A sucrose-rich diet promotes Clostridioides difficile carriage without prior antibiotics and significantly exacerbates both acute disease and long-term colonization

Abstract

Clostridioides difficile is a major cause of healthcare-associated diarrhea, with rising rates of community-acquired infections and asymptomatic carriage. While antibiotic exposure is a well-established risk factor, the role of diet in modulating susceptibility remains underexplored. Here, we demonstrate that a high-sucrose diet profoundly alters host susceptibility to C. difficile in a murine model. Mice consuming sucrose-rich chow exhibited exacerbated disease severity, characterized by increased weight loss, elevated clinical scores, heightened toxin burden, and persistent intestinal inflammation. Mice fed a high-sucrose diet failed to clear C. difficile and remained colonized long-term remaining susceptible to recurrent disease. Critically, high-sucrose-diet mice were susceptible to asymptomatic C. difficile carriage without prior antibiotic treatment, which progressed to overt CDI upon antibiotic exposure. Microbiome and metabolome profiling revealed that consumption of a sucrose-rich diet reshaped the gut microbiota, marked by blooms of Enterococcus and Akkermansia, a reduction in beneficial taxa, and remodeled the metabolome to favor C. difficile germination and growth. These findings establish dietary sucrose as a modulator of colonization resistance and identify a novel model of diet-induced asymptomatic carriage, with implications for the rising burden of community-associated C. difficile infection.