Clostridoides difficile infection (CDI) is a leading cause of hospital-acquired diarrhea and there has been a steady increase in the number of new infections, emphasizing the importance of novel prevention strategies. Use of broad-spectrum antibiotics and disruption of the intestinal microbiome is one of the most important risk factors of CDI. We used a murine model of antibiotic-induced CDI to investigate the relative contributions of high dietary fat and low dietary fiber on disease pathogenesis. We found that high fat, but not low fiber resulted in increased mortality from CDI (HR 4.95) and increased levels of C. difficile toxin production compared to a regular low-fat/high-fiber mouse diet even though we did not observe a significant change in C. difficile carriage. The high-fat diet also increased levels of primary bile acids known to be germination factors for C. difficile spores. Mice fed low-fat/low-fiber diets did not show increased CDI pathogenesis, but did have a larger antibiotic-induced gut microbiome disturbance compared to mice fed a high-fiber diet, characterized by a greater decrease in alpha diversity. This microbiome disturbance was associated with a loss of secondary bile acids and short chain fatty acids, which are both microbial metabolic products previously shown to protect against CDI. These data suggest that a low-fiber diet contributes to antibiotic-induced dysbiosis, while a high-fat diet promotes CDI pathogenesis. These findings indicate that dietary interventions that increase fiber and decrease fat may be an effective prevention strategy for individuals at high risk of CDI.

Dietary fat and fiber impacts intestinal microbiome resilience to antibiotics and Clostridoides difficile infection in mice