Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5

Debugging Metabolic Disease Obesity, now officially recognized as an epidemic in many developed nations, is a key component of “metabolic syndrome,” an array of metabolic disturbances that increase an individual's risk of developing diabetes and heart disease. The rise in obesity rates has been largely attributed to the growing imbalance between food intake and energy expenditure, but recent provocative work has suggested a possible link between obesity and the composition of microbes residing within the gut. Vijay-Kumar et al. (p. 228, published online 4 March; see the Perspective by Sandoval and Seeley) now find that mutant mice deficient in a component of the innate immune system (which defends the body against microbial pathogens) develop hallmark features of metabolic syndrome, accompanied by changes in gut microbiota. Notably, transfer of gut microbiota from the mutant mice to wild-type mice conferred several features of metabolic syndrome to the recipients. Thus, the development of metabolic syndrome may indeed be influenced by gut microbes that are regulated by the innate immune system. The innate immune system may promote metabolic health through effects on gut microbes. Metabolic syndrome is a group of obesity-related metabolic abnormalities that increase an individual’s risk of developing type 2 diabetes and cardiovascular disease. Here, we show that mice genetically deficient in Toll-like receptor 5 (TLR5), a component of the innate immune system that is expressed in the gut mucosa and that helps defend against infection, exhibit hyperphagia and develop hallmark features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity. These metabolic changes correlated with changes in the composition of the gut microbiota, and transfer of the gut microbiota from TLR5-deficient mice to wild-type germ-free mice conferred many features of metabolic syndrome to the recipients. Food restriction prevented obesity, but not insulin resistance, in the TLR5-deficient mice. These results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome.