Microbial Medium-Chain Fatty Acids Induce Hippocampal Neuronal Senescence via Histone Deacetylase Inhibition

The hypothesis: Age-related enrichment of Parabacteroides goldsteinii elevates luminal medium-chain fatty acids (MCFAs) that cross the gut barrier, enter circulation, and are taken up by hippocampal neurons via monocarboxylate transporters. Once inside, MCFAs act as endogenous histone deacetylase (HDAC) inhibitors, increasing histone acetylation at promoters of senescence-associated genes (e.g., Cdkn2a/p16, Cdkn1a/p21) and driving a cell‑autonomous senescent phenotype in neurons, independent of systemic IL‑1β or endothelial senescence. This predicts that (1) hippocampal HDAC activity will be reduced in aged mice colonized with aged microbiota, (2) pharmacological neutralization of MCFAs or genetic ablation of neuronal HDAC3 will prevent MCFA‑induced senescence, and (3) rescuing HDAC activity will improve cognition even when systemic inflammation remains high.

Experimental design: Use young germ‑free mice colonized with either young‑donor or aged‑donor fecal microbiota. A third group receives aged microbiota plus daily oral gavage of an MCFA‑binding polymer (e.g., sulfonated polystyrene) to sequester luminal MCFAs. Measure hippocampal HDAC activity (fluorometric assay), global H3K27ac levels (Western blot), and neuronal senescence markers (p16, p21, SA‑β‑gal) by immunohistochemistry. Assess neurogenesis (BrdU+/NeuN+ cells) and cognitive performance (Morris water maze). In parallel, treat a subset of aged‑microbiota mice with a neuron‑specific HDAC3 activator via AAV‑HDAC3 to test rescue. Controls include vehicle‑gavaged aged‑microbiota mice and young‑microbiota mice receiving the polymer.

Falsifiable outcomes: If MCFAs do not alter hippocampal HDAC activity or histone acetylation, or if MCFA neutralization fails to reduce neuronal senescence markers despite lowering luminal MCFA levels, the hypothesis is refuted. Conversely, if HDAC activation restores neurogenesis and cognition without altering circulating IL‑1β, TNF‑α, or endothelial senescence markers, it supports a direct microbiome‑epigenetic axis driving brain aging.

Mechanistic insight: While prior work links gut‑derived IL‑1β and phenylacetic acid to vascular and immune pathways, this hypothesis positions MCFAs as epigenetic modulators that bypass the immune‑vascular cascade and impose a cell‑intrinsic aging program on hippocampal neurons. It suggests that tracking the 'microbial metabolome age' (e.g., luminal MCFA concentration) could be a more proximal biomarker of brain aging than systemic inflammation, and that targeting neuronal HDAC activity may uncouple cognitive decline from chronic inflammation.