Interleukin‐23 promotes intestinal T helper type17 immunity and ameliorates obesity‐associated metabolic syndrome in a murine high‐fat diet model

Abstract

We addressed the role of interleukin-23 (IL-23) in driving the intestinal T helper type 17 (Th17) response during obesity and metabolic syndrome progression induced by a high-fat diet (HFD). Diet-induced obese and lean mice received HFD or control diet (CTD), respectively, for 20 weeks. The nutritional, metabolic and immune parameters were examined at weeks 9 and 20. Gene and protein IL-23p19 and IL-23 receptor expression was increased in the ileum of obese wild-type mice (WT) fed the HFD for 9 weeks. Mice lacking IL-23 and fed the HFD exhibited greater weight gain, higher fat accumulation, adipocyte hypertrophy and hepatic steatosis. Notably, these mice had more glucose intolerance, insulin resistance and associated metabolic alterations, such as hyperinsulinaemia and hyperlipidaemia. IL-23 deficiency also significantly reduced protein levels of IL-17, CCL20 and neutrophil elastase in the ileum and reduced Th17 cell expansion in the mesenteric lymph nodes of the HFD mice. Of importance, IL-23-deficient mice exhibited increased gut permeability and blood bacterial translocation compared with WT mice fed HFD. Finally, metagenomics analysis of gut microbiota revealed a dramatic outgrowth of Bacteroidetes over Firmicutes phylum with the prevalence of Bacteroides genera in the faeces of IL-23-deficient mice after HFD. In summary, IL-23 appears to maintain the Th17 response and neutrophil migration into the intestinal mucosa, minimizing the gut dysbiosis and protecting against obesity and metabolic disease development in mice.

Gut Microbiota as a Trigger for Metabolic Inflammation in Obesity and Type 2 Diabetes

“…Interestingly, obese women had higher circulating levels of IL-23 compared to healthy controls (260), supporting the assumption of a pro-inflammatory environment in metabolic diseases. Surprisingly, mice lacking IL-23 on a high fat diet, gained more weight and were more glucose intolerant than the controls (261). These mice also exhibit an increased gut permeability and bacterial translocation compared to wild type mice, underlining the important of IL-23 in the gut homeostasis.…”

Longitudinal Analysis of Serum Cytokine Levels and Gut Microbial Abundance Links IL-17/IL-22 With Clostridia and Insulin Sensitivity in Humans

“…Collectively, these results suggest a protective role for IL-17/IL-22-producing cells during onset of diet-related metabolic disorders in mice. While Th17 cells are a major source of IL-17 and IL-22 (16,19), other cell types also produce these cytokines (20) and may be important in this process.…”

Functions of adipose‐resident immune subsets and the impact on metabolic syndrome

“…1 These are tissues so rich in immune cells that one might almost consider them an additional lymphoid organ. 4 In general, a shift in visceral adipose Tcell subsets from regulatory to effector cells tends to be associated with obesity and metabolic syndrome. It is now appreciated that dysregulated interplay between immune cells and metabolism, driven by differences in genetics, diet, microbiota and associated metabolomics, contribute to the tendency to develop altered metabolic states that lead to obesity, type 2 diabetes and other features of the metabolic syndrome.…”

“…3 Another recent study implicates a role for IL-23-driven T helper type 17 immunity: IL-23 knockouts on a high-fat diet showed greater weight gain, higher fat accumulation with enhanced glucose intolerance, insulin resistance and associated metabolic alterations. 4 In general, a shift in visceral adipose Tcell subsets from regulatory to effector cells tends to be associated with obesity and metabolic syndrome. For example, in mice, immunotherapeutic manipulation of the predominance of effector T cells over regulatory T cells results in reversal of insulin resistance, even when mice are kept on a high-fat diet.…”