DOP65 T-cell derived TGFβ1 remodels the rectum mesenchyme in Crohn’s Disease patients with perianal fistulizing disease Article Swipe
Victòria Gudiño
,
Jae‐We Cho
,
A M Corraliza
,
Berta Caballol
,
Alba Garrido-Trigo
,
Maria Carme Masamunt
,
Íngrid Ordás
,
E Ricart
,
Martin Hemberg
,
Julián Panés
,
Azucena Salas
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1093/ecco-jcc/jjac190.0105
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1093/ecco-jcc/jjac190.0105
Background Perianal fistulizing disease (PFD) is a complication occurring in about 20% of Crohn’s Disease (CD) patients. It consists of the formation of new epithelised tracks connecting the intestine with the outer perianal region, which dramatically worsens a patient’s quality of life. The mechanisms driving fistula formation have not been elucidated and therefore, there are currently no specific treatments for PFD. Methods We collected rectum biopsies of CD patients with and without PFD in the absence of rectal inflammation (CD and CD+PFD), and with active rectal inflammation (CDinf and CD+PFDinf) (Fig.1). Rectal tissue samples were processed for RT-qPCR, or histologic analysis, and single-cell RNA sequencing (scRNAseq) for each patient. Results Differential expression gene (DEG) analysis of CD4+ and CD8+ T cells comparing CD vs CD+PFD and CDinf vs CD+PFDinf patients, respectively, revealed increased expression of TGFB1 in patients with fistulae. To investigate the main cellular subsets TGFB1 was interacting with, we performed ligand-receptor interaction analysis using CellphoneDB, which indicated that T-cell derived TGFB1 was primary interacting with the stromal compartment (Fig.2). 365 DEG were found in lamina propria (LP) fibroblasts of CD+PFD compared to CD, including TGFβ1-inducible genes such as TFPI2, SERPINE2 and MMPs 1 and 3. These changes were validated by bulk RT-qPCR, underscoring their potential use as PFD biomarkers (Fig.3). Moreover, we also identified a signature of elastin fibre assembly genes dysregulated in CD+PFD fibroblasts, suggesting molecular changes in the formation of elastin fibres in these patients. To determine whether the differentiation of fibroblasts was altered in the context of PFD, we conducted trajectory analysis using RNA velocity. Whilst fibroblasts in CD patients preferentially differentiate towards myofibroblasts, patients with PFD are biased towards LP fibroblasts, indicating an overall structural rearrangement of the mesenchyme in the rectum of patients with PFD, regardless of their inflammatory status (Fig.4). Importantly, analysis of an independent scRNAseq dataset of CD and ulcerative colitis (UC) patients showed higher expression of TGFB1 in T cells of active CD compared to active UC patients, suggesting that these alterations are already present in CD patients before the onset of a fistulizing phenotype and might potentially contribute to explain the absence of PFD in UC patients. Conclusion Based on these results, we suggest that the rectum of patients suffering from PFD present cellular and transcriptomic differences compared to CD patients without PFD. These changes are inflammation independent and point towards the TGFβ pathway as the main driver of this complication.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1093/ecco-jcc/jjac190.0105
- https://academic.oup.com/ecco-jcc/article-pdf/17/Supplement_1/i140/48951814/jjac190.0105.pdf
- OA Status
- bronze
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4318539682
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- OpenAlex ID
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https://openalex.org/W4318539682Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1093/ecco-jcc/jjac190.0105Digital Object Identifier
- Title
-
DOP65 T-cell derived TGFβ1 remodels the rectum mesenchyme in Crohn’s Disease patients with perianal fistulizing diseaseWork title
- Type
-
articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
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2023-01-30Full publication date if available
- Authors
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Victòria Gudiño, Jae‐We Cho, A M Corraliza, Berta Caballol, Alba Garrido-Trigo, Maria Carme Masamunt, Íngrid Ordás, E Ricart, Martin Hemberg, Julián Panés, Azucena SalasList of authors in order
- Landing page
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https://doi.org/10.1093/ecco-jcc/jjac190.0105Publisher landing page
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https://academic.oup.com/ecco-jcc/article-pdf/17/Supplement_1/i140/48951814/jjac190.0105.pdfDirect link to full text PDF
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YesWhether a free full text is available
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bronzeOpen access status per OpenAlex
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https://academic.oup.com/ecco-jcc/article-pdf/17/Supplement_1/i140/48951814/jjac190.0105.pdfDirect OA link when available
- Concepts
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Lamina propria, Rectum, Stromal cell, Crohn's disease, Inflammation, Pathology, Medicine, CD8, Cancer research, Molecular biology, Chemistry, Biology, Gastroenterology, Internal medicine, Disease, Immunology, Epithelium, Immune systemTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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10Other works algorithmically related by OpenAlex
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