miR-21-5p dysregulation is associated with gut microbiota dysbiosis and pro-oncogenic markers in primary sclerosing cholangitis with concomitant inflammatory bowel disease

Background: Primary sclerosing cholangitis (PSC) is a chronic liver disease frequently associated with inflammatory bowel disease (IBD) and increased risk of colorectal cancer (CRC). Despite the strong association, the underlying mechanisms linking PSC-IBD, gut inflammation, and neoplastic potential remain unclear. This study explores the role of miR-21-5p dysregulation, gut microbiota dysbiosis, and pro-oncogenic markers in shaping the inflammatory and neoplastic microenvironment in PSC-IBD patients. Methods: A case-control study was conducted, including PSC patients with concomitant IBD (n = 14) and control individuals without diagnosed PSC and IBD (n = 20). miR-21-5p levels were evaluated in serum, fecal samples, and colonic biopsies via qPCR. Gut microbiota composition was analyzed using 16S rRNA sequencing. Pro-oncogenic and inflammatory markers in colonic tissue were assessed via qPCR. In vitro studies were performed using cholangiocyte (H69), colorectal cancer (HCT116), and primary monocyte models to investigate the role of miR-21-5p. Results: miR-21-5p was significantly upregulated in the right colon, serum, and fecal samples of PSC-IBD patients compared to controls. Gut microbiota analysis revealed dysbiosis, characterized by an increased Bacteroidota/Bacillota ratio and reduction in bile acid-metabolizing bacteria, including Clostridium sensu stricto 1, Ruminococcaceae UCG-002, and Christensenellaceae_R7_group. Colonic tissue analysis showed increased expression of EMT-related transcription factors TWIST1 and SNAIL, inflammatory cytokines IL-8, CCL2, and COX2, and the stem cell marker LGR5. In vitro studies confirmed miR-21-5p role in upregulating does markers in monocytes and CRC cells. Conclusion: This study found a link between miR-21-5p dysregulation and gut microbiota dysbiosis, colonic inflammation, and pro-oncogenic signaling in PSC-IBD patients. These findings highlight miR-21-5p as a potential modulator of disease progression and neoplastic risk.