The impact of inflammation induced alterations to microbially derived bile acids on susceptibility and severity of Clostridioides difficile infection

炎症诱导的微生物胆汁酸改变对艰难梭菌感染的易感性和严重程度的影响

• 批准号: 10448556
• 负责人: Jenessa Andrzejewski Winston
• 金额: $ 18.73万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448556
• 关键词: Antibiotics; Bile Acids; Bioinformatics; Clostridium difficile; Colitis; Community-Acquired Infections; Complex; Data; Development; Disease; Disease model; Ecosystem; Funding; General Population; Goals; Health Care Costs; Hydrolase; Immune; Immune response; Incidence; Infection; Infectious Diseases Research; Inflammation; Inflammatory Bowel Diseases; Interdisciplinary Study; Interleukin-10; Lactobacillus; Lead; Mediating; Mentors; Metagenomics; Morbidity - disease rate; Mus; Ohio; Operon; Pathogenesis; Patients; Play; Predisposition; Preparation; Preventive measure; Probiotics; Production; Public Health; Reaction; Recording of previous events; Research; Research Training; Risk; Risk Factors; Role; Scientist; Severities; Severity of illness; Shotguns; Spontaneous colitis; Supplementation; Testing; Therapeutic Intervention; Time; Training; Translational Research; Universities; Ursodeoxycholic Acid; Veterinary Medicine; Wild Type Mouse; Work; base; bile salts; career; college; colonization resistance; dehydroxylation; enteric infection; enteric pathogen; experience; gut inflammation; gut microbiome; gut microbiota; host-microbe interactions; innovation; insight; metabolome; metagenome; microbial; microbiota; mortality; murine colitis; novel; novel therapeutic intervention; pediatric patients; prevent; preventive intervention; therapeutic development; treatment group

PROJECT SUMMARY/ABSTRACT Patients with inflammatory bowel disease (IBD) are four times more likely to acquire Clostridioides difficile infection (CDI), and experience higher mortality and excessive complications compared to the general population. The mechanism by which IBD confers susceptibility to CDI is unknown, making it impossible to implement preventative measures for IBD patients. The long-term goal is to investigate how interactions between the gut microbiota and host contribute to colonization resistance against enteric pathogens in complex diseases such as IBD. The overall objective of this application is to define the role of the gut microbiota and the microbially derived secondary bile acids (SBAs) in conferring susceptibility and contributing to the severity of CDI during intestinal inflammation caused by IBD. The central hypothesis is that inflammation-induced alterations in the gut microbiota lead to a decrease in SBAs resulting in loss of colonization resistance against C. difficile thus exacerbating this infection in IBD patients. Guided by preliminary data, this hypothesis will be tested by pursing two specific aims: 1. Determine if supplementation with the exogenous secondary bile acid ursodeoxycholic acid (UDCA) alters susceptibility and disease severity during CDI in IBD; and 2. Determine if modulation of intestinal microbiota derived bile acid composition alters susceptibility and disease severity during CDI in IBD. For Aim 1, IL10-/- colitis mice administered daily UDCA will be challenged with C. difficile. Inflammation-induced alterations in the gut microbiome, bile acid metagenome and metabolome, and host response during CDI will be defined. For Aim 2, precision gut microbiota modulation will be used to compare inflammation-induced (IL10-/- colitis) CDI susceptibility and severity in microbial ecosystems capable of synthesizing SBAs to ones that cannot. This approach is innovative because it utilizes intestinal inflammation as the sole initiator of gut microbiota and bile acid alterations to confer susceptibility to CDI. This contribution is significant because it will lead to novel non- antibiotic therapeutic and preventative interventions for IBD patients with CDI aimed at reducing morbidity, mortality, and health care costs for this patient demographic. Deciphering interactions between the gut microbiota, microbially derived SBAs, and the host may elucidate how intestinal inflammation confers susceptibility to CDI. Finally, this proposal will advance my training in shotgun metagenomics, integration of bioinformatics, murine IBD models, and rational manipulation of the gut microbiota and bile acid metabolome into hypothesis driven research. This will support my transition into an independent clinician scientist in translational and interdisciplinary infectious disease research. This work will be completed at the Ohio State University College of Veterinary Medicine under the guidance of my mentoring team with globally recognized expertise in the fields of metagenomics, bioinformatics, rational gut microbiota manipulation, host-microbe interactions, and IBD pathogenesis.

项目总结/文摘