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

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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.