Hypothesis

We're proposing that age‑related depletion of microbial butyrate leads to loss of histone acetylation at super‑enhancers in both intestinal stem cells (ISCs) and enteric neurons, driving a coordinated transcriptional shift toward inflammatory and neuronal programs that fuels inflammaging and neurodegeneration.

Mechanistic rationale

• It's known that butyrate is a potent HDAC inhibitor that maintains high H3K27ac at enhancers [https://pmc.ncbi.nlm.nih.gov/articles/PMC12740102/].
• In aged muscle stem cells, ~38% loss of TAD insulation correlates with enhancer‑promoter rewiring toward inflammatory and neuronal genes [https://pmc.ncbi.nlm.nih.gov/articles/PMC12740102/].
• Similar TAD erosion likely occurs in gut compartments, but we lack direct data.
• Drosophila ISCs show H3K27me2‑driven lineage infidelity toward enteroendocrine cells when chromatin closes [https://elifesciences.org/articles/62250].
• Mammalian ISC exhaustion links to chromatin closure at Trithorax‑like targets such as ced‑6 and ci [https://pubmed.ncbi.nlm.nih.gov/39371074/].
• The microbiota‑gut‑brain axis exhibits dysbiosis‑driven cytokine elevation and reduced SCFAs that alter microglia via vagus and enteric nerves [https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1362239/full].
• Aging shifts microbiota composition in ways that contribute to neurological diseases like Parkinson’s and Alzheimer’s [https://pubmed.ncbi.nlm.nih.gov/38237031/].

Thus, falling butyrate levels remove HDAC inhibition, allowing HDACs to deacetylate H3K27ac at super‑enhancers, precipitating enhancer decay. Loss of enhancer activity in ISCs shifts lineage output toward pro‑inflammatory enteroendocrine cells; concurrent enhancer decay in enteric neurons reduces expression of genes that preserve barrier integrity and vagal signaling. The resulting cytokine surge and SCFA deficit then feed back to the microbiome, creating a vicious loop.

Testable predictions

1. Correlation – In aged mice, fecal butyrate concentration will inversely correlate with H3K27ac signal at super‑enhancers isolated from FACS‑sorted ISCs and enteric neurons (ChIP‑seq).
2. Rescue – Chronic oral butyrate supplementation in aged mice will restore H3K27ac at these super‑enhancers, normalize TAD insulation (Hi‑C), and reduce serum IL‑6/TNF‑α levels.
3. Necessity – Antibiotic‑induced depletion of butyrate‑producing taxa in young mice will recapitulate the aged enhancer phenotype and accelerate inflammaging markers.
4. Specificity – Supplementation with a non‑HDAC‑inhibiting SCFA (e.g., acetate) will not rescue enhancer acetylation, confirming the HDAC‑inhibition mechanism.

Falsifiability

If butyrate supplementation fails to alter super‑enhancer acetylation or inflammaging readouts despite restoring luminal concentrations, the hypothesis is refuted. Conversely, if enhancer changes occur without changes in butyrate levels, alternative mechanisms must be considered.

Implications

Demonstrating a metabolite‑driven epigenetic coupling between the microbiome and gut‑brain axis would reposition dysbiosis not merely as a source of inflammatory ligands but as a direct regulator of chromatin architecture, offering a precise target for epigenetic‑based anti‑aging interventions.