Luminal and Mucosal Microbiota and Host Gene Expression in Chronic Pouchitis Patients after Fecal Microbiota Transplantation
Introduction and aim: Altered microbiota and impaired host immune function have been linked to the pathogenesis of pouchitis. Recently, we conducted the first randomized clinical trial (RCT) on fecal microbiota transplantation (FMT) therapy in chronic pouchitis. Our aim was to analyze changes in both luminal and mucosal microbiota as well as in host mucosal gene expression before and during one-year follow-up after FMT to get insights into the host-microbiota interactions possibly underlying clinical outcomes of the patients in the RCT-FMT trial.   Methods: We studied 26 chronic pouchitis patients who were treated with either two FMTs from a healthy donor or autologous transplants. Stool samples were collected at baseline and 4, 12, 26 and 52 weeks later. Biopsies from pouch and ileum were collected at baseline and at 52 weeks. Microbiota was analyzed with 16S rRNA gene amplicon sequencing of the V3-V4 region. Differential gene expression (DGE) was assessed by RNA-sequencing.  Results: At baseline the pouchitis patients differed from the healthy donor in luminal microbiota composition and bacterial diversity. Antibiotic type and pattern of use were significant drivers of the luminal microbiota. DGE indicated transition from ileal to colonic gene expression in the pouch and upregulation in inflammation and immune system related pathways in the pouch. At 4 weeks, the non-relapsed FMT patients had a lower microbiota dissimilarity to the donor than the non-relapsed placebo patients (p=0.02). While two FMT-treated patients showed a shift towards the donor's microbiota during the one-year follow-up, the overall FMT microbiota modulation effect was low. Patient's luminal and mucosal microbiota profiles were unstable in both FMT and placebo groups. Expression of the chemokine receptor CXCR4 was downregulated at 52 weeks compared to the baseline in the non-relapsed patients in both FMT and placebo groups. Conclusions: Overall, pouchitis patients have an individual and unstable microbiota. In FMT, the engraftment of donor's microbiota seems to be low in this patient group. The microbiota composition or alterations did not explain the relapse status of the patients. Some evidence on remission related host gene expression pattern was found, specifically CXCR4 expression may have a role in sustained remission.