Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis

Abstract

Healthy 1 st degree IBD relatives Pre-UC Post-UC Matched HC Follow-up Proteolytic activity Microbiotahumanized mice Proteolytic activity Low-grade colonic inflammation Fecal proteolytic activity as early biomarker Microbiota composition BACKGROUND & AIMS: Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. METHODS: We applied 16S ribosomal RNA 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 inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). RESULTS: Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 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. The 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. CONCLU-SIONS: 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 noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.

Intestinal Microbiome in Hematopoietic Stem Cell Transplantation For Autoimmune Diseases: Considerations and Perspectives on Behalf of Autoimmune Diseases Working Party (ADWP) of the EBMT

“…Alternatively, the documented genetic and/ or microbial-independent environmental factors associated with IBD may promote inflammation and oxidative stress, which subsequently results in a shift in microbial composition. A recent study has shown that increased fecal proteolytic activity and microbiota changes precede diagnoses of ulcerative colitis (30). In addition, the altered humoral and cellular acquired immune responses towards bacterial antigens that characterize IBD, particularly Crohn's disease (31), may predate disease onset (32).…”

New Metabolic and Genetic Biomarkers for Diagnosis of Ulcerative Colitis

“…Moreover, the study illustrated an increased level of elastase activity in Bacteroides, isolated from fecal samples. Consequently, the study opened different pathways for early investigation of predisposed people to UC and also for possible treatments by reduction of high proteolytic activity [24].…”

Inflammatory Bowel Disease, Celiac Disease, and Primary Sclerosing Cholangitis: Is There a Link?

“…6 In a recent study, we demonstrated that increased fecal proteolytic activity precedes the clinical diagnosis of ulcerative colitis and associates with gut microbiota changes that are proinflammatory. 7 Future studies will be needed to investigate common environmental and genetic factors involved in the association of these disorders, among others IBD, CeD, type 1 diabetes, and PSC.…”