Moving towards a systems psychiatry paradigm embraces the inherent complex interactions across all levels from micro to macro and necessitates an integrated approach to treatment. Cortical 5-HT2A receptors are key primary targets for the effects of serotonergic psychedelics. However, the therapeutic mechanisms underlying psychedelic therapy are complex and traverse molecular, cellular, and network levels, under the influence of biofeedback signals from the periphery and the environment. At the interface between the individual and the environment, the gut microbiome, via the gut-brain axis, plays an important role in the unconscious parallel processing systems regulating host neurophysiology. While psychedelic and microbial signalling systems operate over different timescales, the microbiota-gut-brain (MGB) axis, as a convergence hub between multiple biofeedback systems may play a role in the preparatory phase, the acute administration phase, and the integration phase of psychedelic therapy. In keeping with an interconnected systems-based approach, this review will discuss the gut microbiome and mycobiome and pathways of the MGB axis, and then explore the potential interaction between psychedelic therapy and the MGB axis and how this might influence mechanism of action and treatment response. Finally, we will discuss the possible implications for a precision medicine-based psychedelic therapy paradigm.