Editors' ChoiceMetabolic Disease

More than a gut feeling

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Science Translational Medicine  28 Aug 2019:
Vol. 11, Issue 507, eaaz0305
DOI: 10.1126/scitranslmed.aaz0305

Abstract

Intestinal IgA contributes to high-fat diet feeding–induced glucose intolerance.

Altered immune function plays a key role in the pathogenesis of obesity and its associated disorders. Mounting evidence shows that chronic, nonresolving inflammation in visceral adipose tissue, liver, and hypothalamus is linked to metabolic diseases, such as insulin resistance and type 2 diabetes. Further, recent work suggests that intestinal immune system also contributes to obesity-related insulin resistance; however, the underlying molecular mechanisms are less well understood.

The dominant immunoglobulin isotype on mucosal surfaces, immunoglobulin A (IgA), plays a crucial role in gut mucosal immunity and homeostasis. Although the role of IgA in the pathogenesis of certain diseases, including inflammatory bowel disease, is well established, its contribution to obesity-associated metabolic dysfunction is unknown. Luck et al. found that high-fat diet–fed obese mice have fewer colonic IgA+ immune cells and less secretory IgA, which likely results from alterations in the secretory factors and immune cells that promote IgA production. To investigate the role of IgA in obesity-induced insulin resistance and metabolic disease, they challenged IgA–/– mice and their wild-type controls with high-fat diet and found that IgA deficiency resulted in higher blood glucose concentrations and worsened tolerance to glucose and insulin. Consistent with a role for IgA in glucose homeostasis, adoptive transfer of intestinal B cells from IgA–/– mice into B cell–deficient mice aggravated the glucose intolerance induced by a high-fat diet. The authors also reported that IgA-deficient mice had exacerbated intestinal and visceral adipose tissue inflammation, both of which might have contributed to the glucose intolerance phenotype seen in the IgA–/– mice. Moreover, loss of IgA altered gut microbial composition, and fecal microbiota transplantation from IgA–/– mice to germ-free mice worsened glucose intolerance, suggesting a potential role for intestinal microbiome alterations in metabolic dysfunction. Last, the authors demonstrated that metformin treatment and bariatric surgery–mediated improvements in glucose homeostasis resulted in increases in fecal secretory IgA content, further supporting a role for IgA in regulating glucose homeostasis. These results highlight the importance of gut IgA as a critical regulator of high-fat diet–induced intestinal inflammation and insulin resistance. Future studies aimed at restoring gut IgA may hold promise for obesity-related metabolic dysfunction.

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