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

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

doi:10.1016/j.chom.2022.12.009

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

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

Microbiology

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Pages (from-to)	213-227.e9
Journal	Cell Host and Microbe
Volume	31
Issue number	2
DOIs	https://doi.org/10.1016/j.chom.2022.12.009
State	Published - Feb 8 2023

Bibliographical 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.

Keywords

celiac disease
diet and autoimmunity
insulin secretion regulation
microbial proteolysis of gluten
microbiota and autoimmunity
type 1 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chom.2022.12.009

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Funsten, M. C., Yurkovetskiy, L. A., Kuznetsov, A., Reiman, D., Hansen, C. H. F., Senter, K. I., Lee, J., Ratiu, J., Dahal-Koirala, S., Antonopoulos, D. A., Dunny, G. M., Sollid, L. M., Serreze, D., Khan, A. A., & Chervonsky, A. V. (2023). Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes. Cell Host and Microbe, 31(2), 213-227.e9. https://doi.org/10.1016/j.chom.2022.12.009

Funsten, MC, Yurkovetskiy, LA, Kuznetsov, A, Reiman, D, Hansen, CHF, Senter, KI, Lee, J, Ratiu, J, Dahal-Koirala, S, Antonopoulos, DA, Dunny, GM, Sollid, LM, Serreze, D, Khan, AA & Chervonsky, AV 2023, 'Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes', Cell Host and Microbe, vol. 31, no. 2, pp. 213-227.e9. https://doi.org/10.1016/j.chom.2022.12.009

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title = "Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes",

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.",

keywords = "celiac disease, diet and autoimmunity, insulin secretion regulation, microbial proteolysis of gluten, microbiota and autoimmunity, type 1 diabetes",

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

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: {\textcopyright} 2022 Elsevier Inc.",

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AU - Yurkovetskiy, Leonid A.

AU - Kuznetsov, Andrey

AU - Reiman, Derek

AU - Hansen, Camilla H.F.

AU - Senter, Katharine I.

AU - Lee, Jean

AU - Ratiu, Jeremy

AU - Dahal-Koirala, Shiva

AU - Antonopoulos, Dionysios A.

AU - Dunny, Gary M.

AU - Sollid, Ludvig M.

AU - Serreze, David

AU - Khan, Aly A.

AU - Chervonsky, Alexander V.

N1 - 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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KW - microbial proteolysis of gluten

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

Abstract

Bibliographical note

Keywords

UN SDGs

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