The emerging view on the roles of butyrate in <i>Clostridioides difficile</i> pathogenesis

The Centers for Disease Control and Prevention classifies <i>Clostridioides difficile</i> as an urgent threat to the nation's health, as it causes 450,000 infections, 15,000 deaths, and 1 billion dollars in excess healthcare costs per year in the United States. Current treatments for <i>C. difficile</i> infections (CDIs) are antibiotics and, in recurrent cases, microbiome restoration therapy (MRT). Antibiotics contribute to antibiotic resistance and recurrent CDIs. Although MRTs (e.g., defined consortia of microbes or fecal transplant) are increasingly accessible, the long-term sustainability and accessibility of these treatments remain to be determined. These limitations highlight the need for more precise strategies for coping with CDI. Because a disrupted (dysbiotic) gut microbiome is the primary risk factor for CDI, a better understanding of the interactions between <i>C. difficile</i>, the microbiome, and the host will aid the development of such treatments. Butyrate is a prominent microbiome-host co-metabolite that is influenced by host dietary fiber intake and differentiates healthy from dysbiotic gut ecosystems. Emerging evidence supports that butyrate is a key determinant of <i>C. difficile</i> fitness and pathogenesis. Here, we review the current literature and gaps in knowledge about how butyrate-rich gut environments exclude <i>C. difficile</i>, and how butyrate impacts <i>C. difficile</i> growth, metabolism, toxin production/release, and sporulation. We further discuss the implications of continued study of butyrate's impacts on CDI, including the eventual development of new strategies to mitigate CDI in at-risk human populations.