Humanity is increasingly afflicted by chronic inflammatory diseases, including inflammatory bowel disease (IBD) and metabolic syndrome (Met Syn), which collectively refers to the constellation of metabolic problems associated with obesity. The grant this application seeks to renew has developed our hypothesis that IBD and Met Syn share commonalities of disease pathophysiology, namely that poor management of gut microbiota plays a key role in driving inflammation that is central to both disease states. A central feature of the microbiota dysbiosis observed in both IBD and Met Syn is a more ?aggressive? microbiota that encroaches upon the gut epithelium, which is likely germane to its promotion of inflammation. One means of inducing microbiota encroachment and its inflammatory consequences is via consumption of a diet lacking fermentable fiber. We found that such low fiber diet-induced encroachment involves ablation of microbiota-mediated innate lymphoid cell (ILC) IL-22 production that normally serves to fortify the epithelium. Consequently, enriching such diets with the fermentable fiber inulin, but not the insoluble/non-fermentable fiber cellulose, restored IL-22 production, reduced microbiota encroachment, ameliorated low-grade inflammation, and protected mice from diet-induced Met Syn. However, we?ve also observed that enriching refined diets with some fermentable fibers also induced some IL-22-independent negative consequences, including exacerbating experimentally-induced colitis and promoting liver cancer thus highlighting that, at present, we lack the knowledge to safely engineer health-promoting foods. Hence, our central overall hypothesis is that better mechanistic understanding of how dietary fiber impacts the host-microbiota relationship will inform efforts to design diets and/or more safely and effectively engineer foods that promote beneficial intestine-microbiota interactions, thus ameliorating gut inflammation and its associated disease states, including IBD and Met Syn. We will investigate this hypothesis via 3 specific aims:
Aim 1 : Identify means by which nourishing microbiota with fiber results in ILC-mediated IL-22 production.
Aim 2 : Define mechanism underlying psyllium?s ability to protect against metabolic syndrome and colitis.
Aim 3 : Develop a means of targeted delivery of colonic IL-22 and investigate its ability to restore gut health and ameliorate inflammatory diseases.

Public Health Relevance

Humanityisincreasinglyafflictedbyanarrayofchronicinflammatorydiseases,includinginflammatorybowel disease(IBD)andtheconstellationofinter-relatedmetabolicdiseasescollectivelyreferredtoasmetabolic syndrome,thehallmarksofwhichincludeobesity,insulinresistance,hyperglycemia,hyperlipidemia,and hepaticsteatosis.Thisproposalseekstoinvestigatemechanismsbywhichenrichingfoodswithdietaryfiber impacthost-microbiotainteractionstoinfluencesdevelopmentofIBDandmetabolicsyndrome.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Perrin, Peter J
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Georgia State University
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United States
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Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit et al. (2018) Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. Cell 175:679-694.e22
Fields, Christopher T; Chassaing, Benoit; Paul, Matthew J et al. (2018) Vasopressin deletion is associated with sex-specific shifts in the gut microbiome. Gut Microbes 9:13-25
Etienne-Mesmin, Lucie; Chassaing, Benoit; Adekunle, Oluwaseyi et al. (2018) Toxin-positive Clostridium difficile latently infect mouse colonies and protect against highly pathogenic C. difficile. Gut 67:860-871
Zou, Jun; Chassaing, Benoit; Singh, Vishal et al. (2018) Fiber-Mediated Nourishment of Gut Microbiota Protects against Diet-Induced Obesity by Restoring IL-22-Mediated Colonic Health. Cell Host Microbe 23:41-53.e4
Fields, Christopher T; Chassaing, Benoit; Castillo-Ruiz, Alexandra et al. (2018) Effects of gut-derived endotoxin on anxiety-like and repetitive behaviors in male and female mice. Biol Sex Differ 9:7
Chassaing, Benoit; Van de Wiele, Tom; De Bodt, Jana et al. (2017) Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut 66:1414-1427
Etienne-Mesmin, Lucie; Chassaing, Benoit; Gewirtz, Andrew T (2017) Tryptophan: A gut microbiota-derived metabolites regulating inflammation. World J Gastrointest Pharmacol Ther 8:7-9
Viennois, Emilie; Merlin, Didier; Gewirtz, Andrew T et al. (2017) Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis. Cancer Res 77:27-40
Etienne-Mesmin, Lucie; Chassaing, Benoit; Adekunle, Oluwaseyi et al. (2017) Genome Sequence of a Toxin-PositiveClostridium difficileStrain Isolated from Murine Feces. Genome Announc 5:
Chassaing, Benoit; Vijay-Kumar, Matam; Gewirtz, Andrew T (2017) How diet can impact gut microbiota to promote or endanger health. Curr Opin Gastroenterol 33:417-421

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