Hypothesis

We propose that the efficacy of microbiome‑based interventions for depression depends on the host’s capacity to convert primary to secondary bile acids via bacterial bile‑salt hydrolase (BSH) activity, which in turn modulates microglial activation through the TGR5 receptor and influences vagal afferent signaling.

Mechanistic reasoning

• Primary bile acids secreted by the liver are deconjugated by gut microbes expressing BSH, generating secondary bile acids such as deoxycholic acid (LCA) and ursodeoxycholic acid (UDCA).
• Secondary bile acids act as agonists of the TGR5 receptor on enteroendocrine L cells and on microglia, promoting anti‑inflammatory cytokine release and enhancing vagal tone.
• Individuals with a high relative abundance of BSH‑positive strains (e.g., Bifidobacterium longum, Lactiplantibacillus plantarum) will produce more secondary bile acids, leading to stronger TGR5‑mediated microglial suppression and greater vagal afferent firing when probiotics are administered.
• Conversely, low BSH activity yields insufficient secondary bile acids, blunting TGR5 signaling and limiting the antidepressant effect of probiotics, even if the strains themselves produce GABA or modulate tryptophan.

Testable predictions

1. In a randomized controlled trial of a GABA‑producing L. plantarum Lp815 supplement, baseline stool metagenomics quantifying BSH gene abundance will predict change in Hamilton Depression Rating Scale (HAM‑D) scores after 6 weeks.
2. Participants in the top quartile of BSH abundance will show a ≥30% reduction in HAM‑D, whereas the bottom quartile will show <10% change.
3. Pharmacologic inhibition of TGR5 (using antagonistic peptide) in a subset of responders will abolish the mood improvement, confirming receptor dependence.
4. Serum levels of secondary bile acids (LCA, UDCA) will rise proportionally to BSH abundance and correlate with increased vagal heart‑rate variability indices.

Falsifiability If BSH abundance fails to predict clinical response, or if TGR5 blockade does not attenuate the probiotic‑induced mood benefit despite confirmed target engagement, the hypothesis is refuted.

Integration with existing evidence This builds on shown vagus‑mediated antidepressant effects of probiotics [https://pmc.ncbi.nlm.nih.gov/articles/PMC12883760/] and on the role of microbial metabolites in gut barrier and neuroinflammation [https://pmc.ncbi.nlm.nih.gov/articles/PMC12366197/]. It also explains why high‑fiber diets improve mood variably: fiber boosts SCFA production but does not directly influence bile‑acid transformation unless BSH‑active taxa are present.

Implications Stratifying patients by functional microbiome profiles (BSH gene load) rather than taxa alone could rescue signal‑to‑noise in psychiatric microbiome trials and guide personalized pre‑biotic or bile‑acid‑supplement strategies.