A High-Carbohydrate Diet Prolongs Dysbiosis and Clostridioides difficile Carriage and Increases Delayed Mortality in a Hamster Model of Infection.

Studies using mouse models of Clostridioides difficile infection (CDI) have demonstrated a variety of relationships between dietary macronutrients on antibiotic-associated CDI; however, few of these effects have been examined in more susceptible hamster models of CDI. In this study, we investigated the effect of a high-carbohydrate diet previously shown to protect mice from CDI on the progression and resolution of CDI in a hamster disease model, with 10 animals per group. Hamsters fed the high-carbohydrate diet developed distinct diet-specific microbiomes during antibiotic treatment and CDI, with lower diversity, persistent C. difficile carriage, and delayed microbiome restoration. In contrast to CDI protection in mice, most hamsters fed a high-carbohydrate diet developed fulminant CDI including several cases of late-onset CDI, that were not observed in hamsters fed a standard lab diet. We speculate that prolonged high-carbohydrate diet-specific dysbiosis in these animals allowed C. difficile to persist in the gut of the animals where they could proliferate postvancomycin treatment, leading to delayed CDI onset. This study, along with similar studies in mouse models of CDI, suggests some high-carbohydrate diets may promote antibiotic-associated dysbiosis and long-term C. difficile carriage, which may later convert to symptomatic CDI. IMPORTANCE The effects of diet on CDI are not completely known. Here, we used a high-carbohydrate diet previously shown to protect mice against CDI to assess its effect on a hamster model of CDI and paradoxically found that it promoted dysbiosis, C. difficile carriage, and higher mortality. A common thread in both mouse and hamster experimental models was that the high-carbohydrate diet promoted dysbiosis and long-term carriage of C. difficile, which may have converted to fulminant CDI only in the highly susceptible hamster model system. If diets high in carbohydrates also promote dysbiosis and C. difficile carriage in humans, then these diets might paradoxically increase chances of CDI relapse despite their protective effects against primary CDI.

An Aniline-Substituted Bile Salt Analog Protects both Mice and Hamsters from Multiple Clostridioides difficile Strains.

Clostridioides difficile infection (CDI) is the major identifiable cause of antibiotic-associated diarrhea. The emergence of hypervirulent C. difficile strains has led to increases in both hospital- and community-acquired CDI. Furthermore, the rate of CDI relapse from hypervirulent strains can reach up to 25%. Thus, standard treatments are rendered less effective, making new methods of prevention and treatment more critical. Previously, the bile salt analog CamSA (cholic acid substituted with m-aminosulfonic acid) was shown to inhibit spore germination in vitro and protect mice and hamsters from C. difficile strain 630. Here, we show that CamSA was less active in preventing spore germination by other C. difficile ribotypes, including the hypervirulent strain R20291. The strain-specific in vitro germination activity of CamSA correlated with its ability to prevent CDI in mice. Additional bile salt analogs were screened for in vitro germination inhibition activity against strain R20291, and the most active compounds were tested against other strains. An aniline-substituted bile salt analog, CaPA (cholic acid substituted with phenylamine), was found to be a better antigerminant than CamSA against eight different C. difficile strains. In addition, CaPA was capable of reducing, delaying, or preventing murine CDI signs with all strains tested. CaPA-treated mice showed no obvious toxicity and showed minor effects on their gut microbiome. CaPA's efficacy was further confirmed by its ability to prevent CDI in hamsters infected with strain 630. These data suggest that C. difficile spores respond to germination inhibitors in a strain-dependent manner. However, careful screening can identify antigerminants with broad CDI prophylaxis activity.

A High-Fat/High-Protein, Atkins-Type Diet Exacerbates Clostridioides (Clostridium) difficile Infection in Mice, whereas a High-Carbohydrate Diet Protects.

Clostridioides difficile (formerly Clostridium difficile) infection (CDI) can result from the disruption of the resident gut microbiota. Western diets and popular weight-loss diets drive large changes in the gut microbiome; however, the literature is conflicted with regard to the effect of diet on CDI. Using the hypervirulent strain C. difficile R20291 (RT027) in a mouse model of antibiotic-induced CDI, we assessed disease outcome and microbial community dynamics in mice fed two high-fat diets in comparison with a high-carbohydrate diet and a standard rodent diet. The two high-fat diets exacerbated CDI, with a high-fat/high-protein, Atkins-like diet leading to severe CDI and 100% mortality and a high-fat/low-protein, medium-chain-triglyceride (MCT)-like diet inducing highly variable CDI outcomes. In contrast, mice fed a high-carbohydrate diet were protected from CDI, despite the high levels of refined carbohydrate and low levels of fiber in the diet. A total of 28 members of the Lachnospiraceae and Ruminococcaceae decreased in abundance due to diet and/or antibiotic treatment; these organisms may compete with C. difficile for amino acids and protect healthy animals from CDI in the absence of antibiotics. Together, these data suggest that antibiotic treatment might lead to loss of C. difficile competitors and create a favorable environment for C. difficile proliferation and virulence with effects that are intensified by high-fat/high-protein diets; in contrast, high-carbohydrate diets might be protective regardless of the source of carbohydrate or of antibiotic-driven loss of C. difficile competitors.IMPORTANCE The role of Western and weight-loss diets with extreme macronutrient composition in the risk and progression of CDI is poorly understood. In a longitudinal study, we showed that a high-fat/high-protein, Atkins-type diet greatly exacerbated antibiotic-induced CDI, whereas a high-carbohydrate diet protected, despite the high monosaccharide and starch content. Our study results, therefore, suggest that popular high-fat/high-protein weight-loss diets may enhance CDI risk during antibiotic treatment, possibly due to the synergistic effects of a loss of the microorganisms that normally inhibit C. difficile overgrowth and an abundance of amino acids that promote C. difficile overgrowth. In contrast, a high-carbohydrate diet might be protective, despite reports on the recent evolution of enhanced carbohydrate metabolism in C. difficile.