Unravelling three-way interactions between Clostridioides difficile, microbiota and the host

<i>Clostridioides difficile</i> infection is a global issue, representing a huge financial burden on healthcare systems worldwide which is further exacerbated by high recurrence rates. Infection is closely linked with the gut microbiome status, with successful <i>C. difficile</i> colonization usually occurring when there is dysbiosis. Our understanding of the molecular mechanisms underlying microbiota-mediated colonization resistance has advanced significantly in recent years, although the nuanced crosstalk occurring between <i>C. difficile</i>, the gut microbiota and host mucosa has yet to be fully elucidated. Deciphering these three-way interactions is critical for the development of effective therapeutic and prophylactic strategies. This review will discuss known interactions between this pathogen, the microbiota and the host in addition to the tools available to dissect complex microbial interchanges.