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

Helen Luck; Saad Khan; Justin H Kim; Julia K Copeland; Xavier S Revelo; Sue Tsai; Mainak Chakraborty; Kathleen Cheng; Yi Tao Chan; Mark K Nøhr; Xavier Clemente-Casares; Marie-Christine Perry; Magar Ghazarian; Helena Lei; Yi-Hsuan Lin; Bryan Coburn; Allan Okrainec; Timothy Jackson; Susan Poutanen; Herbert Gaisano; Johane P Allard; David S Guttman; Margaret E Conner; Shawn Winer; Daniel A Winer

doi:10.1038/s41467-019-11370-y

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

Helen Luck, Saad Khan, Justin H Kim, Julia K Copeland, Xavier S Revelo, Sue Tsai, Mainak Chakraborty, Kathleen Cheng, Yi Tao Chan, Mark K Nøhr, Xavier Clemente-Casares, Marie-Christine Perry, Magar Ghazarian, Helena Lei, Yi-Hsuan Lin, Bryan Coburn, Allan Okrainec, Timothy Jackson, Susan Poutanen, Herbert GaisanoJohane P Allard, David S Guttman, Margaret E Conner, Shawn Winer, Daniel A Winer

35 Citations (Scopus)

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.

Original language	English
Journal	Nature Communications
Volume	10
Issue number	1
Pages (from-to)	3650
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-019-11370-y
Publication status	Published - 1 Dec 2019

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Luck, H., Khan, S., Kim, J. H., Copeland, J. K., Revelo, X. S., Tsai, S., Chakraborty, M., Cheng, K., Tao Chan, Y., Nøhr, M. K., Clemente-Casares, X., Perry, M.-C., Ghazarian, M., Lei, H., Lin, Y.-H., Coburn, B., Okrainec, A., Jackson, T., Poutanen, S., ... Winer, D. A. (2019). Gut-associated IgA+ immune cells regulate obesity-related insulin resistance. Nature Communications, 10(1), 3650. https://doi.org/10.1038/s41467-019-11370-y

Luck, H, Khan, S, Kim, JH, Copeland, JK, Revelo, XS, Tsai, S, Chakraborty, M, Cheng, K, Tao Chan, Y, Nøhr, MK, Clemente-Casares, X, Perry, M-C, Ghazarian, M, Lei, H, Lin, Y-H, Coburn, B, Okrainec, A, Jackson, T, Poutanen, S, Gaisano, H, Allard, JP, Guttman, DS, Conner, ME, Winer, S & Winer, DA 2019, 'Gut-associated IgA+ immune cells regulate obesity-related insulin resistance', Nature Communications, vol. 10, no. 1, pp. 3650. https://doi.org/10.1038/s41467-019-11370-y

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title = "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.",

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AU - Chakraborty, Mainak

AU - Cheng, Kathleen

AU - Tao Chan, Yi

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AU - Clemente-Casares, Xavier

AU - Perry, Marie-Christine

AU - Ghazarian, Magar

AU - Lei, Helena

AU - Lin, Yi-Hsuan

AU - Coburn, Bryan

AU - Okrainec, Allan

AU - Jackson, Timothy

AU - Poutanen, Susan

AU - Gaisano, Herbert

AU - Allard, Johane P

AU - Guttman, David S

AU - Conner, Margaret E

AU - Winer, Shawn

AU - Winer, Daniel A

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N2 - 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.

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

Abstract

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