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.
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.
|Chassaing, Benoit; Ley, Ruth E; Gewirtz, Andrew T (2014) Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. Gastroenterology 147:1363-77.e17|
|Oh, Jason Z; Ravindran, Rajesh; Chassaing, Benoit et al. (2014) TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41:478-92|
|Chassaing, Benoit; Koren, Omry; Carvalho, Frederic A et al. (2014) AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition. Gut 63:1069-80|