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: 10654662
• 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/10654662
• 关键词: Acids; Antibiotics; Bile Acids; Bioinformatics; Childhood; 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; Life Cycle Stages; 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; Training; Translational Research; Universities; Ursodeoxycholic Acid; Veterinary Medicine; Wild Type Mouse; Work; 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; 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.

项目摘要/摘要 炎症性肠病（IBD）患者获得艰难梭菌的可能性是其他患者的四倍。 感染（CDI），并经历更高的死亡率和过多的并发症相比，一般 人口IBD赋予对CDI易感性的机制尚不清楚，因此不可能确定IBD是否对CDI易感。 对IBD患者采取预防措施。长期目标是研究 肠道微生物群和宿主有助于抵抗复杂疾病中的肠道病原体的定植 例如IBD。本申请的总体目标是确定肠道微生物群和微生物代谢的作用。 衍生的次级胆汁酸（SBA）在赋予易感性和导致CDI严重程度方面的作用 IBD引起的肠道炎症。核心假设是炎症引起的肠道变化 微生物群导致SBA减少，导致对C. difficile因此 从而加重IBD患者的感染。在初步数据的指导下，这一假设将通过追求 两个具体目标：1.确定是否补充外源性二级胆汁酸熊去氧胆酸 （UDCA）改变IBD中CDI期间的易感性和疾病严重程度;和2.确定肠道调节是否 微生物群来源的胆汁酸组成改变IBD中CDI期间的易感性和疾病严重程度。对于目标1， 每日给予UDCA的IL 10-/-结肠炎小鼠将用C.很难炎症诱导的改变 将定义肠道微生物组、胆汁酸宏基因组和代谢组以及CDI期间的宿主反应。 对于目标2，将使用精确的肠道微生物群调节来比较炎症诱导的（IL 10-/-结肠炎）CDI 敏感性和严重性的微生物生态系统能够合成SBAs的那些不能。这 这种方法是创新的，因为它利用肠道炎症作为肠道微生物群和胆汁的唯一引发剂。 酸性改变赋予对CDI的易感性。这一贡献是重要的，因为它将导致新的非- 针对IBD患者CDI的抗生素治疗和预防干预，旨在降低发病率， 死亡率和该患者人口的医疗保健费用。解读肠道与 微生物群，微生物来源的SBA和宿主可以阐明肠道炎症如何赋予 对CDI的敏感性最后，这个建议将促进我在鸟枪宏基因组学，整合 生物信息学，小鼠IBD模型，肠道菌群和胆汁酸代谢组的合理操作 假设驱动的研究这将支持我过渡到一个独立的临床科学家， 转化和跨学科的传染病研究。这项工作将在俄亥俄州完成 大学兽医学院在我的导师团队的指导下， 在宏基因组学，生物信息学，合理的肠道菌群操纵，宿主微生物领域的专业知识 相互作用和IBD发病机制。