Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes.

Authors

Matthew C Funsten
Leonid A Yurkovetskiy
Andrey Kuznetsov
Derek Reiman
Camilla H F Hansen
Katharine I Senter
Jean Lee
Jeremy Ratiu, The Jackson LaboratoryFollow
Shiva Dahal-Koirala
Dionysios A Antonopoulos
Gary M Dunny
Ludvig M Sollid
David Serreze
Aly A Khan
Alexander V Chervonsky

Document Type

Article

Publication Date

2-8-2023

Original Citation

Funsten M, Yurkovetskiy L, Kuznetsov A, Reiman D, Hansen C, Senter K, Lee J, Ratiu J, Dahal-Koirala S, Antonopoulos D, Dunny G, Sollid L, Serreze D, Khan A, Chervonsky A. Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes. Cell Host Microbe. 2023;31(2):213-27

Keywords

JMG, SS1, Mice, Animals, Humans, Diabetes Mellitus, Type 1, Glutens, Mice, Inbred NOD, Proteolysis, Diet, Microbiota

JAX Source

Cell Host Microbe. 2023;31(2):213-27

ISSN

1934-6069

PMID

36603588

DOI

https://doi.org/10.1016/j.chom.2022.12.009

Grant

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

Abstract

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.