The Microbiome–Sleep–Psychiatric Axis: Does Circadian Disruption Mediate Microbiome-Associated Psychiatric Risk?

The gut microbiome is studied as a modulator of brain function and a contributor to psychiatric pathophysiology, while sleep and circadian disruption are transdiagnostic psychiatric risk factors. Because the gut microbiota oscillates with host circadian clocks, a three-way “microbiome–sleep–psychiatric axis” has been proposed in which circadian disruption mediates microbiome-associated psychiatric risk. This narrative review translates that axis into an explicit counterfactual mediation framework with named paths, stated identification assumptions, and testable predictions, and appraises the evidence against it. We searched PubMed/MEDLINE, Embase, Scopus, and Web of Science to 30 June 2026, report the strategy in full, and tabulate 18 key human studies and each candidate pathway. The mediator–outcome path is well supported in humans, including by Mendelian randomization, but effect sizes are modest (insomnia–depression pooled OR ≈ 2.1–2.8). The exposure–mediator path is demonstrated only in rodents under extreme perturbation, and microbiome–psychiatry associations are small (β-diversity explaining roughly 0.5–2% of variance). Candidate pathways – glucocorticoid rhythmicity, tryptophan–kynurenine metabolism, short-chain fatty acid signalling, vagal transmission, and microglial–neuroimmune crosstalk – each support one limb of the chain and none the whole. Critically, no human study has estimated any mediated effect, and no cohort has measured the microbiome, a validated circadian phenotype, and psychiatric outcomes with temporal ordering. Existing data remain equally compatible with reverse causation and with confounding by shared environmental disruptors. The circadian mediation hypothesis is therefore falsifiable but untested; we specify the cohort, Mendelian randomization, natural-experiment, and interventional designs that would confirm or refute it.