Gut-specific Delivery of T-helper 17 Cells Reduces Obesity and Insulin Resistance in Mice

Abstract

Background & Aims: Obesity and metabolic syndrome have been associated with alterations to the intestinal microbiota. However, few studies examined the effects of obesity on the intestinal immune system. We investigated changes in subsets of intestinal CD4+ Thelper (Th) cells with obesity and the effects of gut-tropic Th17 cells in mice on a high-fat diet (HFD). Methods: We isolated immune cells from small intestine and adipose tissue of C57BL/6 mice fed a normal chow diet or a HFD for 10 weeks and analyzed the cells by flow cytometry. Mice fed a vitamin A-deficient HFD were compared with mice fed a vitamin Asufficient HFD. Obese RAG1-deficient mice were given injections of only T regulatory cells or a combination of T regulatory cells and Th17 cells (wild type or deficient in integrin b7 subunit-deficient or interleukin 17 [IL17]). Mice were examined for weight gain, fat mass, fatty liver, glucose tolerance, and insulin resistance. Fecal samples were collected before and after T-cell transfer and analyzed for microbiota composition by metagenomic DNA sequencing and quantitative PCR. Results: Mice placed on a HFD became obese, which affected the distribution of small intestinal CD4+ TH cells. Intestinal tissues from obese mice had significant reductions in the proportion of Th17 cells but increased proportion of Th1 cells, compared with intestinal tissues from non-obese mice. Depletion of vitamin A in obese mice further reduced the proportion of Th17 cells in small intestine; this reduction correlated with more weight gain and worsening of glucose intolerance and insulin resistance. Adoptive transfer of in vitrodifferentiated gut-tropic Th17 cells to obese mice reduced these metabolic defects, which required the integrin b7 subunit and IL17. Delivery of Th17 cells to intestines of mice led to expansion of commensal microbes associated with leanness. Conclusions: In mice, intestinal Th17 cells contribute to development of a microbiota that maintains metabolic homeostasis, via IL17. Gut-homing Th17 cells might be used to reduce metabolic disorders in obese individuals.