Abstract
Nutrient handling is an essential function of the gastrointestinal tract. Most nutrient absorption occurs in the small intestine and is coordinated by hormone-producing intestinal epithelial cells known as enteroendocrine cells (EECs)1. In contrast, the colon mostly reclaims water and electrolytes, and handles the influx of microbially-derived metabolites, including short chain fatty acids (SCFA)2-4. Hormonal responses of small intestinal EECs have been extensively studied but much less in known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. We found that colonic EEC deficiency leads to hyperphagia and obesity. Surprisingly, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment and transfer to germ free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we found that differential glutamate production by intestinal microbiota corresponds to increase appetite due to EEC loss. Finally, we show that colonic glutamate administration can directly increase food intake and activate appetite centers in the central nervous system. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.