Dietary fiber modulates the window of susceptibility to Clostridioides difficile infection

Clostridioides difficile epidemiology is rapidly evolving: community-acquired cases are increasing relative to hospital-associated cases, with some patients remaining susceptible to C. difficile infection (CDI) for months after antibiotic usage. Understanding the factors involved in modulating the window of susceptibility to C. difficile is crucial to mitigating CDI cases in the general population. Here, we report that consumption of a low-fiber diet after antibiotic use contributes to a prolonged susceptibility to C. difficile in humans and mice, corresponding with a perturbed microbiome and altered bile acid milieu. We demonstrate that a low fiber diet leads to increased primary conjugated bile acids in humans, including bile acids known to promote C. difficile colonization such as taurocholate (TCA). Using a novel mouse model of CDI, we show that a fiber-free diet leads to prolonged and increased susceptibility to CDI, as well as shifts in bile acids and the microbiome, including depletion of commensals known to promote colonization resistance against C. difficile and a bloom in facultative anaerobes. We thus provide evidence that lack of dietary fiber extends dysbiosis post-antibiotic treatment that promotes enhanced CDI colonization and disease. Our findings suggest that in the context of antibiotic treatment, diet is a critical, modifiable risk factor for CDI. This has significant implications for individuals that are at high risk for contracting CDI and often consume a low-fiber diet, including IBD patients. Additionally, as community-acquired cases of CDI increase, increasing dietary fiber consumption surrounding antibiotic use may represent a low-cost, low-harm method to reduce the risk of CDI in the general population.