Why Butyrate Supplementation Makes Chronic Gut Dysfunction Worse: The Data They Don't Show You — Colon Cancer Risk and the Butyrate Paradox

This is perhaps the most provocative implication. Butyrate, in physiologic amounts, has protective effects against colorectal cancer through multiple mechanisms: histone deacetylase inhibition supporting p21 upregulation (tumor suppressor), differentiation signaling, and other pathways. But in the setting of chronic dysbiosis, high systemic butyrate (from failed oxidation), and excessive HDAC inhibition? The risk calculus inverts. Excessive HDAC inhibition drives: Oncogene activation : Chromatin opening in regions with oncogenic promoters. Upregulation of growth-promoting genes. Genomic instability : Loss of epigenetic silencing of transposable elements and other mutagenic regions. Epithelial proliferation without maturation : HDAC inhibition pushes cells toward proliferative states without proper differentiation. In a chronically inflamed epithelium, this is a pre-malignant signal. Patients with long-standing SIBO, dysbiosis, elevated butyrate, and failed oxidation pathways aren&#8217;t just uncomfortable. They&#8217;re at elevated cancer risk from the very interventions meant to protect them. This isn&#8217;t proven in controlled trials (yet). But the mechanistic logic is sound.