Peripheral players and gut bacteria modulate inflammatory bowel disease phenotype in patients with primary sclerosing cholangitis

Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with underlying inflammatory bowel disease (IBD). We aimed to study how the phenotype in PSC patients compares to IBD alone and its association with altered inflammatory immune responses. Methods A case-control study was conducted involving a cohort of 75 patients, including 16 with PSC (14 with concomitant IBD), 39 with IBD alone, and 20 control individuals. Fecal gut microbiota, colonic tissue proteomics and immune-related gene expression, serum proteomics and targeted metabolomics were analyzed. Results Intestinibacter taxa were increased in patients with PSC. Proinflammatory mRNA markers TWIST1 , COX2 , IL-8 , and CCL2 , and pro-oncogenic markers LGR5 and SNAIL were upregulated in colonic tissue from PSC patients. Additionally, a unique proinflammatory proteomic signature, elevated glycochenodeoxycholic acid (GCDCA), and increased miR-21 were identified in serum from PSC patients. Co-incubation of human-derived monocytes with miR-21 and GCDCA reproduced the inflammatory profile observed in PSC patients. Conclusions These findings suggest an interplay between gut microbiota dysbiosis and the proinflammatory peripheral immune response contributing to the unique PSC phenotype