{
  "abstract": "Background Intestinal fibrosis is the most frequent and severe complication of Crohn’s disease. Although neuro-immune interactions are increasingly recognized in inflammatory bowel diseases, the crosstalk between neurons and fibroblasts and its impact on chronic intestinal fibrosis remain elusive.Methods We mined multiple spatial transcriptomic and single-cell RNA-seq datasets to pinpoint the key cellular drivers in the stenotic segments of Crohn’s disease. Chronic dextran sodium sulfate (DSS) mice model and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis models were established to recapitulate intestinal fibrosis. Pharmacological activation or ablation approaches were employed to dissect the role of TRPV1+ neurons. Primary intestinal fibroblasts and the human intestinal fibroblast cell line (CCD18-co) were used to delineate CGRP-driven fibrogenic mechanisms. Antibiotic cocktails and LC-MS metabolomics uncovered a critical bacterial metabolite.Results TRPV1 + neurons displayed the strongest association with fibrosis in the spatial transcriptomic dataset. Immunofluorescence of intestinal specimens from IBD patients also revealed increased TRPV1+ neurons at fibrotic sites. Capsaicin activation of TRPV1+ neurons markedly exacerbated inflammation and fibrosis in chronic DSS/TNBS colitis. (IDDF2026-ABS-0215 Figure 1)In vivo administration of CGRP, but not substance P, reproduced the pro-fibrotic phenotype, and olcegepant blocked this effect, confirming the importance of CGRP–RAMP1 axis. ELISA also demonstrated higher CGRP concentrations in the fibrotic sites of IBD patients. (IDDF2026-ABS-0215 Figure 2)Single-cell sequencing revealed that RAMP1+ fibroblasts were the primary cells receiving CGRP signals. CGRP-treated primary intestinal fibroblasts or RAMP1-overexpressing CCD18-Co exhibited enhanced collagen production in vitro. Mechanistically, CGRP from activated TRPV1+ neurons interacted with RAMP1+ fibroblasts and thereby triggered the PI3K-Akt signaling pathway, which drove excessive extracellular matrix deposition and finally promoted intestinal fibrosis. (IDDF2026-ABS-0215 Figure 3)Antibiotic treatment was found to alleviate fibrosis. We further applied different antibiotics as independent treatments and identified kynurenic acid (KynA) as a bacterial metabolite enriched in PBS and neomycin-treated mice with milder disease via metabolomics. Functional assays showed that KynA stimulated TRPV1+ neurons and might predispose a subset of Crohn’s disease patients to more severe intestinal fibrosis. (IDDF2026-ABS-0215 Figure 4)Conclusions Intestinal TRPV1-expressing neurons originating from dorsal root ganglia interact with RAMP1 + fibroblasts via CGRP, thereby promoting intestinal fibrosis through PI3K–Akt pathway activation. Patients with elevated KynA exhibited more severe intestinal fibrosis, attributable to heightened TRPV1-neuronal activation.Abstract IDDF2026-ABS-0215 Figure 1Abstract IDDF2026-ABS-0215 Figure 2Abstract IDDF2026-ABS-0215 Figure 3Abstract IDDF2026-ABS-0215 Figure 4",
  "authors": [
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Hongmin Li"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Liangxin Zhang"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Dayi Liang"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Peng Lai"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Mengze Xing"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Xiqi Yin"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Xinying Zhang"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Junli Gong"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Zhen He"
    },
    {
      "affiliations": [
        "The Sixth Affiliated Hospital of Sun Yat-sen University, China"
      ],
      "name": "Ping Lan"
    }
  ],
  "title": "IDDF2026-ABS-0215 Mechanistic study of the gut microbiota-TRPV1+ neuron-CGRP-RAMP1+ fibroblast axis in driving IBD-associated intestinal fibrosis",
  "uid": "c93dbb5f-5982-547f-9a73-1c2b3df3ae0d"
}