protective effect of B. fragilis and PSA against IBD (U.S. Patent Publication No. 2013/0064859, the content of which is herein expressly incorporated by reference in its entirety).
  • PSA was shown to contribute to the anti-colitis activity of B. fragilis colonization in an experimental mouse model, as well as to the prevention of colorectal cancer tumorignensis by B. fragilis colonization in a mouse model of colitis-induced colorectal cancer.
  • Purified PSA was also shown to suppress pro-inflammatory IL-17 production, and prevent intestinal inflammation through induction of IL-10 expression.
  • a pharmaceutical composition comprising a zwitterionic polysaccharide (ZPS) to prevent colorectal tumorigenesis, delay the onset of colorectal tumorigenesis, or reduce the progression of colorectal tumorigenesis.
  • ZPS zwitterionic polysaccharide
  • the pharmaceutical composition may comprise more than one ZPSs.
  • Bacterial ZPSs isolated from strains of B. fragilis, S. aureus , and S. pneumoniae type 1 represent an unusual group of bacterial carbohydrates. ZPSs which include both positively and negatively charged groups have unique immunological properties: molecules as small as 17 kDa elicit a potent CD4 + T cell response in vitro, and ZPS-activated T cells confer protection against experimental intraabdominal abscess formation (Kalka-Moll et al., J. Immunol. 164: 719-24 (2000); U.S. Patent Publication No. 2013/0039949, the content of which is herein expressly incorporated by reference in its entirety).
  • B. fragilis polysaccharide A (PSA) as used herein refers to B.
  • fragilis capsular polysaccharide A as disclosed, for example, in U.S. Pat. No. 5,679,654, the content of which is herein expressly incorporated by reference in its entirety.
  • This polysaccharide has a tetrasaccharide repeating unit containing one cationic free amine and one anionic carboxylate in each repeating unit. (Tzianabos et al., J. Biol. Chem. 267: 18230-5 (1992); U.S. Pat. Nos. 5,679,654 and 5,700,787).
  • PSA is also known as PSA1.
  • ZPS as used herein in some embodiments refers to a naturally occurring polysaccharide having certain structural features including the presence of repeating units, each with at least one positively charged moiety and at least one negatively charged moiety.
  • a ZPS as used herein in one embodiment refers to polysaccharides that have been modified to include the structural features including the presence of repeating units, each with at least one positively charged moiety and at least one negatively charged moiety.
  • ZPSs have a plurality of repeating units, wherein each repeating unit comprises two to ten monosaccharides and a positively charged free amino moiety and a negatively charged moiety selected from the group consisting of carboxylate, phosphate, phosphonate, sulfate, and sulfonate.
  • Molecular weights of the ZPSs useful in the invention typically have molecular weights between 500 Da and 2,000,000 Da, although smaller and larger polysaccharides can also be used.
  • the polysaccharide can be as small as one or two saccharide units.
  • a disaccharide including only one non-acetylated amino sugar and one uronic acid is sufficient to stimulate T-cell proliferation.
  • Polysaccharides that can be used in some embodiments include those naturally occurring polysaccharides that include the requisite charged groups. See, e.g., U.S. Pat. No. 8,206,726, the content of which is herein expressly incorporated by reference in its entirety.
  • polysaccharide repeating units that consist of at least one N-acetyl sugar and at least one uronic acid can be modified to produce the immune response of the present invention.
  • Molecules which may be de-N-acetylated include Salmonella typhi capsular polysaccharide (VI antigen), E. coli K5 capsular polysaccharide, S.
  • the pharmaceutical composition comprising ZPS disclosed herein may be combined with Vitamin D.
  • the ZPS may be administered subcutaneously, transdermally, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the ZPS may also be administered in slow release dosage forms.
  • the amount of ZPS, for example PSA, administered to the subject as risk for colorectal tumorigenesis can be determined according to various parameters such as the age, body weight, response of the subject, condition of the subject to be treated; the type and severity of intestinal inflammatory condition, IBD, or the pathological conditions with one or more symptoms of IBD; the form of the composition in which ZPS is included; the route of administration; and the required regimen.
  • the severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods.
  • the amount of ZPS can be titrated to determine the effective amount for administering to the subject in need of treatment.
  • the ZPS may be administered at a dose of at least 0.01 ⁇ g, optionally at least 0.1 ⁇ g, optionally at least 1 ⁇ g, optionally at least 0.5 ⁇ g, optionally at least 1 ⁇ g, optionally at least 5 ⁇ g, optionally at least 10 ⁇ g, optionally at least 50 ⁇ g, optionally at least 100 ⁇ g, optionally at least 500 ⁇ g, or optionally at least 1 mg.
  • the ZPS may be administered at a dose of 1 ⁇ g to 1000 mg, optionally at a dose of 0.005-500 mg, optionally at a dose of 0.01-200 mg, optionally at a dose of 0.05-100 mg, optionally at a dose of 0.1-50 mg, optionally at a dose of 1-20 mg, optionally at a dose of 0.1-5 mg, or optionally at a dose of about 1-5 mg.
  • the ZPS is administered at a dose of 1 ⁇ g to 10 mg. In some embodiments, the ZPS is administered at a dose of 25 ⁇ g to 1 mg.
  • the subject being treated may be a human. In some embodiments, the subject being treated may be a non-human mammal. A program comparable to that discussed above may be used in veterinary medicine.
  • compositions and techniques for their preparation and use will be known to those of skill in the art in light of the present disclosure.
  • suitable pharmacological compositions and associated administrative techniques one may refer to the detailed teachings herein, which may be further supplemented by texts such as Remington, The Science and Practice of Pharmacy, 20 th ed., (Lippincott, Williams & Wilkins 2003). Except insofar as any conventional media or agent is incompatible with the active compound, such use in the compositions is contemplated.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • pharmaceutically acceptable salt is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, Berge, et al., J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, bes
  • the term “therapeutically effective amount” or “effective amount” refers to an amount of a therapeutic agent that when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject is effective to prevent, delay the onset of, or reduce the progression of colorectal tumorigenesis.
  • a therapeutically effective dose further refers to that amount of the therapeutic agent sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • a therapeutically effective dose refers to that ingredient alone.
  • a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • an effective amount is an amount that inhibits or reduces colorectal tumorigenesis.
  • the present invention herein provides methods for treating or ameliorating a colorectal cancer in a subject, comprising adjusting the composition of gut microbiota in the subject having the colorectal cancer.
  • methods disclosed herein consist essentially of adjusting the composition of gut microbiota in a subject having colorectal cancer.
  • methods disclosed herein consist of adjusting the composition of gut microbiota in a subject having colorectal cancer.
  • methods disclosed herein are not combined with other pharmaceutical(s), e.g., antibiotics, anti-inflammatory drug(s) or chemotherapeutics, e.g., 5-Fluorouracil, Capecitabine, oxaliplatin, Irinotecan, etc.
  • antibiotics e.g., antibiotics, anti-inflammatory drug(s) or chemotherapeutics, e.g., 5-Fluorouracil, Capecitabine, oxaliplatin, Irinotecan, etc.
  • the subject has been diagnosed with colitis-associated colorectal cancer.
  • the subject may have a history of IBD before the diagnosis of colorectal cancer.
  • other types of colorectal cancer are also contemplated including, but not limited to, HNPCC, colorectal cancer associated with Gardner syndrome, colorectal cancer associated with FAP, colorectal adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, squamous cell carcinoma, etc.
  • Subjects at various stages of colorectal cancer may be treated with the presently disclosed methods.
  • a subject may be treated with the presently disclosed methods at the precancer or tumor budding stage, at the dysplasia stage, before or after the tumor invades submucosa, before or after the tumor invades muscularis propria, before or after the tumor invades subserosa or beyond, before or after the tumor invades adjacent organs, before or after the tumor perforates the visceral peritoneum, before or after metastasis, before or after surgery, radiation therapy or chemotherapy, before or after remission, etc.
  • adjusting the composition of gut microbiota in the subject includes administering the subject a composition comprising bacteria, for example, a composition comprising Bacteroides bacteria.
  • Bacteroides bacteria comprise B. fragilis, B. thetaiotaomicron, B. vulgatus , or a mixture thereof.
  • the composition may comprise B. fragilis and B. thetaiotaomicron .
  • the composition may comprise B. fragilis and B. vulgatus .
  • the composition may comprise B. thetaiotaomicron and B. vulgatus .
  • the Bacteroides bacteria can be B. fragilis .
  • the composition comprising bacteria for example a composition comprising Bacteroides bacteria
  • the composition can be administered to the subject via oral administration, rectal administration, transdermal administration, intranasal administration or inhalation.
  • the composition is administered to the subject orally.
  • the composition comprising bacteria, such as Bacteroides bacteria can also be in various forms.
  • the composition can be a probiotic composition, a neutraceutical, a pharmaceutical composition, or a mixture thereof.
  • the therapeutic effect may be characterized as the slowing or stopping of tumor growth in the treated subject, the reduction in tumor number or mass in the treated subject, loss of invasiveness of tumors in the treated subject, or a combination thereof.
  • the tumors may be tumors of distal colon, proximal colon, or both.
  • a reference value may be established based on a control subject that is not treated with the methods disclosed herein or the treated subject prior to treatment.
  • the treated subject may show a decrease of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or about 100%, or a range between any two of these values in the tumor growth in comparison to the reference value.
  • the treated subject may show a decrease of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or about 100%, or a range between any two of these values in the tumor number or tumor mass in comparison to the reference value.
  • the treated subject may show a decrease of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or about 100%, or a range between any two of these values in the tumor invasiveness in comparison to the reference value.
  • cancers or cancer-like diseases such as small intestinal adenocarcinoma, Squamous cell carcinoma of the anus, cholangiocarcinoma, hepatobiliary cancers, and hematologic malignancies such as leukemia, hematopoietic cancer, lymphoma, myeloid leukemia may also be treated by the methods disclosed herein.
  • the methods comprises identifying the subject in need of treatment based on the type of colorectal cancer, development history of the colorectal cancer, presence of dysbiosis, or a combination thereof.
  • the composition comprises Vitamin D, ZPS, or a combination thereof.
  • the composition is administered orally, via fecal transplantation, etc.
  • the composition may be administered one time, intermittently, chronically, or continuously.
  • the amount of bacteria for example Bacteroides bacteria (e.g., B. fragilis ), administered to the subject in need of treatment can be determined according to various parameters such as the age, body weight, response of the subject, condition of the subject to be treated; the type and severity of the colorectal cancer; the form of the composition in which the bacteria is included; the route of administration; and the required regimen.
  • the severity of the colorectal cancer may, for example, be evaluated, in part, by standard prognostic evaluation methods.
  • the amount of bacteria can be titrated to determine the effective amount for administering to the subject in need of treatment.
  • the present invention herein provides methods for relieving gastrointestinal (GI) distress of a subject having a colorectal condition, comprising: determining the colorectal condition of the subject; and relieving GI distress in the subject by adjusting the composition of gut microbiota in the subject.
  • methods disclosed herein consist essentially of adjusting the composition of gut microbiota in a subject having a colorectal condition. In some embodiments, methods disclosed herein consist of adjusting the composition of gut microbiota in a subject having a colorectal condition.
  • methods disclosed herein are not combined with other pharmaceutical(s), e.g., antibiotics, anti-inflammatory drug(s) or chemotherapeutics, e.g., 5-Fluorouracil, Capecitabine, oxaliplatin, Irinotecan, etc.
  • antibiotics e.g., antibiotics, anti-inflammatory drug(s) or chemotherapeutics, e.g., 5-Fluorouracil, Capecitabine, oxaliplatin, Irinotecan, etc.
  • the GI distress comprises abdominal cramps, chronic diarrhea, constipation, intestinal permeability, or a combination thereof.
  • the methods can include reducing intestinal permeability in the subject.
  • adjusting the composition of gut microbiota in the subject includes administering the subject a composition comprising bacteria, for example, a composition comprising Bacteroides bacteria.
  • Bacteroides bacteria comprise B. fragilis, B. thetaiotaomicron, B. vulgatus , or a mixture thereof.
  • the composition may comprise B. fragilis and B. thetaiotaomicron .
  • the composition may comprise B. fragilis and B. vulgatus .
  • the composition may comprise B. thetaiotaomicron and B. vulgatus .
  • the Bacteroides bacteria can be B. fragilis .
  • the composition comprising bacteria for example a composition comprising Bacteroides bacteria
  • the composition can be administered to the subject via oral administration, rectal administration, transdermal administration, intranasal administration or inhalation.
  • the composition is administered to the subject orally.
  • the composition comprising bacteria, such as Bacteroides bacteria can also be in various forms.
  • the composition can be a probiotic composition, a neutraceutical, a pharmaceutical composition, or a mixture thereof.
  • the methods comprises identifying the subject in need of treatment based on abdominal cramps, chronic diarrhea, constipation, intestinal permeability, or a combination thereof.
  • the composition comprises Vitamin D, ZPS, or a combination thereof.
  • the composition is administered orally, via fecal transplantation, etc.
  • the composition may be administered one time, intermittently, chronically, or continuously.
  • the amount of bacteria for example Bacteroides bacteria (e.g., B. fragilis ), administered to the subject in need of treatment can be determined according to various parameters such as the age, body weight, response of the subject, condition of the subject to be treated; the type and severity of the colorectal cancer; the form of the composition in which the bacteria is included; the route of administration; and the required regimen.
  • the severity of the colorectal cancer may, for example, be evaluated, in part, by standard prognostic evaluation methods.
  • the amount of bacteria can be titrated to determine the effective amount for administering to the subject in need of treatment.
  • Azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer mouse model was used to study whether PSA can protect mice from colitis-induced colorectal tumorigenesis.
  • a single AOM injection with three cycles of DSS administration was used to induce colon cancer that mimics colitis-driven tumor development.
  • Mice were treated orally with B. fragilis or B. fragilis ⁇ PSA three times a week starting a week prior to AOM injection until the end of experiment. After initial AOM intraperitoneal injection, 2.5% DSS was given in the drinking water for 6 days followed by regular drinking water. Mice were subjected to a second DSS cycle with 2.5% DSS water at day 25 for 6 days and a third cycle with 1.5% DSS water at day 55 for 4-6 days. Mice were sacrificed on days 81 post AOM injection.
  • Fecal samples are sterilely collected from mice at 1, 2 and 3 weeks after the start of treatment with B. fragilis or vehicle.
  • DNA is isolated fecal samples using the QIAamp DNA Stool Mini Kit (Qiagen). 50 ng DNA is used for qPCR with B. fragilis -specific primers 5′ TGATTCCGCATGGTTTCATT 3′ (SEQ ID NO: 1) and 5′ CGACCCATAGAGCCTTCATC 3′ (SEQ ID NO: 2), and universal 16S primers 5′ ACTCCTACGGGAGGCAGCAGT 3′ (SEQ ID NO: 3) and 5′ ATTACCGCGGCTGCTGGC 3′ (SEQ ID NO: 4) according to Odamaki et al., Appl. Environ. Microbiol. 74: 6814-17 (2008).
  • mice 8 week old mice were given B. fragilis or B. fragilis ⁇ PSA orally and monitored for weight loss during DSS water treatment.
  • Mice treated with PBS or B. fragilis ⁇ PSA showed significantly increased weight loss during the third cycle of DSS treatment compared to mice with B. fragilis ( FIG. 1A ). It indicates the protective effect of B. fragilis colonization and PSA during the development of colitis-induced colon cancer.
  • the number of tumors and the sum of tumor size in B. fragilis colonized mice were also significantly decreased compared to control and B. fragilis ⁇ PSA groups ( FIGS. 1B & 1C ).
  • Monocyte chemoattractant protein 1 MCP-1
  • macrophage inflammatory protein 2 MIP-2
  • KC also called chemokine ligand 1; CXCL1
  • MCP-1 macrophage inflammatory protein 2
  • CXCL1 chemokine ligand 1
  • iNOS inducible nitric oxide synthase
  • FIG. 2 Colonic tissues from B. fragilis colonized mice expressed significantly lower level of TNF ⁇ , IL-6, IL-17A, MCP-1, MIP-2, KC and iNOS compared to untreated controls and B. fragilis ⁇ PSA colonized mice ( FIG. 2 ). It indicates that B. fragilis colonization and PSA regulate the expression level of pro-inflammatory cytokines, chemokines and iNOS during the development of colon cancer.
  • TLR2 Signalling is Required for the Protection from Development of Colon Cancer by B. fragilis Colonization
  • PSA of B. fragilis has been shown to utilize TLR2 signalling to regulate inflammatory responses (Wang et al., J. Exp. Med. 203: 2853-63 (2006)). TLR2 signalling was tested to see whether it is required for the protection of the development of colon cancer in mice colonized by B. fragilis .
  • WT mice colonization with B. fragilis showed significantly decreased weight loss compared to mice treated PBS, whereas TLR2 ⁇ / ⁇ mice showed similar degree of weight loss regardless of B. fragilis colonization ( FIG. 3A ).
  • the number of tumors in distal colon was significantly decreased in WT mice colonized with B. fragilis compared to WT mice treated with PBS, whereas TLR2 ⁇ / ⁇ mice developed similar number of tumors in distal colon regardless of B.
  • FIG. 3B More tumors were found in proximal colon of TLR2 ⁇ / ⁇ mice with or without B. fragilis colonization in comparison to WT ( FIG. 3C ). These results indicate the protection from colitis-induced colon cancer by B. fragilis colonization is through the TLR2 signalling pathway.
  • mice 8 week old mice are given PSA or PBS orally and monitored for weight loss during DSS water treatment.
  • Mice treated with PBS show significantly increased weight loss during the third cycle of DSS treatment compared to mice treated with PSA.
  • the number of tumors and the sum of tumor size in PSA treated mice are also significantly decreased compared to control mice.
  • AOM/DSS-induced colon cancer or genetically engineered IBD mouse models are used (see, e.g., Tong et al., Chin. J. Cancer 30: 450-62 (2011), the content of which is herein expressly incorporated by reference in its entirety).
  • Mice having colorectal cancer are colonized with B. fragilis by fecal transplantation or oral administration.
  • B. fragilis colonization of mouse is monitored during treatment period.
  • the status of colorectal cancer including the size of tumor, number of tumors, tumor growth, tumor remission, and progression to metastasis, etc., is recorded and compared between the treatment and control groups.
  • B. fragilis Patients diagnosed with chronic ulcerative colitis are treated with B. fragilis to determine the preventative effect of adjusting the composition of gut microbiota on colorectal tumorigenesis.
  • B. fragilis is administered orally to the patients.
  • a control group of patients is treated with a placebo.
  • the composition of the patients' gut microbiota is monitored throughout the treatment period.
  • Administration of B. fragilis is suspended after successful colonization of patient's colon by B. fragilis .
  • the status of colorectal tumorigenesis including the onset of tumor, type of tumor, size of tumor, number of tumors, and response or lack thereof to treatment regimens is recorded and compared between the treatment and control groups.
  • Patients diagnosed with chronic ulcerative colitis are treated with a pharmaceutical composition of PSA to determine the preventative effect of PSA on colorectal tumorigenesis.
  • Oral administration is used to introduce the pharmaceutical composition of PSA into the patients.
  • a control group of patients is treated with placebo.
  • the status of colorectal tumorigenesis including the onset of tumor, type of tumor, size of tumor, number of tumors, and response or lack thereof to treatment regimens is recorded and compared between the treatment and control groups.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
US14/274,607 2013-05-10 2014-05-09 Probiotic prevention and treatment of colon cancer Abandoned US20140335131A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US14/274,607 US20140335131A1 (en) 2013-05-10 2014-05-09 Probiotic prevention and treatment of colon cancer
US16/514,796 US10772918B2 (en) 2013-05-10 2019-07-17 Probiotic prevention and treatment of colon cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361822126P 2013-05-10 2013-05-10
US14/274,607 US20140335131A1 (en) 2013-05-10 2014-05-09 Probiotic prevention and treatment of colon cancer

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/514,796 Continuation US10772918B2 (en) 2013-05-10 2019-07-17 Probiotic prevention and treatment of colon cancer

Publications (1)

Publication Number Publication Date
US20140335131A1 true US20140335131A1 (en) 2014-11-13

Family

ID=51864944

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/274,607 Abandoned US20140335131A1 (en) 2013-05-10 2014-05-09 Probiotic prevention and treatment of colon cancer
US16/514,796 Active US10772918B2 (en) 2013-05-10 2019-07-17 Probiotic prevention and treatment of colon cancer

Family Applications After (1)

Application Number Title Priority Date Filing Date
US16/514,796 Active US10772918B2 (en) 2013-05-10 2019-07-17 Probiotic prevention and treatment of colon cancer

Country Status (5)

Country Link
US (2) US20140335131A1 (ja)
EP (1) EP2994161B1 (ja)
JP (2) JP2016521284A (ja)
CA (1) CA2911826C (ja)
WO (1) WO2014182966A1 (ja)

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160022727A1 (en) * 2007-11-09 2016-01-28 California Institute Of Technology Immunomodulating compounds and related compositions and methods
WO2016079735A1 (en) * 2014-11-18 2016-05-26 Z.M.D. Medical Ltd. Bacteria donors and pharmaceutical compositions
WO2016149449A1 (en) * 2015-03-18 2016-09-22 Tufts University Compositions and methods for preventing colorectal cancer
WO2016203217A1 (en) * 2015-06-15 2016-12-22 4D Pharma Research Limited Compositions comprising bacterial strains
US9539281B2 (en) 2011-07-12 2017-01-10 The Brigham And Women's Hospital, Inc. Lipid-containing PSA compositions, methods of isolation and methods of use thereof
US9839655B2 (en) 2015-11-20 2017-12-12 4D Pharma Research Limited Compositions comprising bacterial strains
US20170360856A1 (en) 2015-06-15 2017-12-21 4D Pharma Research Limited Compositions comprising bacterial strains
US9987311B2 (en) 2015-11-23 2018-06-05 4D Pharma Research Limited Compositions comprising bacterial strains
JP2018517677A (ja) * 2015-04-23 2018-07-05 カレイド・バイオサイエンシズ・インコーポレイテッド グリカン治療剤及び治療方法
US10046015B2 (en) 2015-11-20 2018-08-14 4D Pharma Research Limited Compositions comprising bacterial strains
WO2018136617A3 (en) * 2017-01-18 2018-08-23 Evelo Biosciences, Inc. Bacteria for treating cancer
US10080772B2 (en) 2016-07-13 2018-09-25 4D Pharma Plc Compositions comprising bacterial strains
US10086023B2 (en) 2016-03-04 2018-10-02 4D Pharma Plc Compositions comprising bacterial strains
US10086021B2 (en) 2016-12-12 2018-10-02 4D Pharma Plc Compositions comprising bacterial strains
US10226489B2 (en) 2014-12-23 2019-03-12 4D Pharma Research Limited Composition of bacteroides thetaiotaomicron for immune modulation
WO2019047440A1 (zh) * 2017-09-11 2019-03-14 广州知易生物科技有限公司 脆弱拟杆菌提取物在制备防治炎症性肠病的药物或食品中的应用
US10391128B2 (en) 2015-11-23 2019-08-27 4D Pharma Research Limited Compositions comprising bacterial strains
US10456444B2 (en) 2014-12-23 2019-10-29 4D Pharma Research Limited Pirin polypeptide and immune modulation
US10493112B2 (en) 2015-06-15 2019-12-03 4D Pharma Research Limited Compositions comprising bacterial strains
US10500237B2 (en) 2015-06-15 2019-12-10 4D Pharma Research Limited Compositions comprising bacterial strains
CN111249314A (zh) * 2020-03-03 2020-06-09 深圳未知君生物科技有限公司 人体共生菌群在提高肿瘤免疫治疗应答中的作用
US10736926B2 (en) 2015-06-15 2020-08-11 4D Pharma Research Limited Compositions comprising bacterial strains
US10851137B2 (en) 2013-04-10 2020-12-01 4D Pharma Research Limited Polypeptide and immune modulation
US10857177B2 (en) 2015-08-19 2020-12-08 President And Fellows Of Harvard College Lipidated PSA compositions and methods
EP3712246A4 (en) * 2017-11-17 2020-12-23 Shenzhen Yueyao Life Technology Co., Ltd. COMPOSITION FOR INCREASING THE IMMUNE FUNCTION OF T-CELLS AND MANUFACTURING METHOD FOR IT
US10987387B2 (en) 2017-05-24 2021-04-27 4D Pharma Research Limited Compositions comprising bacterial strain
WO2021081247A1 (en) * 2019-10-22 2021-04-29 Cornell University Microbiota based therapies to promote mental health
US11007233B2 (en) 2017-06-14 2021-05-18 4D Pharma Research Limited Compositions comprising a bacterial strain of the genus Megasphera and uses thereof
US11013773B2 (en) 2011-07-14 2021-05-25 4D Pharma Research Limited Lactic acid bacterial strains
US11103566B2 (en) 2010-05-20 2021-08-31 California Institute Of Technology Antigen specific Tregs and related compositions, methods and systems
US11123379B2 (en) 2017-06-14 2021-09-21 4D Pharma Research Limited Compositions comprising bacterial strains
US11123378B2 (en) 2017-05-22 2021-09-21 4D Pharma Research Limited Compositions comprising bacterial strains
US11224620B2 (en) 2016-07-13 2022-01-18 4D Pharma Plc Compositions comprising bacterial strains
CN114028573A (zh) * 2021-12-09 2022-02-11 北京大学第一医院 拟杆菌属肠道菌及其代谢相关物质在制备逆转氟尿嘧啶类药物耐药性的药物中的用途
US11266698B2 (en) 2011-10-07 2022-03-08 4D Pharma Research Limited Bacterium for use as a probiotic for nutritional and medical applications
CN114470003A (zh) * 2022-01-12 2022-05-13 广州知易生物科技有限公司 脆弱拟杆菌或其两性离子荚膜多糖在制备防治消化系统肿瘤药物中的应用
CN114469986A (zh) * 2022-01-12 2022-05-13 广州知易生物科技有限公司 脆弱拟杆菌荚膜多糖a与免疫检查点抑制剂联用在制备治疗消化系统肿瘤药物中的应用
US11331335B2 (en) 2015-06-10 2022-05-17 California Institute Of Technology Sepsis treatment and related compositions methods and systems
US11419887B2 (en) 2010-04-07 2022-08-23 California Institute Of Technology Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems
US11491181B2 (en) 2016-07-15 2022-11-08 President And Fellows Of Harvard College Glycolipid compositions and methods of use
US11584805B2 (en) 2014-07-09 2023-02-21 Dsm Nutritional Products, Llc Oligosaccharide compositions and methods for producing thereof
WO2023044338A1 (en) * 2021-09-14 2023-03-23 Academia Sinica Method for treating colon cancer and/or inflammatory disorder with bacteroides plebeius
US11622973B2 (en) 2007-11-09 2023-04-11 California Institute Of Technology Immunomodulating compounds and related compositions and methods
US11653676B2 (en) 2015-01-26 2023-05-23 Dsm Nutritional Products, Llc Oligosaccharide compositions for use as animal feed and methods of producing thereof
US11865145B2 (en) * 2017-08-07 2024-01-09 Finch Therapeutics Holdings Llc Compositions and methods for maintaining and restoring a healthy gut barrier
US12048720B2 (en) 2017-06-14 2024-07-30 Cj Bioscience, Inc. Compositions comprising bacterial strains

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016521284A (ja) 2013-05-10 2016-07-21 カリフォルニア インスティチュート オブ テクノロジー 大腸ガンのプロバイオティクスによる防止および処置

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311686A1 (en) * 2009-06-03 2010-12-09 Kasper Lloyd H Nutraceutical composition and methods for preventing or treating multiple sclerosis
WO2011153226A2 (en) * 2010-06-01 2011-12-08 Moore Research Enterprises Llc Cellular constituents from bacteroides, compositions thereof, and therapeutic methods employing bacteroides or cellular constituents thereof

Family Cites Families (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56128721A (en) 1980-03-12 1981-10-08 Eisai Co Ltd Antiallergic agent
US4775626A (en) 1986-05-23 1988-10-04 Syntex (U.S.A.) Inc. Method and compositions for protecting anerobic microorganisms
DE3704389A1 (de) 1987-02-12 1988-08-25 Blutspendedienst Dt Rote Kreuz Verfahren zur herstellung von lymphokinen durch induktion lymphoider zellen
DE3840044A1 (de) 1988-11-27 1990-06-07 Behringwerke Ag Glykosphingolipide mit kopplungsfaehiger gruppe im sphingoidanteil, ihre herstellung und verwendung
FI895708A0 (fi) 1989-02-10 1989-11-29 Alko Ab Oy Vattenloeslig soenderdelningsprodukt.
CA2059693C (en) 1991-01-28 2003-08-19 Peter J. Kniskern Polysaccharide antigens from streptococcus pneumoniae
GB2286193A (en) 1991-03-28 1995-08-09 Italfarmaco Spa Anticoagulants and processes for preparing such
IL113812A (en) 1994-05-24 2000-06-29 Yeda Res & Dev Copolymer-1 pharmaceutical compositions containing it and its use
US5679654A (en) 1994-09-02 1997-10-21 Brigham & Women's Hospital, Inc. Capsular polysaccharide immunomodulator
US5700787A (en) 1994-09-02 1997-12-23 Brigham & Women's Hospital, Inc. Capsular polysaccharide immunomodulator
US5858964A (en) 1995-04-14 1999-01-12 Yeda Research And Development Co. Ltd. Pharmaceutical compositions comprising synthetic peptide copolymer for prevention of GVHD
US5679658A (en) 1995-05-08 1997-10-21 Chitogenics, Inc. N,O-carbonxymethylchitosan for prevention of surgical adhesions
CN101002727A (zh) 1996-11-14 2007-07-25 (由国防部长代表的)美利坚合众国政府 经皮免疫之佐剂
US6027733A (en) 1997-03-26 2000-02-22 The Brigham And Women's Hospital, Inc. Method for generating saccharide fragments
ES2189166T3 (es) 1997-04-04 2003-07-01 Fidia Advanced Biopolymers Srl Compuestos del acido hialuronico n-sulfatado, sus derivados y proceso para su preparacion.
ITPD980169A1 (it) 1998-07-06 2000-01-06 Fidia Advanced Biopolymers Srl Ammidi dell'acido ialuronico e dei suoi derivati e processo per la loro preparazione.
BRPI0009163B8 (pt) 1999-03-19 2021-05-25 Glaxosmithkline Biologicals Sa composição imunogênica e vacina que a compreende
EP1459757A1 (en) 1999-04-02 2004-09-22 The Brigham And Women's Hospital, Inc. Immunomodulating polymers
WO2000059515A2 (en) 1999-04-02 2000-10-12 The Brigham And Women's Hospital, Inc. Immunomodulating polymers
US7083777B1 (en) 1999-04-02 2006-08-01 The Brigham And Women's Hospital, Inc. Immunomodulating polymers
US6358939B1 (en) 1999-12-21 2002-03-19 Northern Lights Pharmaceuticals, Llc Use of biologically active vitamin D compounds for the prevention and treatment of inflammatory bowel disease
AUPQ899700A0 (en) 2000-07-25 2000-08-17 Borody, Thomas Julius Probiotic recolonisation therapy
SV2003000753A (es) * 2000-12-05 2003-06-16 Brigham & Womens Hospital Uso de polisacaridos zwitterionicos para la especifica modulacion del progreso inmunologico
CA2434574A1 (en) 2001-01-12 2002-07-18 Amato Pharmaceutical Products, Ltd. An antiallergic agent
DE60238471D1 (de) 2001-03-09 2011-01-13 Id Biomedical Corp Quebec Proteosom-liposaccharid-vakzine-adjuvans
EP1308167A1 (de) 2001-11-06 2003-05-07 Pickl, Winfried, Ao. Univ. Prof. Dr. Antigenpräsentierende Vesikel
JP2003204796A (ja) 2001-11-08 2003-07-22 Japan Science & Technology Corp 非ヒト遺伝子改変動物およびその利用
GB0130123D0 (en) 2001-12-17 2002-02-06 Microbiological Res Agency Outer membrane vesicle vaccine and its preparation
US20030147865A1 (en) 2002-02-07 2003-08-07 Benoit Salomon Cell therapy using immunoregulatory T-cells
AU2003217685A1 (en) 2002-03-08 2003-09-22 Eli Lilly And Company Immunomodulatory polymeric antigens for treating inflammatory pathogies
US7166455B2 (en) 2002-03-13 2007-01-23 The Brigham And Women's Hospital, Inc. Method for overexpression of zwitterionic polysaccharides
US7829289B2 (en) 2002-05-14 2010-11-09 Institut National De La Sante Et De Recherche Medicale T cell subpopulation regulating gut immunity
WO2004050909A2 (en) 2002-12-03 2004-06-17 Dartmouth College Method to measure a t cell response and its uses to qualify antigen-presenting cells
US20040219160A1 (en) 2003-03-31 2004-11-04 The Brigham And Women's Hospital, Inc. Zwitterionic immunomodulators for the treatment of asthma and allergy
US20050048587A1 (en) 2003-07-17 2005-03-03 Tolerrx, Inc. Methods for identifying tolerance modulatory compounds and uses therefor
US6846807B1 (en) * 2003-07-25 2005-01-25 Board Of Regents, The University Of Texas System Colorectal neoplasia prophylaxis
JPWO2005094571A1 (ja) 2004-03-31 2008-02-14 独立行政法人科学技術振興機構 遺伝子改変ヘテロ動物及び該動物を用いたエキソサイトシスの計測方法
US8426146B2 (en) 2005-06-03 2013-04-23 University of Pittsburgh—of the Commonwealth System of Higher Education Multiparameteric method for assessing immune system status
RU2440123C2 (ru) 2005-10-06 2012-01-20 Проби Аб Применение lactobacillus для лечения вирусных инфекций
WO2007092451A2 (en) 2006-02-06 2007-08-16 The Brigham And Women's Hospital, Inc. Zwitterionic polysaccharides for promotion of immune system maturation and health
CN100366737C (zh) 2006-03-01 2008-02-06 哈尔滨美华生物技术股份有限公司 固定化乳糖酶生产方法
WO2007136719A2 (en) * 2006-05-18 2007-11-29 Biobalance Llc Biotherapeutic compositions comprising probiotic escherichia coli and uses thereof
PT2126054T (pt) 2007-01-31 2016-10-12 Yeda Res & Dev Células t reguladoras geneticamente modificadas, redirecionadas e sua utilização na supressão de doenças inflamatórias e autoimunitárias
US8092998B2 (en) 2007-05-31 2012-01-10 Abbott Laboratories Biomarkers predictive of the responsiveness to TNFα inhibitors in autoimmune disorders
EP2217250A4 (en) 2007-11-09 2011-01-05 California Inst Of Techn IMMUNOREGULATORY COMPOUNDS AND RELATED COMPOSITIONS AND METHODS
TWI468188B (zh) 2008-01-30 2015-01-11 Univ Tokushima Anti-cancer effect enhancers consisting of oxaliplatin liposomal preparations and anticancer agents comprising the formulation
US8586029B2 (en) 2008-06-04 2013-11-19 Trustees Of Dartmouth College Prevention or treatment of immune-relevant disease by modification of microfloral populations
US20100275282A1 (en) 2009-04-23 2010-10-28 Round June L Methods and systems for identifying immunomodulatory substances
DK2555753T3 (en) 2010-04-07 2018-11-26 California Inst Of Techn Vesicle for delivering a compound to a mucosal membrane as well as corresponding compositions, methods and systems
JP2013530949A (ja) 2010-05-20 2013-08-01 エル ラウンド ジューン 抗原特異的Ｔｒｅｇ並びに関連する組成物、方法及びシステム
WO2012027032A1 (en) 2010-07-20 2012-03-01 Trustees Of Dartmouth College Method for stimulating foxp3+ regulatory t cell expression of cd39
EP3072524B1 (en) 2010-10-07 2018-01-17 California Institute Of Technology Probiotic therapies for autism
US20130064859A1 (en) 2011-01-28 2013-03-14 Sarkis K. Mazmanian Combinatorial vitamin d and probiotic therapy for inflammatory bowel disease
EP2731617A4 (en) 2011-07-12 2015-07-01 Brigham & Womens Hospital LIPID-CONTAINING PSA COMPOSITIONS, METHODS OF ISOLATION AND METHODS OF USING SAME
WO2013019896A1 (en) 2011-08-01 2013-02-07 Symbiotix Biotherapies, Inc. Platform for identifying and/or characterizing immunomodulatory agents
EP2763540A4 (en) * 2011-09-09 2015-04-22 Univ Yale COMPOSITIONS AND METHODS FOR EVALUATION AND TREATMENT OF DISEASES AND INFLAMMATORY DISORDERS
US9057070B2 (en) 2011-10-03 2015-06-16 California Institute Of Technology Generation of Bacteriodes fragilis capsular polysaccharide A-only producing mutant strain
JP2016521284A (ja) 2013-05-10 2016-07-21 カリフォルニア インスティチュート オブ テクノロジー 大腸ガンのプロバイオティクスによる防止および処置

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311686A1 (en) * 2009-06-03 2010-12-09 Kasper Lloyd H Nutraceutical composition and methods for preventing or treating multiple sclerosis
WO2011153226A2 (en) * 2010-06-01 2011-12-08 Moore Research Enterprises Llc Cellular constituents from bacteroides, compositions thereof, and therapeutic methods employing bacteroides or cellular constituents thereof

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160022727A1 (en) * 2007-11-09 2016-01-28 California Institute Of Technology Immunomodulating compounds and related compositions and methods
US11622973B2 (en) 2007-11-09 2023-04-11 California Institute Of Technology Immunomodulating compounds and related compositions and methods
US11419887B2 (en) 2010-04-07 2022-08-23 California Institute Of Technology Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems
US11103566B2 (en) 2010-05-20 2021-08-31 California Institute Of Technology Antigen specific Tregs and related compositions, methods and systems
US9539281B2 (en) 2011-07-12 2017-01-10 The Brigham And Women's Hospital, Inc. Lipid-containing PSA compositions, methods of isolation and methods of use thereof
US11013773B2 (en) 2011-07-14 2021-05-25 4D Pharma Research Limited Lactic acid bacterial strains
US11266698B2 (en) 2011-10-07 2022-03-08 4D Pharma Research Limited Bacterium for use as a probiotic for nutritional and medical applications
US10851137B2 (en) 2013-04-10 2020-12-01 4D Pharma Research Limited Polypeptide and immune modulation
US11414463B2 (en) 2013-04-10 2022-08-16 4D Pharma Research Limited Polypeptide and immune modulation
US11584805B2 (en) 2014-07-09 2023-02-21 Dsm Nutritional Products, Llc Oligosaccharide compositions and methods for producing thereof
WO2016079735A1 (en) * 2014-11-18 2016-05-26 Z.M.D. Medical Ltd. Bacteria donors and pharmaceutical compositions
US11723933B2 (en) 2014-12-23 2023-08-15 Cj Bioscience, Inc. Composition of bacteroides thetaiotaomicron for immune modulation
US10456444B2 (en) 2014-12-23 2019-10-29 4D Pharma Research Limited Pirin polypeptide and immune modulation
US10226489B2 (en) 2014-12-23 2019-03-12 4D Pharma Research Limited Composition of bacteroides thetaiotaomicron for immune modulation
US10973872B2 (en) 2014-12-23 2021-04-13 4D Pharma Research Limited Pirin polypeptide and immune modulation
US11653676B2 (en) 2015-01-26 2023-05-23 Dsm Nutritional Products, Llc Oligosaccharide compositions for use as animal feed and methods of producing thereof
WO2016149449A1 (en) * 2015-03-18 2016-09-22 Tufts University Compositions and methods for preventing colorectal cancer
US11883422B2 (en) 2015-04-23 2024-01-30 Dsm Nutritional Products, Llc Glycan therapeutic compositions and related methods thereof
US10894057B2 (en) 2015-04-23 2021-01-19 Kaleido Biosciences, Inc. Glycan therapeutic compositions and related methods thereof
JP2021001208A (ja) * 2015-04-23 2021-01-07 カレイド・バイオサイエンシズ・インコーポレイテッド グリカン治療剤及び治療方法
JP2018517677A (ja) * 2015-04-23 2018-07-05 カレイド・バイオサイエンシズ・インコーポレイテッド グリカン治療剤及び治療方法
US11331335B2 (en) 2015-06-10 2022-05-17 California Institute Of Technology Sepsis treatment and related compositions methods and systems
US11331352B2 (en) 2015-06-15 2022-05-17 4D Pharma Research Limited Compositions comprising bacterial strains
AU2016278066B2 (en) * 2015-06-15 2021-09-23 Cj Bioscience, Inc. Compositions comprising bacterial strains
US10391130B2 (en) 2015-06-15 2019-08-27 4D Pharma Research Limited Compositions comprising bacterial strains
US10322151B2 (en) 2015-06-15 2019-06-18 4D Pharma Research Limited Compositions comprising bacterial strains
US11273185B2 (en) 2015-06-15 2022-03-15 4D Pharma Research Limited Compositions comprising bacterial strains
US11040075B2 (en) 2015-06-15 2021-06-22 4D Pharma Research Limited Compositions comprising bacterial strains
US10493112B2 (en) 2015-06-15 2019-12-03 4D Pharma Research Limited Compositions comprising bacterial strains
US10500237B2 (en) 2015-06-15 2019-12-10 4D Pharma Research Limited Compositions comprising bacterial strains
US10780134B2 (en) 2015-06-15 2020-09-22 4D Pharma Research Limited Compositions comprising bacterial strains
US11389493B2 (en) 2015-06-15 2022-07-19 4D Pharma Research Limited Compositions comprising bacterial strains
EP3626248A1 (en) * 2015-06-15 2020-03-25 4D Pharma Research Limited Compositions comprising bacterial strains
US10058574B2 (en) 2015-06-15 2018-08-28 4D Pharma Research Limited Compositions comprising bacterial strains
US11433106B2 (en) 2015-06-15 2022-09-06 4D Pharma Research Limited Compositions comprising bacterial strains
US20170360856A1 (en) 2015-06-15 2017-12-21 4D Pharma Research Limited Compositions comprising bacterial strains
WO2016203217A1 (en) * 2015-06-15 2016-12-22 4D Pharma Research Limited Compositions comprising bacterial strains
US10736926B2 (en) 2015-06-15 2020-08-11 4D Pharma Research Limited Compositions comprising bacterial strains
US10744167B2 (en) 2015-06-15 2020-08-18 4D Pharma Research Limited Compositions comprising bacterial strains
US10857177B2 (en) 2015-08-19 2020-12-08 President And Fellows Of Harvard College Lipidated PSA compositions and methods
US9974815B2 (en) 2015-11-20 2018-05-22 4D Pharma Research Limited Compositions comprising bacterial strains
US9839655B2 (en) 2015-11-20 2017-12-12 4D Pharma Research Limited Compositions comprising bacterial strains
US10357520B2 (en) 2015-11-20 2019-07-23 4D Pharma Research Limited Compositions comprising bacterial strains
US20180078585A1 (en) 2015-11-20 2018-03-22 4D Pharma Research Limited Compositions comprising bacterial strains
US10610550B2 (en) 2015-11-20 2020-04-07 4D Pharma Research Limited Compositions comprising bacterial strains
US10471108B2 (en) 2015-11-20 2019-11-12 4D Pharma Research Limited Compositions comprising bacterial strains
US11058732B2 (en) 2015-11-20 2021-07-13 4D Pharma Research Limited Compositions comprising bacterial strains
US10046015B2 (en) 2015-11-20 2018-08-14 4D Pharma Research Limited Compositions comprising bacterial strains
US10744166B2 (en) 2015-11-23 2020-08-18 4D Pharma Research Limited Compositions comprising bacterial strains
US9987311B2 (en) 2015-11-23 2018-06-05 4D Pharma Research Limited Compositions comprising bacterial strains
US10391128B2 (en) 2015-11-23 2019-08-27 4D Pharma Research Limited Compositions comprising bacterial strains
US10086022B2 (en) 2016-03-04 2018-10-02 4D Pharma Plc Compositions comprising bacterial strains
US10086023B2 (en) 2016-03-04 2018-10-02 4D Pharma Plc Compositions comprising bacterial strains
US10583158B2 (en) 2016-03-04 2020-03-10 4D Pharma Plc Compositions comprising bacterial strains
US10080772B2 (en) 2016-07-13 2018-09-25 4D Pharma Plc Compositions comprising bacterial strains
US10967010B2 (en) 2016-07-13 2021-04-06 4D Pharma Plc Compositions comprising bacterial strains
US10960031B2 (en) 2016-07-13 2021-03-30 4D Pharma Plc Compositions comprising bacterial strains
US10610549B2 (en) 2016-07-13 2020-04-07 4D Pharma Plc Composition comprising bacterial strains
US10610548B2 (en) 2016-07-13 2020-04-07 4D Pharma Plc Compositions comprising bacterial strains
US10086020B2 (en) 2016-07-13 2018-10-02 4D Pharma Plc Compositions comprising bacterial strains
US11224620B2 (en) 2016-07-13 2022-01-18 4D Pharma Plc Compositions comprising bacterial strains
US11491181B2 (en) 2016-07-15 2022-11-08 President And Fellows Of Harvard College Glycolipid compositions and methods of use
US10898526B2 (en) 2016-12-12 2021-01-26 4D Pharma Plc Compositions comprising bacterial strains
US10485830B2 (en) 2016-12-12 2019-11-26 4D Pharma Plc Compositions comprising bacterial strains
US10543238B2 (en) 2016-12-12 2020-01-28 4D Pharma Plc Compositions comprising bacterial strains
US10086021B2 (en) 2016-12-12 2018-10-02 4D Pharma Plc Compositions comprising bacterial strains
WO2018136617A3 (en) * 2017-01-18 2018-08-23 Evelo Biosciences, Inc. Bacteria for treating cancer
US11123378B2 (en) 2017-05-22 2021-09-21 4D Pharma Research Limited Compositions comprising bacterial strains
US11376284B2 (en) 2017-05-22 2022-07-05 4D Pharma Research Limited Compositions comprising bacterial strains
US11382936B2 (en) 2017-05-22 2022-07-12 4D Pharma Research Limited Compositions comprising bacterial strains
US10987387B2 (en) 2017-05-24 2021-04-27 4D Pharma Research Limited Compositions comprising bacterial strain
US11660319B2 (en) 2017-06-14 2023-05-30 4D Pharma Research Limited Compositions comprising bacterial strains
US11779613B2 (en) 2017-06-14 2023-10-10 Cj Bioscience, Inc. Compositions comprising a bacterial strain of the genus Megasphera and uses thereof
US11123379B2 (en) 2017-06-14 2021-09-21 4D Pharma Research Limited Compositions comprising bacterial strains
US11007233B2 (en) 2017-06-14 2021-05-18 4D Pharma Research Limited Compositions comprising a bacterial strain of the genus Megasphera and uses thereof
US12048720B2 (en) 2017-06-14 2024-07-30 Cj Bioscience, Inc. Compositions comprising bacterial strains
US11865145B2 (en) * 2017-08-07 2024-01-09 Finch Therapeutics Holdings Llc Compositions and methods for maintaining and restoring a healthy gut barrier
WO2019047440A1 (zh) * 2017-09-11 2019-03-14 广州知易生物科技有限公司 脆弱拟杆菌提取物在制备防治炎症性肠病的药物或食品中的应用
EP3712246A4 (en) * 2017-11-17 2020-12-23 Shenzhen Yueyao Life Technology Co., Ltd. COMPOSITION FOR INCREASING THE IMMUNE FUNCTION OF T-CELLS AND MANUFACTURING METHOD FOR IT
WO2021081247A1 (en) * 2019-10-22 2021-04-29 Cornell University Microbiota based therapies to promote mental health
CN111249314A (zh) * 2020-03-03 2020-06-09 深圳未知君生物科技有限公司 人体共生菌群在提高肿瘤免疫治疗应答中的作用
WO2023044338A1 (en) * 2021-09-14 2023-03-23 Academia Sinica Method for treating colon cancer and/or inflammatory disorder with bacteroides plebeius
CN114028573A (zh) * 2021-12-09 2022-02-11 北京大学第一医院 拟杆菌属肠道菌及其代谢相关物质在制备逆转氟尿嘧啶类药物耐药性的药物中的用途
CN114469986A (zh) * 2022-01-12 2022-05-13 广州知易生物科技有限公司 脆弱拟杆菌荚膜多糖a与免疫检查点抑制剂联用在制备治疗消化系统肿瘤药物中的应用
WO2023134200A1 (zh) * 2022-01-12 2023-07-20 广州知易生物科技有限公司 脆弱拟杆菌或其两性离子荚膜多糖在制备防治消化系统肿瘤药物中的应用
CN114470003A (zh) * 2022-01-12 2022-05-13 广州知易生物科技有限公司 脆弱拟杆菌或其两性离子荚膜多糖在制备防治消化系统肿瘤药物中的应用

Also Published As

Publication number Publication date
WO2014182966A1 (en) 2014-11-13
US20190336545A1 (en) 2019-11-07
EP2994161A4 (en) 2017-01-11
EP2994161B1 (en) 2020-10-28
CA2911826A1 (en) 2014-11-13
JP2016521284A (ja) 2016-07-21
JP6944965B2 (ja) 2021-10-06
CA2911826C (en) 2022-08-23
US10772918B2 (en) 2020-09-15
JP2019142884A (ja) 2019-08-29
EP2994161A1 (en) 2016-03-16

Similar Documents

Publication Publication Date Title
US10772918B2 (en) Probiotic prevention and treatment of colon cancer
Yan et al. Probiotics and probiotic-derived functional factors—Mechanistic insights into applications for intestinal homeostasis
Tang et al. Administration of probiotic mixture DM# 1 ameliorated 5-fluorouracil–induced intestinal mucositis and dysbiosis in rats
Luther et al. Helicobacter pylori DNA decreases pro-inflammatory cytokine production by dendritic cells and attenuates dextran sodium sulphate-induced colitis
Packey et al. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases
Sartor Targeting enteric bacteria in treatment of inflammatory bowel diseases: why, how, and when
Du et al. Development of gut inflammation in mice colonized with mucosa-associated bacteria from patients with ulcerative colitis
Mizuno et al. Lipoteichoic acid is involved in the ability of the immunobiotic strain Lactobacillus plantarum CRL1506 to modulate the intestinal antiviral innate immunity triggered by TLR3 activation
JP2016539119A (ja) 化学療法に対する応答性のマーカーとしての微生物叢組成物、及び癌処置の有効性を改善するための微生物モジュレーター（プレ、プロ又はシンバイオティクス）の使用
Oswari et al. Comparison of stool microbiota compositions, stool alpha1‐antitrypsin and calprotectin concentrations, and diarrhoeal morbidity of I ndonesian infants fed breast milk or probiotic/prebiotic‐supplemented formula
Kazmierczak-Siedlecka et al. Gut microbiota modulation in the context of immune-related aspects of Lactobacillus spp. and Bifidobacterium spp
JP2022540186A (ja) ビフィドバクテリウム・ビフィダム菌株、その組成物及び関連用途
Singh et al. Microbiome and host crosstalk: A new paradigm to cancer therapy
Bennedsen et al. The gut microbiota can orchestrate the signaling pathways in colorectal cancer
EP3546566A1 (en) Bacteria inducing th1 cells
Li et al. Complex probiotics alleviate ampicillin-induced antibiotic-associated diarrhea in mice
Compare et al. The bacteria-hypothesis of colorectal cancer: pathogenetic and therapeutic implications
Sartor Microbial–host interactions in inflammatory bowel diseases and experimental colitis
Ha et al. Anti‐Inflammatory Effect of a Peptide Derived from the Synbiotics, Fermented Cudrania tricuspidata with Lactobacillus gasseri, on Inflammatory Bowel Disease
Carlé et al. Perinatal foodborne titanium dioxide exposure-mediated dysbiosis predisposes mice to develop colitis through life
Schirbel et al. Targeting the innate immune system in pediatric inflammatory bowel disease
Yang et al. Dietary eggshell membrane powder improves survival rate and ameliorates gut Dysbiosis in Interleukin-10 knockout mice
Conrad et al. The gut microbiota and inflammatory bowel disease
Hadad et al. In vivo evidence: Repression of mucosal immune responses in mice with colon cancer following sustained administration of Streptococcus thermophiles
Bukharin et al. Genome sequence data announcement of Bifidobacterium bifidum strain ICIS-202 isolated from a healthy human intestine stimulating active nitrogen oxide production in macrophages

Legal Events

Date Code Title Description
AS Assignment

Owner name: CALIFORNIA INSTITUE OF TECHNOLOGY, CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MAZMANIAN, SARKIS K;LEE, YUNKYUNG;REEL/FRAME:033081/0962

Effective date: 20140611

AS Assignment

Owner name: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF

Free format text: CONFIRMATORY LICENSE;ASSIGNOR:CALIFORNIA INSTITUTE OF TECHNOLOGY;REEL/FRAME:033255/0770

Effective date: 20140611

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION