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⁺ T-helper (T_H) cells with obesity and the effects of gut-tropic T_H17 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 A-sufficient HFD. Obese RAG1-deficient mice were given injections of only regulatory T cells or a combination of regulatory T cells and T_H17 cells (wild type or deficient in integrin β7 subunit 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 polymerase chain reaction.

Results: Mice placed on a HFD became obese, which affected the distribution of small intestinal CD4⁺ T_H cells. Intestinal tissues from obese mice had significant reductions in the proportion of T_H17 cells but increased proportion of T_H1 cells, compared with intestinal tissues from nonobese mice. Depletion of vitamin A in obese mice further reduced the proportion of T_H17 cells in small intestine; this reduction correlated with more weight gain and worsening of glucose intolerance and insulin resistance. Adoptive transfer of in vitro-differentiated gut-tropic T_H17 cells to obese mice reduced these metabolic defects, which required the integrin β7 subunit and IL17. Delivery of T_H17 cells to intestines of mice led to expansion of commensal microbes associated with leanness.

Conclusions: In mice, intestinal T_H17 cells contribute to development of a microbiota that maintains metabolic homeostasis, via IL17. Gut-homing T_H17 cells might be used to reduce metabolic disorders in obese individuals.

Keywords: Glucose Tolerance; Intestinal Microbiota; Mucosal Immunity.