Hypothesis

Variable success of microbiome‑targeted mental health interventions stems from differences in host capacity to internalize bacterial extracellular vesicles (BEVs) that carry neuroactive RNAs, short‑chain fatty acids, and peptidoglycan fragments. Individuals whose gut epithelium and microglia express high‑affinity scavenger receptors for BEVs will show robust epigenetic reprogramming of stress‑response genes after probiotic or FMT treatment, whereas low‑uptake phenotypes will not, explaining the observed heterogeneity in clinical trials.

Mechanistic basis

• BEVs released by gut microbes (e.g., Lactobacillus, Bifidobacterium) transport miRNA‑like species and butyrate that can cross the intestinal barrier and reach the brain via the vagus nerve or systemic circulation (5).
• Once in the brain, BEV cargo is taken up by microglia and neurons through receptors such as SR‑A (SCARA1) and LOX‑1 (OLR1), triggering downstream histone deacetylase inhibition and DNA methylation changes at promoters of BDNF, GABA‑synthesizing enzymes, and corticotropin‑releasing hormone (7).
• Polymorphisms in the genes encoding these receptors (e.g., SCARA1 rs4794405, OLR1 rs7882257) alter binding affinity and intracellular trafficking, creating a spectrum of vesicle‑uptake efficiency across the population.
• High‑uptake genotypes therefore experience stronger BEV‑mediated epigenetic changes, leading to measurable improvements in mood and cognition after microbiome modulation; low‑uptake genotypes receive insufficient neuronal signaling and show little benefit.

Testable predictions

1. Baseline genotyping predicts response – In a randomized controlled trial of a defined psychobiotic (e.g., Lactobacillus helveticus R0052 + Bifidobacterium longum R0175), participants stratified by SCARA1/OLR1 genotype will show a significant interaction: high‑uptake alleles confer ≥50 % greater reduction in depressive‑symptom scores (MADRS) compared with low‑uptake alleles (p < 0.01).
2. BEV levels correlate with clinical outcome – Serial stool and blood samples will reveal that individuals who exhibit a ≥2‑fold increase in circulating BEV‑associated butyrate and miR‑124 after treatment are the same genotypes that improve clinically (Spearman ρ > 0.6, p < 0.001).
3. Blocking vesicle uptake abolishes effect – In germ‑free mice colonized with a BEV‑producing strain, administration of an SR‑A antagonist (e.g., fucoidan) prior to probiotic feeding will prevent the increase in hippocampal BDNF and the rescue of anxiety‑like behavior, confirming causality.
4. Cross‑species validation – Human induced pluripotent stem cell‑derived microglia carrying CRISPR‑edited high‑ or low‑uptake receptor variants will differ in BEV internalization and subsequent HDAC activity, providing a mechanistic bridge from genetics to epigenetics.

Falsifiability

If genotype does not moderates probiotic efficacy, or if BEV blockade fails to alter neurochemical outcomes despite confirmed vesicle presence, the hypothesis would be refuted. Likewise, a lack of correlation between circulating BEV markers and symptom change across genotypes would undermine the proposed causal chain.

By integrating microbial vesicle biology with host‑genetic variability, this hypothesis shifts the focus from "fixing the microbiome" to "matching the microbiome to the host’s vesicle‑receiving capacity," offering a clear path toward truly personalized psychobiotic interventions.