Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes
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Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes. / Funsten, Matthew C.; Yurkovetskiy, Leonid A.; Kuznetsov, Andrey; Reiman, Derek; Hansen, Camilla H.F.; Senter, Katharine I.; Lee, Jean; Ratiu, Jeremy; Dahal-Koirala, Shiva; Antonopoulos, Dionysios A.; Dunny, Gary M.; Sollid, Ludvig M.; Serreze, David; Khan, Aly A.; Chervonsky, Alexander V.
I: Cell Host and Microbe, Bind 31, Nr. 2, 2023, s. 213-227.e9.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Microbiota-dependent proteolysis of gluten subverts diet-mediated protection against type 1 diabetes
AU - Funsten, Matthew C.
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 - Publisher Copyright: © 2022 Elsevier Inc.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - celiac disease
KW - diet and autoimmunity
KW - insulin secretion regulation
KW - microbial proteolysis of gluten
KW - microbiota and autoimmunity
KW - type 1 diabetes
U2 - 10.1016/j.chom.2022.12.009
DO - 10.1016/j.chom.2022.12.009
M3 - Journal article
C2 - 36603588
AN - SCOPUS:85147344238
VL - 31
SP - 213-227.e9
JO - Cell Host & Microbe
JF - Cell Host & Microbe
SN - 1931-3128
IS - 2
ER -
ID: 337601068