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

项目摘要/摘要 炎症性肠病(IBD)患者感染艰难梭状芽胞杆菌的可能性是普通人的四倍 感染(CDI)，与一般情况相比，死亡率和过度并发症更高 人口。IBD导致CDI易感性的机制尚不清楚，因此不可能 对IBD患者实施预防措施。其长期目标是研究 肠道微生物区系和宿主在复杂疾病中对肠道病原体的定植抵抗力 比如IBD。本申请的总体目标是确定肠道微生物区系和微生物区系的作用 衍生二次胆汁酸(SBAs)在提高CDI易感性和加重CDI严重程度中的作用 IBD引起的肠道炎症。中心假设是炎症引起的肠道变化 微生物区系导致SBAs减少，从而导致对艰难梭菌的定植抵抗力丧失 加剧了IBD患者的这种感染。在初步数据的指导下，这一假说将通过追逐来检验 两个特定的目标：1.确定是否补充外源性次级胆汁酸熊去氧胆酸 (UDCA)改变IBD CDI过程中的易感性和疾病严重程度；以及2.确定肠道的调节 在IBD的CDI过程中，微生物区系衍生的胆汁酸成分改变了易感性和疾病严重程度。对于目标1， 每天服用UDCA的IL10/结肠炎小鼠将受到艰难梭菌的挑战。炎症诱导的改变 在肠道微生物组，胆汁酸代谢组和代谢组，以及在CDI过程中的宿主反应将被定义。 对于目标2，将使用精确的肠道微生物区系调节来比较炎症诱导(IL10-/-结肠炎)CDI 能够合成SBA的微生物生态系统对不能合成SBA的微生物生态系统的敏感性和严重性。这 方法是创新的，因为它利用肠道炎症作为肠道微生物区系和胆汁的唯一发起者 酸蚀变使其对CDI易感性。这一贡献意义重大，因为它将导致新的非 对患有CDI的IBD患者进行抗生素治疗和预防干预，旨在降低发病率， 死亡率，以及这些患者的医疗保健费用。破译肠道之间的相互作用 微生物区系、微生物衍生的SBAs和宿主可能阐明肠道炎症是如何引发的 对CDI的易感性。最后，这项提议将推进我在鸟枪式元基因组学、整合 生物信息学，小鼠IBD模型，肠道微生物区系和胆汁酸代谢组的合理操作 转变为假说驱动的研究。这将支持我转变为一名独立的临床科学家 翻译和跨学科的传染病研究。这项工作将在俄亥俄州立大学完成 大学兽医学院在我的指导团队的指导下拥有全球公认的 在元基因组学、生物信息学、合理肠道微生物区系操作、宿主-微生物领域的专业知识 相互作用，与IBD发病机制。

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.