Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome
Abstract
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.
Acknowledgement
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.
Data Availability
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16S-V4 rRNA sequencing data have been deposited at NCBI BioProject database (http://www.ncbi.nlm.nih.gov/bioproject/) and are publicly available as of the date of publication. Accession numbers are listed in the key resources table.
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This paper does not report original code. References to all code used are available in the Method details section.
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Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Contributions
Conceptualization, Y.K. and I.I.I.; methodology, Y.K., Y.H., and I.I.I.; software, Y.H. and H.H.W.; formal analysis, Y.K. and Y.H.; investigation, Y.K., M.E., Y.H., A.M.B., L.P.A., T.T., K.A., and M.S.L.; resources, H.H.W., D.M., K.H., and I.I.I.; data curation, Y.K., M.E., and Y.H.; writing—original draft, Y.K. and I.I.I.; writing — review and editing, M.E., Y.K., Y.H., A.M.B., S.L.R., D.M., K.H., and I.I.I.; supervision, S.L.R., H.H.W., D.M., K.H., and I.I.I.; funding acquisition, Y.K. and I.I.I.
Conflict of Interest
H.H.W. is a scientific advisor of SNIPR Biome, Kingdom Supercultures, and Fitbiomics, who were not involved in the study. K.H. is a scientific advisory board member of Vedanta Biosciences and 4BIO CAPITAL, who were not involved in the study.
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Additional details
- Eprint ID
- 117359
- Resolver ID
- CaltechAUTHORS:20221011-128968500.20
- PMCID
- PMC9556172
- DOI
- 10.1016/j.cell.2022.08.005
- DK098378
- NIH
- AI144808
- NIH
- AI163069
- NIH
- AI146817
- NIH
- PATH1019125
- Burroughs Wellcome Fund
- DK093674
- NIH
- DK113375
- NIH
- MSD Life Science Foundation
- Russell Berrie Foundation
- 20H05627
- Japan Society for the Promotion of Science (JSPS)
- MCB-2025515
- NSF
- R01AI132403
- NIH
- R01DK118044
- NIH
- R01EB031935
- NIH
- PATH1016691
- Burroughs Wellcome Fund
- Irma T. Hirschl Trust
- Created
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2022-10-12Created from EPrint's datestamp field
- Updated
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2022-10-12Created from EPrint's last_modified field