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.
Bibliographical noteFunding Information:
We would like to kindly thank CAGEF at the University of Toronto for the gut microbiota sequencing, STTARR facility for the immunohistochemistry work, and Maryam Alghamdi, Carrie Li, Fariba Abedi, Monica L. Ponta, Aimee Paterson, and Melissa Kissoon for their work related to the bariatric human data, including study setup, patient screening, recruitment, visits, data and sample collections, and processing. This work is supported in part by Canadian Institutes of Health Research (CIHR) grants 119414, 142708, and 148385 (D.A.W.), Diabetes Canada grant OG-3-15-5014 (D.A.W.), and the Canadian Liver Foundation (CLF) (2017 operating grant). The bariatric surgery research is supported by CIHR 303157 and UTRS 152465. D.A.W. is a recipient of a Canada Research Chair, and the Ontario Ministry of Innovation Early Researcher Award. S.K. is a recipient of the Queen Elizabeth II Graduate Scholarship in Science and Technology (QEII-GSST)/Aventis Pasteur, and the Banting and Best Diabetes Centre (BBDC) Graduate Scholarship. H.L. is a recipient of the CIHR Canada Graduate Scholarship-Doctoral (CGS-D) Award.
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