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Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome

Kawano, Yoshinaga and Edwards, Madeline and Huang, Yiming and Bilate, Angelina M. and Araujo, Leandro P. and Tanoue, Takeshi and Atarashi, Koji and Ladinsky, Mark S. and Reiner, Steven L. and Wang, Harris H. and Mucida, Daniel and Honda, Kenya and Ivanov, Ivaylo I. (2022) Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome. Cell, 185 (19). 3501-3519.e20. ISSN 0092-8674. doi:10.1016/j.cell.2022.08.005.

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How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.

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Ladinsky, Mark S.0000-0002-1036-3513
Additional Information:We thank Guilhermina Carriche and Iliyan Iliev for help with gnotobiotic experiments. We thank members of the Ivanov lab for technical help. We thank Sridhar Radhakrishan from ResearchDiets for custom diet design. This work was supported by funding from NIH (DK098378, AI144808, AI163069, AI146817) and Burroughs Wellcome Fund (PATH1019125) to I.I.I. and NIH (DK093674, DK113375) to D.M. Y.K was supported by fellowships from MSD Life Science Foundation, the Russell Berrie Foundation, and the Naomi Berrie Diabetes Center at CUIMC. K.H. is funded by a Grant-in-Aid for Specially Promoted Research from the Japan Society for the Promotion of Science (20H05627). H.H.W. acknowledges funding from NSF (MCB-2025515), NIH (R01AI132403, R01DK118044, R01EB031935), Burroughs Wellcome Fund (PATH1016691), and the Irma T. Hirschl Trust.
Funding AgencyGrant Number
Burroughs Wellcome FundPATH1019125
MSD Life Science FoundationUNSPECIFIED
Russell Berrie FoundationUNSPECIFIED
Japan Society for the Promotion of Science (JSPS)20H05627
Burroughs Wellcome FundPATH1016691
Irma T. Hirschl TrustUNSPECIFIED
Issue or Number:19
Record Number:CaltechAUTHORS:20221011-128968500.20
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:117359
Deposited By: Research Services Depository
Deposited On:12 Oct 2022 22:59
Last Modified:12 Oct 2022 22:59

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