Frontiers in Immunology (Jun 2024)

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D

  • Xin Yang,
  • Xin Yang,
  • Juan Huang,
  • Jian Peng,
  • Pai Wang,
  • Pai Wang,
  • F. Susan Wong,
  • Ruirui Wang,
  • Dapeng Wang,
  • Li Wen

DOI
https://doi.org/10.3389/fimmu.2024.1413177
Journal volume & issue
Vol. 15

Abstract

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IntroductionType 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β cells. Toll-like receptor 9 (TLR9) plays a role in autoimmune diseases, and B cell-specific TLR9 deficiency delays T1D development. Gut microbiota are implicated in T1D, although the relationship is complex. However, the impact of B cell-specific deficiency of TLR9 on intestinal microbiota and the impact of altered intestinal microbiota on the development of T1D are unclear.ObjectivesThis study investigated how gut microbiota and the intestinal barrier contribute to T1D development in B cell-specific TLR9-deficient NOD mice. Additionally, this study explored the role of microbiota in immune regulation and T1D onset.MethodsThe study assessed gut permeability, gene expression related to gut barrier integrity, and gut microbiota composition. Antibiotics depleted gut microbiota, and fecal samples were transferred to germ-free mice. The study also examined IL-10 production, Breg cell differentiation, and their impact on T1D development.ResultsB cell-specific TLR9-deficient NOD mice exhibited increased gut permeability and downregulated gut barrier-related gene expression. Antibiotics restored gut permeability, suggesting microbiota influence. Altered microbiota were enriched in Lachnospiraceae, known for mucin degradation. Transferring this microbiota to germ-free mice increased gut permeability and promoted IL-10-expressing Breg cells. Rag-/- mice transplanted with fecal samples from Tlr9fl/flCd19-Cre+ mice showed delayed diabetes onset, indicating microbiota’s impact.ConclusionB cell-specific TLR9 deficiency alters gut microbiota, increasing gut permeability and promoting IL-10-expressing Breg cells, which delay T1D. This study uncovers a link between TLR9, gut microbiota, and immune regulation in T1D, with implications for microbiota-targeted T1D therapies.

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