Dietary-protein sources modulate host susceptibility to Clostridioides difficile infection through the gut microbiota

Clostridioides difficile causes nosocomial antibiotic-associated diarrhea on a global scale. Susceptibility to C. difficile infection (CDI) is influenced by the composition and metabolism of gut microbiota, which in turn are affected by diet. However, the mechanism underlying the interplay between diet and gut microbiota that modulates susceptibility to CDI remains unclear. Here, we show that a soy protein diet increases the mortality of antibiotic-treated, C. difficile-infected mice while also enhancing the intestinal levels of amino acids (aas) and relative abundance of Lactobacillus genus. Indeed, Ligilactobacillus murinus-mediated fermentation of soy protein results in the generation of aas, thereby promoting C. difficile growth, and the process involves the anchored cell wall proteinase PrtP. Thus, mutual interaction between dietary protein and the gut microbiota is a critical factor affecting host susceptibility to CDI, suggesting that dietary protein sources can be an important determinant in controlling the disease. [Display omitted] •A soy protein diet increases the susceptibility to C. difficile infection•A soy protein diet increases the gut amino acids, which promote C. difficile growth•A soy protein diet enhances the relative abundance of Lactobacillus genus•Lactobacillus supplies gut amino acids by digestion of soy protein Susceptibility to Clostridioides difficile infection is influenced by gut microbiota and diet. Yakabe et al. demonstrate that soy protein promotes the growth of C. difficile by enhancing the intestinal levels of amino acids (aas). Furthermore, soy protein enhances the relative abundance of Lactobacillus, which digests soy protein to generate aas.