Early periprosthetic joint infection constitutes one of the most frightening complications of joint replacement. Recently, some evidence has highlighted the potential link between dysregulation of the gut microbiota and degenerative diseases of joints. It has been hypothesized that microbiome dysbiosis may increase the risk of periprosthetic joint infection by facilitating bacterial translocation from these sites to the bloodstream or by impairing local or systemic immune responses. Although the processes tying the gut microbiome to infection susceptibility are still unknown, new research suggests that the presurgical gut microbiota-a previously unconsidered component-may influence the patient's ability to resist infection. Exploring the potential impact of the microbiome on periprosthetic joint infections may therefore bring new insights into the pathogenesis and therapy of these disorders. For a successful therapy, a proper surgical procedure in conjunction with an antibacterial concept is essential. As per the surgical approach, different treatment strategies include surgical irrigation, debridement, antibiotic therapy, and implant retention with or without polyethylene exchange. Other alternatives could be one-stage or two-stage revisions surgery. Interventions that either directly target gut microbes as well as interventions that modify the composition and/or function of the commensal microbes represent an innovative and potentially successful field to be explored. In recent times, innovative therapeutic methods have arisen in the realm of microbiome restoration and the management of gut-related ailments. These progressive approaches offer fresh perspectives on tackling intricate microbial imbalances in the gastrointestinal tract. These emerging therapies signify a shift towards more precise and individualized approaches to microbiome restoration and the management of gut-related disorders. Once a more advanced knowledge of the pathways linking the gut microbiota to musculoskeletal tissues is gained, relevant microbiome-based therapies can be developed. If dysbiosis is proven to be a significant contributor, developing treatments for dysbiosis may represent a new frontier in the prevention of periprosthetic joint infections.