<p>There is a complex, bidirectional interaction between the gut microbiota and the central nervous system, known as the gut-brain axis. Esketamine, as the right-handed isomer of ketamine, has been approved by the US FDA for the treatment of treatment-resistant depression (TRD), and its rapid antidepressant effect may involve modulation of gut microbiota. In addition, other ketamine isomers (such as R-ketamine) and racemic mixtures (R, S-ketamine) may also affect the gut microbiota through different pathways. This article reviews the potential regulatory mechanisms of ketamine and its isomers on gut microbiota, including anti-inflammatory effects, regulation of neurotransmitter metabolism, and intestinal barrier repair. It discusses, their clinical implications and future research directions.</p>