Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON, M5G 2C4, Canada.
Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Nat Commun. 2019 Aug 13;10(1):3650. doi: 10.1038/s41467-019-11370-y.
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.
肠道免疫系统正在成为肥胖相关胰岛素抵抗的一个重要贡献者，但肠道 B 细胞在这方面的作用尚不清楚。在这里，我们表明高脂肪饮食（HFD）喂养会改变肠道 IgA 免疫细胞，而 IgA 是葡萄糖稳态的关键免疫调节剂。肥胖小鼠的 IgA 免疫细胞较少，分泌型 IgA 和 IgA 促进免疫介质也较少。HFD 喂养的 IgA 缺陷小鼠表现出葡萄糖代谢功能障碍，这一表型可以通过肠相关全 B 细胞的过继转移来重现。从机制上讲，IgA 是控制肠道和脂肪组织炎症、肠道通透性、微生物侵袭和肠道微生物组组成的关键环节，在 HFD 期间。目前的降血糖疗法，包括二甲双胍，会影响小鼠肠道相关 IgA B 细胞群体，而减重手术方案会改变人类粪便分泌型 IgA 的水平。这些发现确定了肠道 IgA 免疫细胞作为饮食诱导的代谢性疾病中全身葡萄糖调节的黏膜介体。
