Bile Acids Are the Channel

01The evidence

• Interactions between bile acids and the gut microbiota are now implicated in neurological and psychiatric disorders, with receptor-level mechanisms proposed rather than mere correlations.Review, 2026
• Bile acids are established signalling molecules in the nervous system, acting through dedicated receptors rather than as detergents, which makes a receptor-mediated gut-brain route mechanistically plausible.Bile acids and neurological disease

02The tension

Vagotomy experiments give inconsistent results. Cytokine measurements correlate with behaviour but anti-cytokine treatments often fail to change it. Bile acid differences are consistently observed and consistently treated as confounders of liver or diet status rather than as the signal.

03The theory

The microbiota's most concentrated chemical output that can reach the brain is the secondary bile acid pool, produced by bacterial conversion of host primary bile acids. Those molecules are ligands for FXR and TGR5, both expressed in the brain, and their concentrations change by orders of magnitude with diet and with antibiotic exposure.

A receptor mechanism predicts a double dissociation. Blocking the receptor should abolish the behavioural effect regardless of the microbiome, while cutting the vagus should leave it intact as long as the bile acid pool circulates. Cytokine mechanisms predict the opposite pattern for vagotomy in some models; vagal mechanisms predict the reverse for both.

The dose-response is also distinctive. Receptor occupancy saturates, so the behavioural effect should saturate at a bile acid concentration well below the concentrations that cause systemic toxicity. That gives a measurable ceiling.

The theory is narrow on purpose. It does not claim that the microbiome affects behaviour only through bile acids. It claims that the reproducible, large effects that survive controls are carried by this channel, and that the others are smaller or conditional.

04What this is not

05Predictions

• P1FXR or TGR5 knockout should abolish the behavioural effect while vagotomy preserves it.
• P2Secondary bile acid concentrations should predict behavioural phenotype better than cytokine levels in the same animals.
• P3A bile acid sequestrant should reverse the effect within days, faster than a microbiome transplant could.

06What would refute it

An effect that survives receptor blockade, or disappears with vagotomy at unchanged bile acid levels, would relocate the mechanism.

07What it would change

It would give the microbiome-brain field a pharmacological handle, which is the thing it most conspicuously lacks.