Hypothesis: Butyrate‑induced ketogenesis uncouples autophagy activation from synaptic loss in mood regulation

Core idea When gut‑derived butyrate raises hepatic β‑hydroxybutyrate (BHB), neurons receive an alternative fuel that satisfies AMPK‑driven energy demand without triggering the autophagic consumption of synaptic proteins. In this scenario, prebiotic‑mediated microbiome shifts improve mood not merely by boosting bulk autophagy but by rerouting the autophagic program toward mitophagy and lipid droplet clearance while preserving synapses via ketone‑supported ATP production.

Mechanistic chain

1. Prebiotics increase butyrate‑producing taxa → ↑ colonic butyrate absorption.
2. Butyrate acts as an HDAC inhibitor in hepatocytes, stimulating HMGCS2 and boosting ketogenesis → ↑ plasma BHB.
3. BHB crosses the blood‑brain barrier, serving as a neuronal energy substrate and also inhibiting neuronal HDACs, which further upregulates autophagy genes (LC3, BECN1) but in a context of ample acetyl‑CoA.
4. AMPK activation (from mild energy stress) drives ULK1‑dependent autophagosome formation; however, sufficient ATP from β‑oxidation of BHB prevents the autophagic machinery from targeting synaptic vesicles or postsynaptic densities, steering it instead toward damaged mitochondria (mitophagy) and lipid droplets.
5. The net effect is reduced neuroinflammation (via microglial mitophagy) and preserved synaptic density, translating into anxiolytic and antidepressant‑like behavior.

Testable predictions

• In mice fed a prebiotic (e.g., inulin), plasma BHB will rise concurrently with increased brain LC3‑II/I ratio and reduced phospho‑S6 (a marker of mTOR inhibition).
• Pharmacological blockade of ketogenesis (using mercaptoacetate) will abolish the prebiotic‑induced increase in BHB and prevent the improvement in sucrose‑preference and forced‑swim test performance, despite unchanged autophagy markers.
• Cell‑specific RNA‑seq will show that neurons from prebiotic‑treated, BHB‑blocked mice exhibit up‑regulated autophagy‑related transcripts alongside heightened expression of synaptic‑degradation genes (e.g., ubiquitin‑proteasome subunits), whereas mice with intact ketogenesis show selective enrichment of mitophagy genes (Pink1, Parkin) and stable synaptic‑protein levels.
• In human pilots, CSF BHB levels will correlate positively with CSF LC3‑II/I ratio and inversely with hippocampal‑volume loss only in participants receiving a personalized prebiotic regimen.

Falsifiability If prebiotic administration improves mood‑related behaviors without any detectable rise in circulating BHB, or if ketogenic inhibition fails to block the behavioral benefit while autophagy flux remains elevated, the hypothesis would be refuted. Conversely, a consistent link between BHB elevation, autophagy selectivity, and synaptic preservation across species would support the claim.

References

• Gut‑derived SCFAs suppress histone acetylation via HDAC inhibition, upregulating autophagic function as a metabolic adaptation to nutrient stress [https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.817433/full].
• Butyrate‑producing bacteria restore autophagy in germ‑free models by normalizing energy metabolism [https://pmc.ncbi.nlm.nih.gov/articles/PMC6984609/].
• Microglial autophagy clears neurotoxic proteins and prevents neurodegeneration [https://doi.org/10.1038/s41467-020-15119-w].
• Sustained AMPK hyper‑activation in neurons causes autophagy‑mediated synaptic loss [https://doi.org/10.1038/s41419-019-1464-x].
• Gut‑derived LPS suppresses hippocampal autophagy and induces depression‑like behaviors [https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.817433/full].
• Reduced BECN1 autophagy protein appears in post‑mortem hippocampus of MDD patients [https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.817433/full].

Implications This reframes the autophagy‑mood link from a nonspecific ‘clean‑up’ to a fuel‑dependent triage system: the same autophagic signal can be neuroprotective or destructive depending on whether the neuron can meet its ATP demand via ketone bodies. Personalized prebiotic prescriptions could therefore be paired with metabolic profiling (plasma BHB, hepatic HMGCS2 expression) to predict who will obtain a synaptic‑sparing autophagic response.