Standard mouse diets lead to differences in severity in infectious and non-infectious colitis

<i>Clostridioides difficile</i> infects the large intestine and can result in debilitating and potentially fatal colitis. The intestinal microbiota is a major factor influencing the severity of disease following infection. Factors like diet that shape microbiota composition and function may modulate <i>C. difficile</i> colitis. Here, we report that mice fed two distinct standard mouse chows (LabDiet 5010 and LabDiet 5053) exhibited significantly different susceptibility to severe <i>C. difficile</i> infection. Both diets are grain-based with comparable profiles of macro and micronutrient composition. Diet 5010-fed mice had severe morbidity and mortality compared to Diet 5053-fed mice despite no differences in <i>C. difficile</i> colonization or toxin production. Furthermore, Diet 5053 protected mice from toxin-induced epithelial damage. This protection was microbiota-dependent as germ-free mice or mice harboring a reduced diversity microbiota fed Diet 5053 were not protected from severe infection. However, cohousing with mice harboring a complex microbiota restored the protective capacity of Diet 5053 but not Diet 5010. Metabolomic profiling revealed distinct metabolic capacities between Diet 5010- and Diet 5053-fed intestinal microbiotas. Diet 5053-mediated protection extended beyond <i>C. difficile</i> infection as Diet 5053-fed mice displayed less severe dextran sodium sulfate-induced colitis than Diet 5010-fed mice, highlighting a potentially broader capacity for Diet 5053 to limit colitis. These findings demonstrate that standard diet formulations in combination with the host microbiota can drive variability in severity of infectious and non-infectious murine colitis systems, and that diet holds therapeutic potential to limit the severity of <i>C. difficile</i> infection through modulating the functional capacity of the microbiota.IMPORTANCEDiet is a major modulator of the microbiota and intestinal health. This report finds that two different standard mouse diets starkly alter the severity of colitis observed in a pathogen-mediated (<i>Clostridioides difficile</i>) and non-infectious (dextran sodium sulfate) mouse colitis experimental systems. These findings in part explain study-to-study variability using these mouse systems to study disease. Since the gut microbiota plays a key role in intestinal homeostasis, diet-derived modulation of the microbiota is a promising avenue to control disease driven by intestinal inflammation and may represent a potential intervention strategy for at-risk patients.