Short-chain fatty acids (SCFAs), principally acetate, propionate and butyrate, are produced by the gut microbiota through the fermentation of non-digestible carbohydrates. Beyond serving as energy substrates, SCFAs act as signalling molecules that influence metabolism, immune function and physiological homeostasis across multiple organ systems. This Review consolidates the fragmented literature on SCFAs and provides an overview of their production, metabolism and physiological actions. We discuss the microbial and dietary determinants of SCFA production, including the roles of the gut microbiome, cross-feeding interactions and dietary carbohydrates. We then examine the mechanisms through which SCFAs exert their effects, focusing on receptor-mediated signalling, epigenetic regulation and tissue-specific physiological functions. Finally, we evaluate the current evidence linking SCFAs to metabolic health and disease and consider the translational potential of targeting SCFA pathways through dietary and therapeutic approaches. At a time when inadequate dietary fibre intake is a growing public health concern, this Review highlights the physiological importance of SCFAs and their potential role in metabolic health and disease prevention. This Review provides an overview of the biology of short-chain fatty acids, with a focus on their synthesis, signalling and physiological effects, highlighting their translational potential for metabolic and inflammatory diseases.
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