Dataset Information

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

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.

SUBMITTER: Luck H

PROVIDER: S-EPMC6692361 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Luck Helen H Khan Saad S Kim Justin H JH Copeland Julia K JK Revelo Xavier S XS Tsai Sue S Chakraborty Mainak M Cheng Kathleen K Tao Chan Yi Y Nøhr Mark K MK Clemente-Casares Xavier X Perry Marie-Christine MC Ghazarian Magar M Lei Helena H Lin Yi-Hsuan YH Coburn Bryan B Okrainec Allan A Jackson Timothy T Poutanen Susan S Gaisano Herbert H Allard Johane P JP Guttman David S DS Conner Margaret E ME Winer Shawn S Winer Daniel A DA

Nature communications 20190813 1

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 met ...[more]

PMID: 31409776

Similar Datasets

Project description:Background & aimsLiver CRIg+ (complement receptor of the immunoglobulin superfamily) macrophages play a critical role in filtering bacteria and their products from circulation. Translocation of microbiota-derived products from an impaired gut barrier contributes to the development of obesity-associated tissue inflammation and insulin resistance. However, the critical role of CRIg+ macrophages in clearing microbiota-derived products from the bloodstream in the context of obesity is largely unknown.MethodsWe performed studies with CRIg-/-, C3-/-, cGAS-/-, and their wild-type littermate mice. The CRIg+ macrophage population and bacterial DNA abundance were examined in both mouse and human liver by either flow cytometric or immunohistochemistry analysis. Gut microbial DNA-containing extracellular vesicles (mEVs) were adoptively transferred into CRIg-/-, C3-/-, or wild-type mice, and tissue inflammation and insulin sensitivity were measured in these mice. After coculture with gut mEVs, cellular insulin responses and cGAS/STING-mediated inflammatory responses were evaluated.ResultsGut mEVs can reach metabolic tissues in obesity. Liver CRIg+ macrophages efficiently clear mEVs from the bloodstream through a C3-dependent opsonization mechanism, whereas obesity elicits a marked reduction in the CRIg+ macrophage population. Depletion of CRIg+ cells results in the spread of mEVs into distant metabolic tissues, subsequently exacerbating tissue inflammation and metabolic disorders. Additionally, in vitro treatment of obese mEVs directly triggers inflammation and insulin resistance of insulin target cells. Depletion of microbial DNA blunts the pathogenic effects of intestinal EVs. Furthermore, the cGAS/STING pathway is crucial for microbial DNA-mediated inflammatory responses.ConclusionsDeficiency of CRIg+ macrophages and leakage of intestinal EVs containing microbial DNA contribute to the development of obesity-associated tissue inflammation and metabolic diseases.

Dataset Information

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

Publications

Gut-associated IgA<sup>+</sup> immune cells regulate obesity-related insulin resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure