Gut · 2026
TL1A-activated T cells remodel the rectal mucosa in patients with Crohn's disease with perianal fistulising disease.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Gudiño Victoria, Cho Jae Won, Caballol Berta, Sanzo-Machuca Ángela, Corraliza Ana, Veny Marisol, Dotti Isabella, Genaro Livia Moreira, Melón-Ardanaz Elisa, Masamunt Maria Carme, Esteller Miriam, Teubel Iris, Robbins Lisseth, Giner Àngel, Prieto Cristina, Ferrer Elena, Leal Raquel Franco, Martin-Cardona Albert, Loras Carme, Esteve Maria, Rimola Jordi, Fernández-Clotet Agnès, Ordás Ingrid, Ricart Elena, Panés Julian, Hemberg Martin, Salas Azucena
Аннотация
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.
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.