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.

溃疡性结肠炎（Ulcerative colitis, UC）的发病机制与宿主-菌群互作紊乱密切相关，但当前临床治疗手段仅靶向宿主炎症通路。为阐明UC中宿主-菌群互作失调的具体机制，本研究收集并分析了来自40例临床、内镜及组织学疾病活动度存在差异的UC患者的6项粪便或血清组学（-omic）数据集。另收集210例样本组成独立验证队列，其中包括73例UC患者、117例克罗恩病（Crohn’s disease, CD）患者及20例健康对照，并对其进行单独分析。对两个队列的数据进行整合分析后发现，部分临床活动期UC患者体内源自普通拟杆菌（Bacteroides vulgatus）的蛋白酶丰度显著升高。为验证“普通拟杆菌蛋白酶可促进UC疾病活动”这一假说，本研究首先对普通拟杆菌分泌的蛋白酶进行了表征，随后筛选出合适的广谱蛋白酶抑制剂以评估其在结肠炎模型中的作用。体外实验显示，蛋白酶抑制剂可有效改善普通拟杆菌诱导的肠道屏障功能损伤；同时可在单定植普通拟杆菌的IL-10敲除小鼠中预防结肠炎发生。进一步实验证实，将携带高丰度普通拟杆菌蛋白酶的UC患者粪便移植至无菌（germ-free）小鼠体内，可诱导依赖蛋白酶活性的结肠炎。综上，本研究通过多组学（multi-omics）整合分析策略，加深了对驱动UC发生的菌群功能异常的认知，并提出靶向抑制普通拟杆菌蛋白酶可作为治疗UC的全新策略。