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Nat Commun. 2019 Aug 13;10(1):3650. doi: 10.1038/s41467-019-11370-y.

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

Author information

1
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON, M5G 2C4, Canada.
2
Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
3
10-352 Toronto Medical Discovery Tower, 101 College Street, Toronto, ON, M5G 1L7, Canada.
4
Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, ON, M5S 3B2, Canada.
5
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, 55455, USA.
6
Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.
7
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, T6G 2R3, Canada.
8
Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, School of Traditional Chinese Medicine and Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
9
Department of Medicine, Division of Infectious Diseases, University Health Network, Toronto, ON, M5G 2N2, Canada.
10
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
11
Toronto Western Hospital, University Health Network, Toronto, ON, M5T 2S8, Canada.
12
Department of Surgery, University of Toronto, Toronto, ON, M5T 1P5, Canada.
13
Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
14
Department of Microbiology, University Health Network/Sinai Health System, Toronto, ON, M5G 2M9, Canada.
15
Toronto General Hospital, University Health Network, Toronto, ON, M5G 2C4, Canada.
16
Department of Virology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
17
Department of Laboratory Medicine, St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada.
18
Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, ON, M5G 2C4, Canada. dan.winer@uhn.ca.
19
Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada. dan.winer@uhn.ca.
20
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada. dan.winer@uhn.ca.
21
Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. dan.winer@uhn.ca.
22
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945, USA. dan.winer@uhn.ca.
23
10-352 Toronto Medical Discovery Tower, 101 College Street, Toronto, ON, M5G 1L7, Canada. dan.winer@uhn.ca.

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.

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