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Folate Attenuates Ulcerative Colitis via PI3K/AKT/NF-κB/MLCK Axis Inhibition to Restore Intestinal Barrier Integrity.

Shize Zhang1, Tian Cheng1, Yuang Chen1

  • 1Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

Biology
|November 27, 2025
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Summary

Folate acts as a protective factor against ulcerative colitis (UC). Supplementing with folate in a colitis model reduced disease severity and restored intestinal barrier function by targeting specific molecular pathways.

Keywords:
PI3K/AKT/NF-κB/MLCK/MLC2 axisfolateintestinal barriermendelian randomizationulcerative colitis

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Area of Science:

  • Gastroenterology
  • Nutritional Science
  • Molecular Biology

Background:

  • Vitamin homeostasis is crucial for managing inflammatory bowel disease (IBD).
  • The precise role of vitamins in IBD pathogenesis and treatment is not fully understood.
  • Previous research suggests a potential link between vitamin levels and IBD, but mechanisms are unclear.

Purpose of the Study:

  • To investigate the protective role of folate in ulcerative colitis (UC).
  • To elucidate the molecular mechanisms by which folate influences intestinal barrier integrity.
  • To assess the therapeutic potential of folate supplementation in a preclinical model of colitis.

Main Methods:

  • Two-sample Mendelian randomization analysis to identify genetic associations with circulating vitamin levels.
  • Utilized a dextran sodium sulfate (DSS)-induced colitis mouse model for in vivo studies.
  • Employed in vitro models with epithelial cells stimulated by TNF-α/IFN-γ, alongside RNA sequencing and immunoblotting for mechanistic analysis.

Main Results:

  • Mendelian randomization identified folate as protective against UC.
  • DSS-induced colitis mice showed reduced serum folate levels; folate supplementation ameliorated disease severity and inflammation.
  • Folate supplementation restored epithelial barrier integrity and function, both in vivo and in vitro.
  • Folate suppressed the PI3K/AKT/NF-κB/MLCK/MLC2 signaling pathway, mediating barrier restoration.

Conclusions:

  • Folate plays a significant protective role in ulcerative colitis.
  • Folate supplementation demonstrates therapeutic potential for UC by restoring intestinal barrier function.
  • The PI3K/AKT/NF-κB/MLC2 pathway is a key molecular target for folate's beneficial effects in the gut.