Gut microbiota and metabolome in UC

Objective: The gut microbiota has been implicated in onset and progression of ulcerative colitis (UC). Here, we assess the potential causal involvement of the microbiota and -associated faecal water (FW) metabolome in altering key functional parameters of the colonic epithelium. Design: Faecal samples were collected from N=51 healthy controls (HC), N=36 patients with active UC (UC-A), and N=41 subjects in remission N=41 (UC-R). The faecal microbiome was characterised through amplicon sequencing and volatile organic acid, non-volatile organic acid, and bile acid profiles of the FW were determined. Using in vitro incubation experiments, the impact of the FW metabolome on butyrate oxidation rates/gene expression and cell death (cytotoxicity) of HT-29 cells, cytokine production by PBMC, and barrier integrity of CaCo2 monolayers was evaluated. Results: The FW metabolome of samples from patient as well as from individuals hosting the Bact2 enterotype (69% of UC-A patients, 31% of UC-R, and 3% of HC), characterized by lower levels of median- and short-chain fatty acids and furan compounds, did not alter butyrate oxidation rates but affected associated gene expression profiles. After exposure to FW from UC patients/Bact2-carriers, PBMC IL-8 production lowered and IL1-ß production increased. FW from patients increased cytotoxicity, associated with sulphide compound levels. Bact2 carrier status, displaying higher levels of bile acids, was predictive of a lowering of barrier function upon incubation of monolayers. Conclusions: The FW metabolome of patients and individuals hosting a dysbiotic microbiota could contribute to the disruption of functional processes of the colonic epithelium as observed in UC.