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.
BACKGROUND: Cross-sectional studies in ulcerative colitis (UC) have shown at best a moderate association between histologic and clinical measures of disease activity, but few longitudinal studies have evaluated this relationship. As endoscopy and histology are both independent predictors of clinical outcomes in UC, there remains a need to assess these measures in parallel to demonstrate clinical benefit. HICKORY (NCT02100696) is an ongoing Phase 3 study evaluating etrolizumab in anti-tumor necrosis factor (aTNF)–experienced patients with moderate-to-severe UC. The correlation between histologic changes and established disease activity measures at end of induction (week 14) was assessed using data from the open-label induction (OLI) cohort of HICKORY. METHODS: Study analysis is based on data from patients in the OLI cohort who received ≥1 dose of etrolizumab 105 mg subcutaneously every 4 weeks during the 14-week induction phase. Baseline and week 14 biopsies were scored by 1 of 4 central readers using the Nancy histologic index (NHI) and the Robarts histopathology index (RHI) in patients who had active baseline histology (NHI >1 and RHI >3) and complete scoring at week 14 (n = 97). Binary week 14 histologic outcomes were characterized by presence or absence of neutrophils (NHI ≤1 or RHI ≤3 and Geboes subgrades 2B.0/3.0). Mayo Clinic score (MCS) endoscopic subscore (ES) was used to assess endoscopy. Pairwise associations were quantified by Spearman correlation (ρ; for correlation between change from baseline scores) and Cohen kappa coefficients (κ; for agreement among week 14 outcomes). ΔNHI and ΔRHI were compared to determine presence of a minimum clinically important difference (MCID) in MCS (∆MCS ≥3 from baseline). RESULTS: At week 14, 22% (21/97), 23% (22/97), and 8% (8/97) of patients achieved resolution of neutrophilic inflammation based on either NHI or RHI/Geboes, endoscopic improvement (ES ≤ 1), and endoscopic remission (ES = 0), respectively. Among patients with endoscopic improvement and endoscopic remission, neutrophilic resolution was achieved in 55% (12/22) and 75% (6/8) of patients, respectively. ΔNHI and ΔRHI were highly correlated (ρ = 0.91). There was weak to no association between ΔNHI/ΔRHI/ΔES and Δfecal calprotectin (ρ = –0.02 to 0.38), ΔC-reactive protein (ρ = 0.03 to 0.07), Δalbumin (ρ = –0.19 to –0.10), Δhemoglobin (ρ = –0.22 to –0.19), and Δsegmented neutrophils in the blood (ρ = –0.06 to 0.01). Weak correlations were observed between ΔNHI/ΔRHI and ΔES (ρ = 0.26–0.27), Δrectal bleeding (ρ = 0.24–0.28), and Δstool frequency (ρ = 0.40–0.42). Correlations between NHI, RHI/Geboes, and ES with symptomatic outcomes were weak (κ = 0.28–0.45). Difference in the mean grouped by achievement of ΔMCS ≥3 suggests MCIDs in ΔNHI and ΔRHI of 1.2 and 8.6, respectively. CONCLUSION(S): The analysis showed weak to moderate agreement between changes in histologic scores and changes in endoscopic scores, and weak to no agreement between changes in histologic scores and changes in laboratory results at week 14. There was a weak correlation between histologic scores and symptoms at the end of induction. MCID results suggest that both the NHI and RHI appear to effectively evaluate neutrophilic resolution, making the changes in score more clinically interpretable.
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