Eicosapentaenoic acid enhances intestinal stem cell-mediated colonic epithelial regeneration by activating the LSD1-WNT signaling pathway.

Introduction: Inflammatory bowel disease (IBD) is often associated with impaired proliferation and differentiation of intestinal stem cells (ISCs). Eicosapentaenoic acid (EPA), which is predominantly found in fish oil, has been recognized for its intestinal health benefits, although the potential mechanisms are not well understood.

Objectives: This study aimed to investigate the regulatory role and mechanism of EPA in colonic epithelial regeneration, specifically from the perspective of ISCs.

Methods: Wild-type mice whose diet was supplemented with 5% EPA-enriched fish oil were subjected to dextran sulfate sodium (DSS) to induce colitis. We utilized intestinal organoids, ISC-specific lysine-specific demethylase 1 (LSD1) knockout mice, and WNT inhibitor-treated mice to explore how EPA influences ISC proliferation and differentiation. ISC proliferation, differentiation and apoptosis were assessed using tdTomato and propidium iodide tracer testing, histological analyses, and immunofluorescence staining.

Results: EPA treatment significantly mitigated the symptoms of DSS-induced acute colitis, as evidenced by lower body weight loss and decreased disease activity index, histological scores and proinflammatory cytokine levels. Additionally, EPA increased the numbers of proliferative cells, absorptive cells, goblet cells, and enteroendocrine cells, which enhanced the regeneration of intestinal epithelium. Pretreatment with EPA increased ISC proliferation and differentiation, and protected against TNF-α-induced cell death in intestinal organoids. Mechanistically, EPA upregulated G protein-coupled receptor 120 (GPR120) to induce LSD1 expression, which facilitated ISC proliferation and differentiation in organoids. ISC-specific ablation of LSD1 negated the protective effect of EPA on DSS-induced colitis in mice. Moreover, EPA administration activated the WNT signaling pathway downstream of LSD1 in ISCs, while inhibiting WNT signaling abolished the beneficial effects of EPA.

Conclusions: These findings demonstrate that EPA promotes ISC proliferation and differentiation, thereby enhancing colonic epithelial regeneration through the activation of LSD1-WNT signaling. Consequently, dietary supplementation with EPA represents a promising alternative therapeutic strategy for managing IBD.