Role of intestinal commensal-induced Th17 cells and mucosal immunity in metabolic disease

Project Summary Obesity and metabolic syndrome are complex physiological conditions that underly many comorbidities, including cardiovascular disease, diabetes, and inflammatory bowel diseases (IBD). The mechanisms by which diet-induced obesity leads to disease are incompletely understood and a topic of intense investigation. Changes in intestinal mucosal immunity, such as decreased barrier function and intestinal inflammation precede and drive adipose-tissue inflammation. Elucidation of the specific nature and mechanisms by which mucosal immunity regulates systemic metabolic disease holds promise for conceptually novel targeted interventions for chronic metabolic diseases. We found that segmented filamentous bacteria (SFB) induce anti-inflammatory Th17 cells in the small intestinal lamina propria that protect from DIO and pre-diabetic changes induced by feeding mice with high-fat/high-sugar diet (HFD). Therefore, commensal-induced Th17 cells can protect from systemic disease. We also found that intestinal Th17 cells decrease intestinal lipid absorption and expression of lipid sensors in intestinal epithelium. This suggests that Th17 cells modulate epithelial cell function in nutrient sensing and transport. Here, we propose to examine the mechanisms by which commensal-induced Th17 cells protect from DIO. We hypothesize that under conditions of increased lipid consumption commensal Th17 cells protect from DIO by decreasing intestinal inflammation and interfering with lipid sensing and absorption in the intestinal epithelium. We will test this by 1) examining the role of commensal-induced Th17 cells in preventing or decreasing HFD-induced dysregulation of mucosal immune homeostasis; 2) testing whether Th17 cells protect by decreasing lipid absorption and characterizing in detail the effects of mucosal Th17 cells in intestinal lipid absorption and lipid metabolism of intestinal epithelial cells; and 3) examining the interplay between intestinal group 3 innate lymphoid cells (ILC3) and Th17 cells in HFD-induced disease and the role of ILC3 and Th17 cell- controlled microbiota. Altogether, these studies will address fundamental questions on the role of mucosal immunity, and specifically intestinal CD4 T cells, in protection from metabolic disease.