Metaomics Reveals Microbiome Based Proteolysis as a Driver of Ulcerative Colitis Severity

Ulcerative colitis (UC) is driven by disturbed host-microbiota relations, but current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions go awry in UC, we collected and analyzed six fecal or serum based –omic datasets from 40 UC patient samples displaying varying clinical, endoscopic, and histologic disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn's disease (CD), 20 healthy controls) was collected and analyzed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an over-abundance of proteases that originated from the bacterium, Bacteroides vulgatus. To test the hypothesis that B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases and then selected an appropriate broad-spectrum protease inhibitor to evaluate their involvement in colitis models. Protease inhibition improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus IL10 deficient monocolonized mice. Furthermore, transplantation of feces from UC patients with over-abundant B. vulgatus proteases into germ-free mice induced colitis dependent on protease activity. Together, these results stemming from a multi-omics approach, improve understanding of functional alterations in microbiota that drive UC and suggest inhibition of B. vulgatus proteases as a novel strategy to treat this disease.