Perianal fistulas affect approximately 20% of people with Crohn's disease and, despite their impact, the mechanisms that promote their development are still unknown. To address this knowledge gap, the group analysed biopsies of the rectal mucosa of Crohn's disease patients with and without perianal fistulas. Using single-cell RNA sequencing techniques, they obtained a detailed map of the cellular and molecular alterations associated with fistula development.
According to Azucena Salas, leader of the project: “This study is the first to use these samples and this technique to investigate the initial processes involved in the formation of perianal fistulas. This facilitates the future generating of large cohorts of patients, since it is easier to collect rectal biopsies than fistula tissue, which has classically been used in previous studies."
The results show that patients with fistulising Crohn's disease present an overactivation of the TL1A signalling pathway, an inflammatory mechanism that remodels rectal tissue and potentially makes it more susceptible to developing a fistula. This discovery opens up a new perspective with regard to the origin of the lesions.
To date, TNF inhibitors have been practically the only recommended treatment for perianal fistulas, and they do not always work. This study shows that there are TNF-independent mechanisms, through TL1A, that remain active in patients with fistula, which opens the door to exploring new therapeutic targets.
According to Victoria Gudiño, first-named author of the study and IDIBAPS researcher: "Identifying the TL1A pathway brings us closer to understanding the root causes of perianal disease and gives us a solid basis for developing new drugs that can prevent the formation of fistulas or help to heal them.”
Furthermore, the fact that these alterations were detected in non-inflamed rectal tissue suggests that they may act as early risk markers, which in the future could help identify which patients need more intensive monitoring or prevention strategies.
The study was carried out in collaboration with Brigham and Women's Hospital (Boston), Mutua Terrassa, and the University of Campinas (Brazil), and it establishes a new framework for investigating the mechanisms behind fistula formation in Crohn's disease, a field that so far has been very little explored.
