Restoration of Mucosal and Fecal Microbiome, Mycobiome and Metabolome is Associated with Response to Fecal Microbiota Transplantation and Anti-Inflammatory Diet in Active Ulcerative Colitis

Abstract

Background: Fecal microbiota transplantation with anti-inflammatory diet (FMT-AID) has been associated with clinical response and deep remission in patients with active ulcerative colitis (UC). The present study aims to assess FMT-associated bacterial, fungal and metabolomic shifts in mucosal and fecal niches in active UC, and to correlate these changes with clinical and endoscopic outcomes of FMT. To decipher if baseline microbial signatures in UC are associated with these outcomes and can determine FMT engraftment. Methods: Patients with active UC randomized to receive either FMT-AID or standard medical therapy (SMT) and non-IBD controls were recruited. Fecal and mucosal microbiome and mycobiome were characterized (16S-rRNA and ITS1, respectively) in 104 paired pre- and post-intervention samples (n=52, fecal; n=52, mucosal) from patients with UC, along with 54 control samples (27 mucosal and 21 fecal samples). A subset of samples (n=71; 40 paired pre-and post-FMT samples and 31 control samples) were used for untargeted metabolomics. Findings: FMT-AID associates with enrichment of beneficial bacterial (mucosal-Odoribacter splanchnicus and fecal- Slackia isoflavoniconvertens, Agathobaculum butyriciproducens, etc.) and fungal (Aspergillus penicilloides) members, and reduction in bacterial and fungal pathobionts (mucosal- Enterococcus, Veillonella, Malassezia; fecal- Enterococcus, Candida tropicalis). These alterations correlated with UC-associated clinical, biochemical and endoscopic parameters. SMT failed to achieve similar improvements. FMT-AID also restored mucosal and fecal metabolome with ‘health-associated’ metabolites. Higher pre-intervention abundances of beneficial taxa in mucosa and feces were associated with positive outcomes of FMT-AID. Pre-FMT fecal bacteriome also correlated with post-FMT engraftment of beneficial bacteria. Interpretation: Enrichment of specific beneficial bacterial, fungal and metabolomic signatures in fecal and mucosal niches was associated with positive clinical, biochemical and endoscopic outcomes following FMT-AID in patients with UC. Pre-FMT bacteriome was associated with post-FMT engraftment of beneficial bacteria and clinical response. Funding: The work has been funded by the Indian Council of Medical Research: Center for Advanced Research and Excellence in Intestinal Diseases (grant number: 55/4/11/CARE-ID/2018-NCD-II); Science and Engineering Research Board (SERB): Core Research Grant (CRG/2019/005292); and Scheme for Promotion of Academic and Research Collaboration (SPARC P1492).