Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Diet and commensals can affect the development of autoimmune diseases like type 1 diabetes (T1D). However, whether dietary interventions are microbe-mediated was unclear. We found that a diet based on hydrolyzed casein (HC) as a protein source protects non-obese diabetic (NOD) mice in conventional and germ-free (GF) conditions via improvement in the physiology of insulin-producing cells to reduce autoimmune activation. The addition of gluten (a cereal protein complex associated with celiac disease) facilitates autoimmunity dependent on microbial proteolysis of gluten: T1D develops in GF animals monocolonized with Enterococcus faecalis harboring secreted gluten-digesting proteases but not in mice colonized with protease deficient bacteria. Gluten digestion by E. faecalis generates T cell-activating peptides and promotes innate immunity by enhancing macrophage reactivity to lipopolysaccharide (LPS). Gnotobiotic NOD Toll4-negative mice monocolonized with E. faecalis on an HC + gluten diet are resistant to T1D. These findings provide insights into strategies to develop dietary interventions to help protect humans against autoimmunity.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cell Host and Microbe |
| Vol/bind | 31 |
| Udgave nummer | 2 |
| Sider (fra-til) | 213-227.e9 |
| ISSN | 1931-3128 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
The authors are grateful to Grace Ryan, Brandon Hawkins, and Laura Sams for their assistance with the experiments; to Sarah Owens and the staff of the Environmental Sample Preparation and Sequencing Facility at Argonne National Laboratory for their assistance; to the Genetic Engineering Technologies Core group at the Jackson Laboratory for assistance in generating Tgm2 KO mice; to Barbara Mickelson of Envigo for help with diet formulations; to Drs. Barbara Murray and Kavindra Singh for the mutant strain TX5243 and for their valuable advice; to Dr. Michael Fischbach for his kind gift of penta-acylated LPS; and to Dr. Joseph Pickard for critical reading of the manuscript. L.A.Y. was supported by NIH T32 GM007183 . C.H.F.H. was supported in part by the Carlsberg Foundation, Denmark . L.M.S. and S.D.-K. were supported by the South-Eastern Norway Regional Health Authority (project number 2015009 ). D.S. was supported by grants DK46266 , DK95735 , and OD-020351 . A.V.C. was supported by NIH grants R01AI082418 , R21AI115683 , R01AI158744 , DOD grant W911NF-17-1-0402 , and a grant SRA-2015-8-Q-R from Juvenile Diabetes Research Foundation . This work was also supported by NIH/NIDDK Digestive Disease Research Core Center grant DK42086 . The graphical abstract was created with BioRender.com .
Publisher Copyright:
© 2022 Elsevier Inc.
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