Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity

Abstract

Ulcerative colitis (UC) is driven by disruptions in host-microbiota homeostasis, however current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions become disrupted in UC, we collected and analyzed six fecal or serum based –omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic, and amplicon sequencing profiles of fecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic, and histologic measures of 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 whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus -induced barrier dysfunction in vitro , and prevented colitis in B. vulgatus monocolonized, IL-10 deficient mice. Furthermore, transplantation of feces from UC patients with a high abundance of B. vulgatus proteases into germ-free mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provides a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.

Mucosal host–microbe interactions associate with clinical phenotypes in inflammatory bowel disease

“…The co-occurrence of Bacteroides with lower expression of interleukin signaling pathways is supported by experimental work that found potential anti-inflammatory and protective roles for these bacteria in the context of intestinal inflammation [34,39,40]. Still, the relative contributions of each of these species, as well as their behavior in the context of intestinal inflammation, remains elusive, although our data might reflect an overrepresentation of anti-inflammatory members [34-39,43]. The positive associations between Bacteroides and expression of metal ion response genes and metallothioneins (MTs) are intriguing in the context of IBD because aberrant MT homeostasis and intracellular zinc metabolism have been implicated in disease pathophysiology [44–48].…”

Novel histological repertoire of crypt-associated anomalies in inflamed colon mucosa

“…That crypt-associated anomalies never reach the stadium of asymmetric branching as they are digested by mast cells and/or gut microbiome proteases 25 26…”

Short-Term Metformin Treatment Enriches Bacteroides dorei in an Obese Liver Steatosis Zucker Rat Model

“…Furthermore, B. vulgatus has been shown to be protective against Escherichia coli induced colitis of interleukin-2-deficient gnotobiotic mice ( Waidmann et al, 2003 ). In contrast, several studies revealed that B. vulgatus is generally viewed as a pathobiont ( Ó Cuív et al, 2017 ), often associated with colitis in murine ( Bloom et al, 2011 ) model systems, as well as human ulcerative colitis ( Mills et al, 2022 ), irritable bowel disease ( Ryan et al, 2020 ), and celiac disease ( Schippa et al, 2010 ; Bloom et al, 2011 ; Wu et al, 2021 ). It has also been shown that B. vulgatus has an increased protease activity compared to other Bacteroides spp., and can cause barrier dysfunction ( Riepe et al, 1980 ; Mills et al, 2022 ).…”