Trpv1 deficiency aggravates intestinal barrier dysfunction and fibrosis in HFD-fed colitis mice via miR-31/Wnt16 signaling

Abstract Background Inflammatory bowel disease (IBD) is closely and epidemiologically linked to long-term high-fat diet (HFD) exposure. Transient receptor potential vanilloid 1 (TRPV1) is critically involved in IBD pathogenesis and significantly downregulated in the intestinal mucosa of obese populations. Nevertheless, whether TRPV1 mediates HFD-exacerbated chronic IBD remains poorly defined. Results Myeloid-cell-specific Trpv1 knockout ( Trpv1 ∆ Mye ) mice were used to investigate the roles of macrophage Trpv1 in dextran sulfate sodium-induced chronic colitis with long-term HFD exposure. Single-cell RNA sequencing, bulk RNA sequencing, and in vitro cell line experiments were conducted to elucidate the mechanism through which Trpv1 downregulation exacerbates HFD-related colitis. Quantitative reverse transcription-polymerase chain reaction and Western blot assays were performed for mechanistic validation and molecular verification. Results showed that Trpv1 ∆ Mye mice subjected to long-term HFD developed exacerbated intestinal inflammation, prominent intestinal fibrosis, and impaired intestinal barrier integrity. Mechanistically, myeloid-cell-specific Trpv1 deletion promoted macrophage pro-inflammatory and pro-fibrotic polarization and uncovered a novel miR-31/Wnt16 axis associated with the activation of non-canonical Wnt signaling, which in turn was associated with epithelial barrier dysfunction and stromal fibrogenesis. Conclusions Together, our findings unveil a cell-type-specific role of macrophage Trpv1 in diet-exacerbated IBD and delineate a precise miR-31/Wnt16 signaling pathway, which may provide novel insights for the clinical management of IBD patients with metabolic comorbidities.