Category: signaling
Short-chain fatty acids (SCFAs — acetate C2, propionate C3, butyrate C4) are the dominant end-products of gut bacterial fermentation of dietary fiber + resistant starch + some peptides. Concentrations in colonic lumen reach 50–150 mM total; ratio ~60:20:20 (acetate:propionate:butyrate). Functions: (1) Colonocyte fuel — butyrate is the preferred energy substrate for colonocytes (β-oxidation in mitochondria → 70% of colonocyte ATP); deficiency contributes to "starved-colonocyte" hypothesis of UC. (2) Histone deacetylase inhibition — butyrate (and propionate, weaker) inhibit class I HDACs (HDAC1/2/3/8) → hyperacetylation → tumor-suppressor gene re-expression + Treg differentiation (FoxP3 induction via HDAC inhibition + GPR43) + BDNF (cross-link [[bdnf_trkb_neurotrophic]]). (3) GPCR signaling — GPR43 (FFAR2) responds to acetate + propionate > butyrate → L-cell GLP-1 + PYY secretion (cross-link [[fxr_tgr5_bile_acid_receptor]] + [[insulin_glucose_homeostasis]]); GPR41 (FFAR3) similar; GPR109A responds to butyrate > niacin → anti-inflammatory in macrophages. (4) Mucin synthesis + barrier function — butyrate ↑MUC2, ↑tight junctions (claudins) → gut-barrier integrity. (5) Immune regulation — local IL-10/Treg induction (mucosal immunity); systemic via SCFA spillover to portal then peripheral circulation. Clinical relevance: Clostridium difficile risk after broad-spectrum antibiotics (loss of butyrate-producing Faecalibacterium, Roseburia, Eubacterium); IBD (↓butyrate-producers); colon cancer (chemoprevention via HDAC inhibition); metabolic syndrome (↑acetate → adipogenesis + lipogenesis). Therapeutics: dietary fiber (psyllium, inulin, oat β-glucan, resistant starch) → fermentable substrate; FMT for rCDI; rifaximin (non-absorbed antibiotic) for IBS-D + HE; metformin partly works via microbiome (↑Akkermansia + butyrate-producers). Cross-links: [[bdnf_trkb_neurotrophic]], [[fxr_tgr5_bile_acid_receptor]], [[insulin_glucose_homeostasis]], [[ampk_signaling]].