Dietary and synbiotic strategy to limit gut microbiome dysbiosis and protect against Clostridioides difficile infection

限制肠道微生物群失调并预防艰难梭菌感染的饮食和合生策略

基本信息

批准号：
10396969
负责人：
Catherine Lozupone
金额：
$ 77.63万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-23 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10396969
关键词：
Affect Anaerobic Bacteria Antibiotics Apical Bacteria Bacterial Genes Bile Acids Butyrates Cancer Patient Carbon Cecum Chemicals Clostridium difficile Clostridium symbiosum Complex Coupled Diet Dietary Fats Dietary Fiber Dietary Intervention Epithelial Cells Excretory function Fatty acid glycerol esters Feces Fiber Germination Gluconates Gnotobiotic Goals Grant Growth Health Promotion Hematologic Neoplasms Hematology Hospitalization Hypoxia In Vitro Incidence Individual Infant Infection Infection prevention Intestines Lead Link Maintenance Malignant Neoplasms Metabolism Morbidity - disease rate Mus Oncology Oxidative Stress Oxygen Pathogenicity Pathology Patients Pharmaceutical Preparations Play Population Predisposition Prevention Prevention strategy Probiotics Process Production Recovery Recurrence Reproduction spores Resistance Risk Factors Role Sodium Source Stem cell transplant Taurine Testing Toxin Volatile Fatty Acids Work bile acid metabolism bile salts cohort dietary dysbiosis gut microbiome gut microbiota high risk high-fat/low-fiber diet insight intestinal barrier intestinal epithelium intestinal hypoxia microbial microbiome microbiome composition microbiota mortality novel novel strategies prebiotics prevent preventive intervention protective effect recurrent infection resilience saturated fat western diet

项目摘要

Summary Clostridioides difficile infection (CDI) is an important cause of morbidity and mortality and rates are on the rise, indicating that safe and new approaches are urgently needed for treatment and prevention. Emerging evidence suggests that a high-fat/low-fiber diet may promote CDI. Diets high in saturated fat lead to the production of primary bile acids that can promote infection by germinating C. difficile spores. Diets deficient in fiber perpetuate C. difficile colonization in mice, and this effect was linked at least in part with a loss of Short Chain Fatty Acids (SCFAs). Our preliminary murine studies show that a high-fat/low-fiber diet resulted in increased microbiome disturbance following broad spectrum antibiotic challenge, increased cecal levels of primary bile acids that germinate C. difficile spores, markedly decreased levels of secondary bile acids that can kill C. difficile, and increased morbidity and mortality upon C. difficile exposure. These results suggest that dietary intervention has promise for preventing CDI in individuals at high risk. Aim 1A will determine the effects of dietary levels of fat and fiber in preventing antibiotic induced gut microbiome disturbance and CDI, using conventional mice fed varied diets. Aim 1B will directly evaluate the role of increased intestinal levels of primary bile acids in the increased C. difficile pathogenicity by chemically inhibiting the ileal apical sodium-dependent bile salt transporter. Oncology patients have high incidence of CDI, driven by risk factors that include frequent hospitalization, antibiotic use, and use of chemotherapeutic drugs. Aim 2 will test a higher-fiber/lower-fat dietary intervention for prevention of C. difficile recurrence and maintenance of gut microbiome diversity in oncology patients. Production of SCFAs may be one mechanism contributing to the protective effects of fiber in CDI. Metabolism of the SCFA butyrate by intestinal epithelial cells plays a key role in the establishment of intestinal hypoxia, which is important because reversion to hypoxia is a key process in promoting the reestablishment of an anaerobe dominated complex gut microbiome following disturbance. SCFA production from fiber is limited in individuals with a low complexity facultative anaerobe- dominated microbiome, which is common in individuals with recurrent CDI. In our earlier work, we have identified butyrate-producers, including Clostridium symbiosum and Anaerostipes caccae that specialize to infant and disturbed guts and that can produce butyrate using a simple substrate, gluconic acid, as a sole source of carbon. Thus, in Aim 3 we will test the hypothesis that synbiotic treatment with disturbance adapted butyrate-producers and gluconic acid will increase butyrate production, increase intestinal hypoxia and facilitate the activity of anaerobic secondary bile acid producers that prevent CDI, using mice humanized with a disturbed/ low-complexity microbiota.

概括艰难梭菌感染（CDI）是发病率和死亡率的重要原因，且发病率呈上升趋势，表明迫切需要安全和新的治疗和预防方法。新出现的证据表明高脂肪/低纤维饮食可能会促进 CDI。高饱和脂肪饮食会导致初级胆汁酸可以通过使艰难梭菌孢子发芽来促进感染。饮食缺乏纤维使艰难梭菌在小鼠体内定植永久化，这种效应至少部分与短链的丧失有关脂肪酸 (SCFA)。我们的初步小鼠研究表明，高脂肪/低纤维饮食会导致广谱抗生素挑战后微生物组紊乱，初级胆汁盲肠水平增加使艰难梭菌孢子发芽的酸，显着降低了可以杀死艰难梭菌的次级胆汁酸的水平。艰难梭菌，并且暴露于艰难梭菌后发病率和死亡率增加。这些结果表明饮食干预有望预防高危人群的 CDI。目标 1A 将确定以下效果：膳食脂肪和纤维水平可预防抗生素引起的肠道微生物组紊乱和 CDI，使用喂食不同饮食的传统小鼠。目标 1B 将直接评估增加肠道的作用通过化学抑制回肠来增加艰难梭菌致病性中的初级胆汁酸水平顶端钠依赖性胆汁盐转运蛋白。受风险驱动，肿瘤患者 CDI 发生率较高因素包括频繁住院、抗生素使用和化疗药物的使用。目标 2 将进行测试高纤维/低脂肪饮食干预，用于预防艰难梭菌复发和维持肿瘤患者肠道微生物组的多样性。 SCFA 的生产可能是一种促进机制纤维对 CDI 的保护作用。肠上皮细胞对 SCFA 丁酸盐的代谢起着重要作用在肠道缺氧的建立中发挥着关键作用，这一点很重要，因为恢复缺氧是关键促进厌氧菌主导的复杂肠道微生物组重建的过程干扰。由纤维产生的短链脂肪酸 (SCFA) 仅限于具有低复杂性兼性厌氧菌的个体。占主导地位的微生物组，这在患有复发性 CDI 的个体中很常见。在我们早期的工作中，我们有确定了丁酸盐生产者，包括共生梭菌 (Clostridium symbiosum) 和 Anaerostipes caccae，它们专门生产丁酸盐婴儿和肠道紊乱，可以使用简单的底物葡萄糖酸作为唯一的底物产生丁酸盐碳源。因此，在目标 3 中，我们将检验这样的假设：合生素治疗与干扰适应丁酸盐生产者和葡萄糖酸将增加丁酸盐产量，增加肠道缺氧并促进厌氧次级胆汁酸生产者的活动，从而预防 CDI，使用具有紊乱/低复杂性微生物群的小鼠人源化。