From energy substrate to guardian: the dual roles of short-chain fatty acids in gut health of animals

Short-chain fatty acids (SCFA), mainly acetate, propionate, and butyrate, are produced by anaerobic microbial fermentation of indigestible dietary components in the animal gut. These metabolites are important energy substrates, yet their influence extends well beyond energy supply to gut and systemic homeostasis. This review summarizes the production, transport, and physiological roles of SCFA in gastrointestinal health. Short-chain fatty acids are produced by anaerobic microbial fermentation, but their major substrates and sites of production differ between monogastric and ruminant animals. In monogastric animals, SCFA originate primarily from hindgut fermentation of dietary fiber, whereas in ruminants, microbial breakdown of feed carbohydrates in the rumen is the dominant source. Their absorption and transport rely on passive diffusion and carrier-mediated mechanisms involving monocarboxylate transporters (MCT), sodium-coupled monocarboxylate transporters (SMCT), and anion exchangers. Within the intestinal mucosa, SCFA regulate energy metabolism, epithelial barrier integrity, microbial composition, and immune homeostasis. Their molecular targets include G protein-coupled receptors (GPCR) and AMP-activated protein kinase (AMPK), they also inhibit histone deacetylases (HDAC). These signals feed into downstream cascades along the mitogen-activated protein kinase (MAPK), mammalian target of rapamycin-signal transducer and activator of transcription 3 (mTOR–STAT3), and nuclear factor kappa-B (NF-κB) pathways. Through these mechanisms, SCFA strengthen tight junction assembly, stimulate the secretion of mucin and defensins, suppress pathogen expansion, and promote colonization of beneficial microbiota. They also promote the differentiation of regulatory T cells (Treg) and the production of anti-inflammatory cytokines, helping maintain mucosal immune balance. In conclusion, SCFA act concurrently as metabolic intermediates, epigenetic modulators, and immune mediators, coupling microbial fermentation to host physiology. Understanding their multifaceted actions offers novel insights into nutritional strategies and microbial modulation to improve gastrointestinal health and productivity in animals.