Despite antibiotic stewardship and improved sanitation, Clostridioides difficile infection (CDI) remains a major public health problem. Dietary modification is promising for prevention. Using a murine model of CDI, we show that mice-fed low-fiber diets with both high- and low-fat content had high mortality, but this was ameliorated with fiber supplementation. We found increased presence of intestinal pathobionts, including Escherichia-Shigella, Proteus, and Enterococcus, in blood, liver, and spleen in mice on low-fiber diets. Elevated proinflammatory cytokines and blood urea nitrogen in mice that succumbed to illness before the experimental endpoint indicate sepsis as the cause of death. Despite higher mortality, mice fed a high-fat/low-fiber diet did not have higher cecal TcdA/B toxin levels, displayed less cecal and colonic inflammation 3 days post-C. difficile inoculation, and had a delayed onset of morbidity compared to other diets. Our data suggest dietary fiber is associated with reduced CDI morbidity, potentially via mediation of intestinal barrier function and an appropriate immune response to CDI, thereby protecting against secondary sepsis.
Keywords: Biological sciences; Diet; Health sciences; Systems biology.
© 2026 The Author(s).