Why Butyrate Supplementation Makes Chronic Gut Dysfunction Worse: The Data They Don't Show You — HDAC Inhibition: The Unexpected Consequence

HDACs are not demons. They&#8217;re normal regulatory enzymes. The balanced oscillation between histone acetylation and deacetylation allows cells to respond dynamically to their environment. Too much acetylation without deacetylation? The chromatin stays &#8220;open,&#8221; gene expression becomes chaotic, the cell loses epigenetic control. Low-dose, physiologic butyrate (produced from fiber fermentation in a healthy system) provides mild HDAC inhibition&#8212;enough to support anti-inflammatory gene programs without disrupting epigenetic stability. High-dose, pathologic butyrate (from supplementation in a compromised system where it can&#8217;t be oxidized) floods the cell with HDAC inhibition. The consequences: Excessive chromatin opening : Genes that should be silenced turn on. Oncogenes. Pro-inflammatory mediators. Metabolic chaos genes. Mast cell activation : HDAC inhibition drives mast cell degranulation and increases tryptase, histamine, and other mediators. This is why patients feel histamine symptoms worsen. Neuroinflammation : Butyrate crosses the blood-brain barrier. Excessive HDAC inhibition in microglia and astrocytes upregulates inflammatory cytokines. Brain fog, fatigue, anxiety, cognitive fog worsen. Epithelial permeability : Paradoxically, when HDAC inhibition becomes excessive, claudin expression becomes dysregulated. Tight junctions destabilize. LPS transloc