Ruta Inciuraite Provides Compelling Insights into the Role of miRNA and Gut Bacteria in Ulcerative Colitis

Please find a lay language summary below this text.

At the start of the miGut-Health consortium call on 1 October, Ruta Inciuraite, PhD candidate in Biology and team member from LSMU, presented compelling research findings on the role of microRNAs (miRNAs) in spatially distinct populations of colonic epithelial cells in ulcerative colitis (UC). Her insights stem from two recently published papers: The microRNA Expression in Crypt-Top and Crypt-Bottom Colonic Epithelial Cell Populations Demonstrates Cell-Type Specificity and Correlates with Endoscopic Activity in Ulcerative Colitis (first part of the research presented) and Constituents of stable commensal microbiota imply diverse colonic epithelial cell reactivity in patients with ulcerative colitis (follow-up study). Both studies are described here briefly, following Ruta’s 20-minute-long presentation.

As background, colonic epithelial barrier dysfunction is one of the early events in UC as cells and their secreted products form and maintain intestinal barrier function. miRNAs, which are involved in regulating intestinal epithelial integrity and barrier permeability, play a critical role in this process. However, the exact cellular context of miRNA deregulation during colonic inflammation remains unknown.

To address this, the LSMU team has embarked on a search for cell type-specific deregulation of miRNAs in the UC, and conducted comprehensive miRNA expression profiling on colon tissue and colonic crypt-bottom and crypt-top cell population levels in active and quiescent UC. In Study part 1, miRNA profiling was performed in colon tissue samples from a cohort of 76 patients, while in Study part 2, colon tissues of Study group II (48 participants) were used to enrich two distinct epithelial cell populations, followed by miRNA expression analysis.

The studies revealed that sequencing of enriched colonic epithelial cells shows cell type-specific miRNA expression during colonic inflammation in UC, while miRNAs in crypt-top and crypt-bottom colonic epithelial cells exhibit a co-expression pattern which is related to UC activity. In conclusion, it was found that miRNA expression was specific to colonic epithelial cell populations and UC state, reflecting endoscopic disease activity. Irrespective of the UC state, deregulated epithelial miRNAs were associated with a regulation of the intestinal barrier integrity.

Although these studies advanced the understanding of miRNA dysregulation in UC, several questions remained unanswered due to the complex, multifactorial nature of the disease. For example, does consistently resident gut microbiota have the potential to influence the cellular responses of the host intestine, and do these responses differ between UC patients and non-IBD controls? To explore these questions, the follow-up study focused on identifying unaltered faecal microbiota members during UC and assessing the interplay of these bacteria with colonic epithelial cells. The first step was the identification of stably abundant faecal microbiota, showing that a substantial portion of the gut microbiota is consistently present and remains unchanged throughout the pathogenesis of UC. Furthermore, UC patient-derived colonic epithelial cells showed diverse reactivity to constituent bacteria, indicating that intestinal bacteria may differently influence the responses of colonic epithelial cells of healthy and diseased individuals.

Despite the decreased bacterial diversity and alterations in gut microbiota during UC, a significant portion of these microorganisms are consistently present and remain unchanged throughout the pathogenesis of the disease. Two species belonging to the most stable and unaltered commensal genera of the gut – E. coli and P. vulgatus – do not cause colonic epithelial stress and are not recognised as pathogens. Nevertheless, both species show a tendency to regulate differentially the tight junction formation in the control- as well as UC patient-derived colonic epithelial cell monolayers. In summary, stably abundant gut microbiota likely contributes to the impairment of the intestinal epithelial barrier during UC without inducing significant cellular stress responses, changes in small RNA expression, or their release.

• Lay Language Summary

  At the miGut-Health consortium meeting on 1 October, Ruta Inciuraite, a PhD candidate from LSMU, shared her research on how microRNAs (miRNAs) and gut bacteria affect ulcerative colitis (UC). Her findings were based on two studies: one about how miRNAs work in different gut cells during UC and another about how stable gut bacteria interact with these cells.

  UC often starts with problems in the gut’s protective barrier, made up of specialised cells and their secretions. miRNAs help control this barrier, but they act differently depending on the type of cell and how active the disease is. By studying miRNAs in colon tissue and two types of cells – crypt-bottom cells, which are stem cells, and crypt-top cells, which handle absorption and defence – researchers found that miRNAs play an important role in maintaining the barrier, even during UC.

  In a follow-up study, they looked at whether gut bacteria could influence these intestinal epithelial cells. The team found that while the overall diversity of bacteria decreases during UC, some species, like E. coli and P. vulgatus, remain stable. These bacteria did not harm the gut cells but seemed to affect how the barrier works, especially in people with UC compared to healthy individuals. The research suggests that stable gut bacteria, while not directly harmful, might still weaken the gut barrier during UC. These findings help us understand how changes in the gut’s environment contribute to the disease.