Novel fecal biomarkers that precede clinical diagnosis of ulcerative colitis.

Abstract Background and aims Altered gut microbiota composition and function have been associated with inflammatory bowel diseases (IBD) including ulcerative colitis (UC), but causality and mechanisms remain unknown. Methods We applied 16S rRNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at-risk for IBD (pre-UC) that later developed UC (post-UC), and matched healthy controls (HC). Results Microbiota composition of post-UC subjects was different from HC and pre-UC; however, functional analysis revealed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified over 22,000 gene families that were significantly different between HC, pre-UC and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa, and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. Bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC or post-UC microbiota. Mice colonized with or born from pre-UC colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC colonized mice. Conclusions We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a non-invasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with anti-proteases.