Gut-associated IgA+ immune cells regulate obesity-related insulin resistance

作者：Helen Luck, Saad M. Khan, Justin H. Kim, Julia K. Copeland, Xavier Revelo, Sue Jean Tsai, Mainak Chakraborty, Kathleen Cheng, Yi Tao Chan, Mark Klitgaard Nøhr, Xavier Clemente‐Casares, Marie-Christine Perry, Magar Ghazarian, Helena Lei, Yi-Hsuan Lin, Bryan A. Coburn, Allan Okrainec, Timothy D. Jackson, Susan Marie Poutanen, Herbert Y. Gaisano, Johane P. Allard, David S. Guttman, Margaret E. Conner, Shawn Winer, Daniel A. Winer · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-11370-y · 被引用次数：207 · 研究领域：Immune Cell Function and Interaction、Diabetes and associated disorders、IL-33, ST2, and ILC Pathways

Abstract The intestinal immune system is emerging as an important contributor to obesity-related insulin resistance, but the role of intestinal B cells in this context is unclear. Here, we show that high fat diet (HFD) feeding alters intestinal IgA + immune cells and that IgA is a critical immune regulator of glucose homeostasis. Obese mice have fewer IgA + immune cells and less secretory IgA and IgA-promoting immune mediators. HFD-fed IgA-deficient mice have dysfunctional glucose metabolism, a phenotype that can be recapitulated by adoptive transfer of intestinal-associated pan-B cells. Mechanistically, IgA is a crucial link that controls intestinal and adipose tissue inflammation, intestinal permeability, microbial encroachment and the composition of the intestinal microbiome during HFD. Current glucose-lowering therapies, including metformin, affect intestinal-related IgA + B cell populations in mice, while bariatric surgery regimen alters the level of fecal secretory IgA in humans. These findings identify intestinal IgA + immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease.