The intestinal tract is inhabited by a large diverse community of bacteria collectively referred to as the gut microbiota. Alterations in gut microbiota composition are associated with a variety of disease states including obesity, diabetes, and inflammatory bowel disease (IBD). Antibiotics alter host metabolism and transplant of microbiota from diseased persons (or mice) to germfree mice transfers some aspects of disease phenotype, suggesting that altered microbiota may play a role in disease manifestation. There are myriad potential mechanisms by which alterations in gut microbiota might promote disease including increasing energy harvest, production of toxic metabolites, and molecular mimicry of host proteins. Our study of mice with a discrete innate immune deficiency, namely loss of the flagellin receptor toll-like receptor 5 (TLR5), led us to hypothesize that an overarching mechanism by which an aberrant microbiota negatively impacts health is by driving chronic inflammation. More specifically, we hypothesize that the histopathologically-evident gut inflammation that defines IBD is a severe but relatively rare outcome of an altered host-microbiota relationship while a much more common consequence of such disturbances is """"""""low-grade"""""""" inflammation, characterized by elevated proinflammatory gene expression that associates with, and may promote, metabolic syndrome. However, the extent to which altered microbiota are a cause and/or consequence of inflammation, and the mechanisms that mediate this interrelationship remains ill defined. Thus, the overall goal of this proposal is to decipher he interrelationship between microbiota composition, inflammatory signaling, and metabolic syndrome. We utilize WT and TLR5-deficient (T5KO) mice as a highly tractable model in which we can both control and measure microbiota composition and pro-inflammatory signaling. Specifically, we will: 1) Define the role of inflammasome activation in the low-grade inflammation, metabolic syndrome, and gut microbiota alterations in T5KO mice. 2) Determine how loss of TLR5 influences the pro-inflammatory potential of the gut microbiota. 3) Investigate the minimal requirements for T5KO metabolic syndrome. That TLR5- deficient humans may be prone to metabolic syndrome supports the relevance of these mechanistic studies. However, the broader importance of this work is that it will advance understanding of the normal means by which a stable microbiota is maintained and elucidate how alterations in microbiota, irrespective of underlying cause, can promote low-grade inflammation and metabolic syndrome.

Public Health Relevance

Humanity is facing an epidemic of inter-related metabolic diseases collectively referred to as metabolic syndrome, the hallmarks of which include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis. Metabolic syndrome greatly increases risk of developing diabetes, cardiovascular disease, and liver dysfunction. The incidence of metabolic syndrome and its highly morbid, chronic, and very costly downstream diseases threaten to overwhelm the world's healthcare systems and economies thus making it an enormous public health problem in dire need of reckoning. This proposal seeks to investigate mechanisms by which alterations in the gut microbiota might promote metabolic syndrome. Work will be performed in tractable mouse models but we envisage that our work will increase understanding of mechanisms that might underlie the epidemic increase in metabolic disease in humanity and/or advance the possibility of manipulating the gut microbiota to treat and/or prevent metabolic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK099071-02
Application #
8708067
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perrin, Peter J
Project Start
2013-08-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Etienne-Mesmin, Lucie; Chassaing, Benoit; Adekunle, Oluwaseyi et al. (2017) Genome Sequence of a Toxin-Positive Clostridium difficile Strain Isolated from Murine Feces. Genome Announc 5:
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) Toxin-positive Clostridium difficile latently infect mouse colonies and protect against highly pathogenic C. difficile. Gut :
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
Miles, Jennifer P; Zou, Jun; Kumar, Matam-Vijay et al. (2017) Supplementation of Low- and High-fat Diets with Fermentable Fiber Exacerbates Severity of DSS-induced Acute Colitis. Inflamm Bowel Dis 23:1133-1143
Zhang, Benyue; Oyewole-Said, Damilola; Zou, Jun et al. (2017) TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation. Blood Adv 1:1796-1806
Chassaing, Benoit; Raja, Shreya M; Lewis, James D et al. (2017) Colonic Microbiota Encroachment Correlates With Dysglycemia in Humans. Cell Mol Gastroenterol Hepatol 4:205-221
Etienne-Mesmin, Lucie; Vijay-Kumar, Matam; Gewirtz, Andrew T et al. (2016) Hepatocyte Toll-Like Receptor 5 Promotes Bacterial Clearance and Protects Mice Against High-Fat Diet-Induced Liver Disease. Cell Mol Gastroenterol Hepatol 2:584-604
Singh, Vishal; Yeoh, Beng San; Carvalho, Frederic et al. (2015) Proneness of TLR5 deficient mice to develop colitis is microbiota dependent. Gut Microbes 6:279-83

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