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  • 1
    Publication Date: 2012-06-23
    Description: The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(-/-), but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(-/-) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393783/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393783/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Devkota, Suzanne -- Wang, Yunwei -- Musch, Mark W -- Leone, Vanessa -- Fehlner-Peach, Hannah -- Nadimpalli, Anuradha -- Antonopoulos, Dionysios A -- Jabri, Bana -- Chang, Eugene B -- DK-42086/DK/NIDDK NIH HHS/ -- DK47722/DK/NIDDK NIH HHS/ -- F31AT006073/AT/NCCIH NIH HHS/ -- P30 DK042086/DK/NIDDK NIH HHS/ -- R01 DK047722/DK/NIDDK NIH HHS/ -- R01 DK097268/DK/NIDDK NIH HHS/ -- R37 DK047722/DK/NIDDK NIH HHS/ -- T32 DK007074/DK/NIDDK NIH HHS/ -- UH3DK083993/DK/NIDDK NIH HHS/ -- England -- Nature. 2012 Jul 5;487(7405):104-8. doi: 10.1038/nature11225.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Section of Gastroenterology, The University of Chicago, Knapp Center for Biomedical Discovery, 900 East 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722865" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bile Acids and Salts/metabolism ; Bilophila/*drug effects/growth & development ; Colitis/*chemically induced/immunology/*microbiology/pathology ; Diet, Fat-Restricted ; Dietary Fats/*pharmacology ; Inflammation/chemically induced/immunology/microbiology ; Inflammatory Bowel Diseases/chemically induced/microbiology/pathology ; Interleukin-10/*deficiency/genetics ; Metagenome/*drug effects ; Mice ; Mice, Inbred C57BL ; Milk/chemistry ; Molecular Sequence Data ; Safflower Oil/pharmacology ; Sulfites/metabolism ; Taurine/metabolism ; Taurocholic Acid/*metabolism/pharmacology ; Th1 Cells/drug effects/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-04-23
    Description: Mucosal surfaces constantly encounter microbes. Toll-like receptors (TLRs) mediate recognition of microbial patterns to eliminate pathogens. By contrast, we demonstrate that the prominent gut commensal Bacteroides fragilis activates the TLR pathway to establish host-microbial symbiosis. TLR2 on CD4(+) T cells is required for B. fragilis colonization of a unique mucosal niche in mice during homeostasis. A symbiosis factor (PSA, polysaccharide A) of B. fragilis signals through TLR2 directly on Foxp3(+) regulatory T cells to promote immunologic tolerance. B. fragilis lacking PSA is unable to restrain T helper 17 cell responses and is defective in niche-specific mucosal colonization. Therefore, commensal bacteria exploit the TLR pathway to actively suppress immunity. We propose that the immune system can discriminate between pathogens and the microbiota through recognition of symbiotic bacterial molecules in a process that engenders commensal colonization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164325/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164325/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Round, June L -- Lee, S Melanie -- Li, Jennifer -- Tran, Gloria -- Jabri, Bana -- Chatila, Talal A -- Mazmanian, Sarkis K -- AI 080002/AI/NIAID NIH HHS/ -- AI 088626/AI/NIAID NIH HHS/ -- DK 078938/DK/NIDDK NIH HHS/ -- DK 083633/DK/NIDDK NIH HHS/ -- R01 AI085090/AI/NIAID NIH HHS/ -- R01 AI085090-01/AI/NIAID NIH HHS/ -- R01 AI085090-01S1/AI/NIAID NIH HHS/ -- R01 AI085090-02/AI/NIAID NIH HHS/ -- R01 AI085090-03/AI/NIAID NIH HHS/ -- R01 DK078938/DK/NIDDK NIH HHS/ -- R01 DK078938-01A2/DK/NIDDK NIH HHS/ -- R01 DK078938-02/DK/NIDDK NIH HHS/ -- R01 DK078938-03/DK/NIDDK NIH HHS/ -- R01 DK078938-04/DK/NIDDK NIH HHS/ -- R21 AI080002/AI/NIAID NIH HHS/ -- R21 AI080002-01/AI/NIAID NIH HHS/ -- R21 AI080002-02/AI/NIAID NIH HHS/ -- R21 AI088626/AI/NIAID NIH HHS/ -- R21 AI088626-01/AI/NIAID NIH HHS/ -- R21 AI088626-02/AI/NIAID NIH HHS/ -- R21 DK083633/DK/NIDDK NIH HHS/ -- R21 DK083633-01A1/DK/NIDDK NIH HHS/ -- R21 DK083633-02/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2011 May 20;332(6032):974-7. doi: 10.1126/science.1206095. Epub 2011 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. jround@caltech.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21512004" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteroides fragilis/*growth & development/*immunology ; Colon/immunology/microbiology ; Germ-Free Life ; Homeostasis ; Humans ; *Immune Tolerance ; Immunity, Mucosal ; Interleukin-10/metabolism ; Intestinal Mucosa/*immunology/*microbiology ; Metagenome ; Mice ; Mice, Inbred C57BL ; Models, Biological ; Polysaccharides, Bacterial/immunology/*metabolism ; Signal Transduction ; Specific Pathogen-Free Organisms ; Symbiosis ; T-Lymphocytes, Regulatory/immunology ; Th17 Cells/immunology ; Toll-Like Receptor 2/immunology/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-02-11
    Description: Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076739/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076739/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DePaolo, R W -- Abadie, V -- Tang, F -- Fehlner-Peach, H -- Hall, J A -- Wang, W -- Marietta, E V -- Kasarda, D D -- Waldmann, T A -- Murray, J A -- Semrad, C -- Kupfer, S S -- Belkaid, Y -- Guandalini, S -- Jabri, B -- DK42086/DK/NIDDK NIH HHS/ -- K08 CA142892/CA/NCI NIH HHS/ -- P30 DK042086/DK/NIDDK NIH HHS/ -- P30 DK042086-19/DK/NIDDK NIH HHS/ -- R01 DK067180/DK/NIDDK NIH HHS/ -- R01 DK067180-06/DK/NIDDK NIH HHS/ -- R01 DK067180-07/DK/NIDDK NIH HHS/ -- R01 DK67180/DK/NIDDK NIH HHS/ -- R01DK71003/DK/NIDDK NIH HHS/ -- R56 DK071003/DK/NIDDK NIH HHS/ -- R56 DK071003-05/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Mar 10;471(7337):220-4. doi: 10.1038/nature09849. Epub 2011 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307853" target="_blank"〉PubMed〈/a〉
    Keywords: Adjuvants, Immunologic/*pharmacology ; Administration, Oral ; Adolescent ; Adult ; Animals ; Celiac Disease/chemically induced/etiology/*immunology ; Cells, Cultured ; Child ; Child, Preschool ; Coculture Techniques ; Dendritic Cells/drug effects/enzymology/immunology/metabolism ; Diet ; Forkhead Transcription Factors/metabolism ; Gliadin/administration & dosage/immunology ; Glutens/administration & dosage/*immunology ; HLA-DQ Antigens/genetics/immunology ; Humans ; Immune Tolerance/drug effects ; Inflammation/immunology ; Interleukin-12/biosynthesis/immunology/secretion ; Interleukin-15/genetics/*immunology ; Interleukin-23/immunology/secretion ; Intestinal Mucosa/cytology/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Mitogen-Activated Protein Kinase 8/metabolism ; Phosphorylation/drug effects ; Receptors, Interleukin-12/deficiency ; T-Lymphocytes, Regulatory/cytology/drug effects/immunology/metabolism ; Tretinoin/immunology/*pharmacology ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-11-07
    Description: T cell infiltration of solid tumors is associated with favorable patient outcomes, yet the mechanisms underlying variable immune responses between individuals are not well understood. One possible modulator could be the intestinal microbiota. We compared melanoma growth in mice harboring distinct commensal microbiota and observed differences in spontaneous antitumor immunity, which were eliminated upon cohousing or after fecal transfer. Sequencing of the 16S ribosomal RNA identified Bifidobacterium as associated with the antitumor effects. Oral administration of Bifidobacterium alone improved tumor control to the same degree as programmed cell death protein 1 ligand 1 (PD-L1)-specific antibody therapy (checkpoint blockade), and combination treatment nearly abolished tumor outgrowth. Augmented dendritic cell function leading to enhanced CD8(+) T cell priming and accumulation in the tumor microenvironment mediated the effect. Our data suggest that manipulating the microbiota may modulate cancer immunotherapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sivan, Ayelet -- Corrales, Leticia -- Hubert, Nathaniel -- Williams, Jason B -- Aquino-Michaels, Keston -- Earley, Zachary M -- Benyamin, Franco W -- Lei, Yuk Man -- Jabri, Bana -- Alegre, Maria-Luisa -- Chang, Eugene B -- Gajewski, Thomas F -- 5T32CA009594-25/CA/NCI NIH HHS/ -- P30 DK42086/DK/NIDDK NIH HHS/ -- T32 AI007090/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 27;350(6264):1084-9. doi: 10.1126/science.aac4255. Epub 2015 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of Chicago, Chicago, IL 60637, USA. ; Department of Medicine, University of Chicago, Chicago, IL 60637, USA. ; Section of Genetic Medicine, University of Chicago, Chicago, IL 60637, USA. ; Department of Pathology, University of Chicago, Chicago, IL 60637, USA. Department of Medicine, University of Chicago, Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26541606" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal/*therapeutic use ; Antigens, CD274/*immunology ; Bifidobacterium/genetics/*immunology ; CD8-Positive T-Lymphocytes/immunology ; Dendritic Cells/immunology ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome/*immunology ; Gene Expression Regulation ; Humans ; Immunity/genetics ; Immunotherapy/methods ; Lymphocyte Activation ; Melanoma/*immunology/*therapy ; Mice ; Mice, Inbred C57BL ; RNA, Ribosomal, 16S/genetics ; Skin Neoplasms/*immunology/*therapy ; Symbiosis ; T-Lymphocytes/immunology ; Tumor Microenvironment/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-11-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bouziat, Romain -- Jabri, Bana -- New York, N.Y. -- Science. 2015 Nov 13;350(6262):742-3. doi: 10.1126/science.aad6768.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Committee on Immunology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. ; Committee on Immunology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. bjabri@bsd.uchicago.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26564835" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capillary Permeability/*immunology ; Humans ; Intestines/*immunology/*microbiology ; Microbiota/*immunology ; Salmonella Infections/*immunology ; Salmonella typhimurium/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    ISSN: 1365-2559
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We recently showed that refractory sprue is distinct from coeliac disease, the former being characterized by abnormal intraepithelial T-lymphocytes expressing a cytoplasmic CD3 chain (CD3c), lacking CD3 and CD8 surface expression, and showing TCRγ gene rearrangements. To take advantage of the abnormal phenotype of CD3c + CD8 − intraepithelial lymphocytes (IEL) in refractory sprue we developed a simple method to distinguish coeliac disease from refractory sprue.〈section xml:id="abs1-2"〉〈title type="main"〉Methods and resultsComparative immunohistochemical studies using anti-CD3 and anti-CD8 antibodies were applied on paraffin-embedded and frozen biopsy specimens in refractory sprue (n = 6), coeliac disease (n = 10), healthy controls (n = 5) and suspected refractory sprue (n = 6). Comparable results were obtained on fixed and frozen biopsy specimens. In four of the six patients with suspected refractory sprue, abnormal CD3c + CD8 − IEL and TCRγ gene rearrangements were found, as in refractory sprue; the remaining two patients had normal (CD3 + CD8 +) IEL and no TCRγ gene rearrangements. Both patients had coeliac disease, as one failed to comply with a gluten-free diet, while the other was a slow responder.〈section xml:id="abs1-3"〉〈title type="main"〉ConclusionThis simplified immunostaining method using anti-CD3 and anti-CD8 antibodies on paraffin sections can distinguish active coeliac disease from refractory sprue and should prove useful in clinical practice.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2018-07-10
    Description: Intraepithelial lymphocytes (IELs) expressing the TCR ( IELs) provide continuous surveillance of the intestinal epithelium. However, the mechanisms regulating the basal motility of these cells within the epithelial compartment have not been well defined. We investigated whether IL-15 contributes to IEL localization and migratory behavior in addition to its role in IEL differentiation and survival. Using advanced live cell imaging techniques in mice, we find that compartmentalized overexpression of IL-15 in the lamina propria shifts the distribution of T cells from the epithelial compartment to the lamina propria. This mislocalization could be rescued by epithelial IL-15 overexpression, indicating that epithelial IL-15 is essential for IEL migration into the epithelium. Furthermore, in vitro analyses demonstrated that exogenous IL-15 stimulates IEL migration into cultured epithelial monolayers, and inhibition of IL-2Rβ significantly attenuates the basal motility of these cells. Intravital microscopy showed that impaired IL-2Rβ signaling induced IEL idling within the lateral intercellular space, which resulted in increased early pathogen invasion. Similarly, the redistribution of T cells to the lamina propria due to local IL-15 overproduction also enhanced bacterial translocation. These findings thus reveal a novel role for IL-15 in mediating T cell localization within the intestinal mucosa and regulating IEL motility and patrolling behavior as a critical component of host defense.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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