Microbiome Driven Proteolysis as a Contributing Factor to Severity of Ulcerative Colitis Disease Activity

微生物组驱动的蛋白水解是溃疡性结肠炎疾病活动严重程度的影响因素

• 批准号: 10529090
• 负责人: David J Gonzalez
• 金额: $ 54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10529090
• 关键词: Address; Animals; Bacteria; Bacteroides; Basic Science; Biochemical; Blood; Cell Culture Techniques; Chronic; Chronic Disease; Clinical; Colitis; Collagen; Colonic inflammation; Coupled; Crohn' s disease; Data Set; Development; Diagnosis; Disease; Disease Management; Epithelial; Feces; Functional disorder; Genetic; Genomics; Germ-Free; Goals; Histologic; Human; Immune response; In Vitro; Individual; Inflammatory; Inflammatory Bowel Diseases; Integration Host Factors; Interleukin-10; Intestinal permeability; Investigation; Link; Mediating; Metagenomics; Microbiology; Modeling; Mucins; Mucositis; Mus; Nature; North America; Pathway interactions; Patients; Peptide Fragments; Peptide Hydrolases; Persons; Play; Prevalence; Protease Inhibitor; Proteins; Proteolysis; Publishing; Regulation; Role; Sampling; Serine Proteinase Inhibitors; Serum; Severities; Severity of illness; Shotguns; Stress; Structure; Taxonomy; Testing; Therapeutic; Tight Junctions; Translational Research; Transplantation; Ulcerative Colitis; Validation; Work; bacterial genetics; base; cohort; data integration; design; effective therapy; gut microbiome; gut microbiota; host microbiome; host microbiota; improved; in vitro Model; in vivo; in vivo Model; inhibitor; intestinal barrier; metaproteomics; microbial; microbiome; microbiome research; microbiota; mutant; novel; novel strategies; novel therapeutic intervention; prevent; tool

Ulcerative colitis (UC) is a chronic disease characterized by inflammation of the mucosa of the colon. UC has a significant global burden, and is characterized by an aberrant immune response directed towards the gut microbiota. Current treatment options exclusively target host inflammatory pathways and are often ineffective in managing disease. Nearly 1 million individuals in North America are currently living with UC and its prevalence in humans continues to grow worldwide. The considerable number of growing cases, coupled with the lack of an effective therapy, stresses the need for investigation into new therapeutic interventions against UC. Our group recently characterized host-microbiome interactions governing UC through six fecal or serum based –omic datasets from 40 UC patients displaying a wide range of clinical, endoscopic, and histologic disease activity. After broad-scale analyses, the six datasets provided powerful evidence towards a central hypothesis: Bacteroides vulgatus proteases can drive UC disease severity. Metaproteomics pinpointed B. vulgatus proteases as a distinguishing feature of severity. Shotgun metagenomics guided taxonomic inferences and revealed that the B. vulgatus association was driven primarily by protein regulation as opposed to microbial abundances. An abundance of serine protease inhibitors found in the patient serum suggested the importance of proteases. The metapeptidome showed increased peptide fragments correlated with UC disease severity. An independent 210-person cohort validated the strong connection between B. vulgatus proteases and UC disease severity. Testing our hypothesis, we demonstrate B. vulgatus can disrupt intestinal epithelial permeability in vitro, and protease inhibition was sufficient to restore epithelial barrier. Monocolonization of B. vulgatus into germfree IL-10 deficient mice demonstrated colonization induces colitis in these animals and protease inhibition is sufficient to prevent colitis development. Furthermore, transplantation of feces from UC patients with over-abundant B. vulgatus proteases into germ-free mice induced colitis dependent on protease activity (Mills et al., Nature Microbiology 2021). Based on our published work, we have formulated two testable hypotheses to further build on these new findings: 1) proteolysis is a central mechanism utilized by B. vulgatus to induce colitis in vitro and in vivo relevant to UC and 2) B. vulgatus proteases degrade key components of the intestinal barrier. The specific aims of this application are to define the genomic context, roles, and develop specific inhibitors against B. vulgatus proteases in UC (Aim 1), characterize the targets and dynamics of B. vulgatus mediated proteolysis in UC (Aim 2). To complete this proposal, we will use a multifaceted approach of state-of-the-art biochemical, cell culture, bacterial genetics, and in vivo models. Ultimately, this work has the potential to break new ground in UC basic and translational research.

溃疡性结肠炎（UC）是一种颜色的慢性疾病。缺乏有效的疗法，强调了对新的治疗干预措施的需求E六个数据集为中心的假设提供了有力的证据：vulgatus蛋白酶可以将UC疾病的严重性视为vulgatus的一项区别在患者血清中发现的抑制剂表明，ES的重要性与UC疾病的严重程度相关。我们已经提出了两个可检验的假设，以进一步建立在这些新发现上：1）由vulgatus tile tilly the typo dectiine和2）与UC相关的体外和体内诱导结肠炎和2）B. vulgatus蛋白酶降低了特定目的的关键成分，以定义特定的目的基因组环境，并针对UC中的vulgatus蛋白酶开发特定的核心（AIM 1），表征了vulgatus B. vulgatus介导的protisisisis的靶标和动力学（AIM 2）。状态 - 生化，细胞培养和体内模型，最终，这项工作有可能在UC基本和转化研究中脱颖而出。