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Clostridioides difficile is a Gram-positive, obligate anaerobic, spore-producing intestinal opportunistic pathogen. CDI outbreaks in Europe and the Americas in recent years are a major health concern. Intestinal short-chain fatty acids (SCFAs) are an important energy source for colonic epithelial cells, and the roles of SCFAs in reducing intestinal inflammation, inhibiting intestinal tumors, and regulating gut microbial homeostasis are being actively researched. Furthermore, SCFAs attenuate CDI or directly inhibit C. difficile growth through different pathways in vivo and in vitro. This review assesses the role of SCFAs in CDI and discusses the potential use of these molecules as therapeutic targets for CDI. • Short-chain fatty acids inhibit Clostridioides difficile infection by enhancing host antibacterial immune response. • Dietary interventions regulate the production of short-chain fatty acids to reduce Clostridioides difficile infection. • The gut microbiota plays a role in regulating gut homeostasis by producing short-chain fatty acids. [ABSTRACT FROM AUTHOR]