{
  "abstract": "Background Perianal fistulising disease (PFD) is a complication that affects about 20% of patients with Crohn’s disease (CD) whose aetiology remains unknown.Objectives To identify predisposing events driving fistula formation.Design Rectal biopsies from patients with CD with or without PFD (CD+PFD and CD, respectively; n=31) were collected and subjected to single-cell RNA sequencing. Functional analyses were conducted using peripheral CD3 + T cells, intestinal tissue explants, primary fibroblasts and two-dimensional epithelial monolayer cell cultures.Results The rectal mucosa of patients with CD+PFD is imprinted with cellular and transcriptomic alterations specific to PFD and independent of luminal inflammation, potentially driven by tumour necrosis factor-like ligand 1A (TL1A) activation in CD4 + T cells. We identified lymphotoxin beta (LTB or its functional heterotrimer LTα1β2) as a novel mediator downstream of TL1A that, along with interleukin (IL)-22, induces a PFD-associated signature in rectal fibroblast and epithelial cells, respectively. This signature includes an increased abundance of fibroblasts, an induction of matrix-degrading enzymes, transcriptomic rewiring of the lamina propria S1 fibroblasts and an anti-bacterial and immune responses in epithelial cells. Notably, the induction of LTα1β2 and IL-22 occurs independently of tumour necrosis factor (TNF) signalling, revealing a new TL1A-LTα1β2/IL-22 axis that remains active under anti-TNF therapy.Conclusion Our findings revealed unique cellular alterations in the rectum of patients with CD+PFD, highlighting the previously unrecognised involvement of TL1A in mediating this signature and supporting the need for exploring the role of TL1A inhibition as a therapeutic approach for PFD.",
  "authors": [
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Victoria Gudiño"
    },
    {
      "affiliations": [
        "Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Jae Won Cho"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Berta Caballol"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain",
        "Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain"
      ],
      "name": "Ángela Sanzo-Machuca"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Ana Corraliza"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Marisol Veny"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Isabella Dotti"
    },
    {
      "affiliations": [
        "IBD Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, State University of Campinas, Campinas, Brazil"
      ],
      "name": "Livia Moreira Genaro"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Elisa Melón-Ardanaz"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Maria Carme Masamunt"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Miriam Esteller"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Iris Teubel"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Lisseth Robbins"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Àngel Giner"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Cristina Prieto"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Elena Ferrer"
    },
    {
      "affiliations": [
        "IBD Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, State University of Campinas, Campinas, Brazil"
      ],
      "name": "Raquel Franco Leal"
    },
    {
      "affiliations": [
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain",
        "Digestive Diseases Department, Hospital Universitari MutuaTerrassa, Terrassa, Spain"
      ],
      "name": "Albert Martin-Cardona"
    },
    {
      "affiliations": [
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain",
        "Digestive Diseases Department, Hospital Universitari MutuaTerrassa, Terrassa, Spain"
      ],
      "name": "Carme Loras"
    },
    {
      "affiliations": [
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain",
        "Digestive Diseases Department, Hospital Universitari MutuaTerrassa, Terrassa, Spain"
      ],
      "name": "Maria Esteve"
    },
    {
      "affiliations": [
        "CLC Group, Radiology Department, CDI, University of Barcelona, Hospital Clinic de Barcelona, Barcelona, Spain"
      ],
      "name": "Jordi Rimola"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Agnès Fernández-Clotet"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Ingrid Ordás"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Elena Ricart"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Julian Panés"
    },
    {
      "affiliations": [
        "Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Martin Hemberg"
    },
    {
      "affiliations": [
        "Inflammatory Bowel Disease Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain",
        "Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain"
      ],
      "name": "Azucena Salas"
    }
  ],
  "title": "TL1A-activated T cells remodel the rectal mucosa in patients with Crohn’s disease with perianal fistulising disease",
  "uid": "c78dd077-c5cf-5a5b-b618-a22573aa60aa"
}