Microbial butyrate synthesis indicates therapeutic efficacy of azathioprine in IBD patients.

BACKGROUND AND AIMS The microbial ecosystem seems to be an important player for therapeutic interception in inflammatory bowel disease (IBD). We assessed longitudinal microbiome changes in IBD patients undergoing therapy with either azathioprine (AZA) or anti-tumor-necrosis-factor (anti-TNF) antibodies. We predicted the metabolic microbial community exchange and linked it to clinical outcome. METHODS Fecal and blood samples were collected from 65 IBD patients at baseline and after 12 and 30 weeks on therapy. Clinical remission was defined as i.e. CDAI < 150 in Crohn´s disease (CD), partial Mayo score < 2 in ulcerative colitis (UC) and fecal calprotectin values < 150µg/g and C-reactive protein < 5mg/dl. 16S rRNA amplicon sequencing was performed. To predict microbial community metabolic processes, we constructed multi-species genome-scale metabolic network models. RESULTS Paired Bray-Curtis distance between baseline and follow-up timepoints was significantly different for UC patients treated with anti-TNF antibodies. Longitudinal changes in taxa composition at phylum level showed a significant decrease of Proteobacteria and an increase of Bacteroidetes in CD patients responding to both therapies. At family level, Lactobacilli were associated with persistent disease and Bacteroides abundance with remission in CD. In-silico simulations of microbial metabolite exchange predicted a 1.7-fold higher butyrate production capacity of patients in remission compared to patients without remission (p=0.041). In this model, the difference of butyrate production between patients in remission and patients without remission was most pronounced in the CD group treated with AZA (p=0.008). CONCLUSIONS In-silico simulation identifies microbial butyrate synthesis predictive of therapeutic efficacy in IBD.