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Molecular Mechanism of Butyrate Modulating Treg/Th17 Balance in UC Through cAMP-PKA/mTOR Axis

Minhao Li1, Tinglong Wang2, Mei Yuan3

  • 1Department of General Surgery, Wuxi No.2 People's Hospital, Wuxi, China.

Immunological Investigations
|September 7, 2025
PubMed
Abstract

Insights

Butyrate alleviates ulcerative colitis (UC) by restoring immune balance through the cAMP-PKA/mTOR pathway. This short-chain fatty acid treatment reduces inflammation and fibrosis, offering potential new therapies for UC.

Area of Science:

  • Gastroenterology
  • Immunology
  • Molecular Biology

Background:

  • Ulcerative colitis (UC) is a chronic inflammatory bowel disease.
  • Imbalance in regulatory T cells (Tregs) and T helper 17 cells (Th17) contributes to UC pathogenesis.
  • Short-chain fatty acids, like butyrate, are implicated in gut health but their precise mechanisms in UC require elucidation.

Purpose of the Study:

  • To investigate the therapeutic effects of butyrate on ulcerative colitis in a mouse model.
  • To elucidate the role of the cAMP-PKA/mTOR signaling pathway in mediating butyrate's effects on Treg/Th17 balance.
  • To explore butyrate's potential in preventing colon fibrosis associated with UC.

Main Methods:

  • Induction of UC in mice using dextran sulfate sodium (DSS).
  • Administration of varying doses of butyrate and assessment of disease activity index (DAI), body weight, colon length, and spleen index.
  • Histopathological analysis (HE and Masson staining), assessment of fibrosis markers, flow cytometry for immune cell subsets, and analysis of the cAMP-PKA/mTOR pathway via RT-qPCR and Western blotting.

Main Results:

  • Butyrate treatment dose-dependently reduced UC severity, including DAI and spleen index, and reversed colon pathology.
  • Butyrate inhibited colon fibrosis and decreased fibrosis markers.
  • Butyrate restored Treg/Th17 balance and immune homeostasis by modulating the cAMP-PKA/mTOR signaling pathway, confirmed by inhibitor experiments.

Conclusions:

  • Butyrate effectively alleviates acute intestinal inflammation in UC and inhibits chronic fibrosis.
  • The cAMP-PKA/mTOR signaling pathway is a critical mediator of butyrate's therapeutic effects in restoring immune homeostasis in UC.
Keywords:
ButyrateTreg/Th17 balancecAMP-PKA/mTOR signaling pathwayimmune regulationulcerative colitis

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