Prebiotic dietary fibers, gut microbiota, and short-chain fatty acid production: from fermentation mechanisms to clinical translation.

The importance of the gut microbiota in regulating host homeostasis, immune responses, metabolism, and dietary interactions is increasingly recognized. Short-chain fatty acids (SCFAs), microbial metabolites produced through the fermentation of dietary substrates, play a central role in mediating these interactions. Drawing on mechanistic evidence from in vivo studies and insights from in vitro host-microbe fermentation models, this review critically examines how prebiotic dietary fibers have influenced the human gut microbial ecosystem, fermentation pathways, and SCFA production over the past decade. Major prebiotic classes, including fructooligosaccharides, galactooligosaccharides, inulin, resistant starches, pectins, xylooligosaccharides, human milk oligosaccharides, and selected polyphenols, are discussed in relation to their fermentability, microbial selectivity, and capacity to stimulate acetate, propionate, and butyrate production. Evidence from human intervention studies generally demonstrates modest yet biologically meaningful improvements in intestinal barrier integrity, inflammatory regulation, glucose homeostasis, lipid metabolism, and gut-brain communication. However, responses remain highly variable and are strongly influenced by baseline microbiota composition, habitual dietary patterns, medication exposure, intervention duration, and host metabolic status. Important gaps remain in linking mechanistic findings with clinical outcomes, explaining inter-individual differences in prebiotic responses, and standardizing methods for assessing microbiota and SCFAs. To address these limitations, this review proposes an integrated framework connecting prebiotic properties, microbial fermentation, SCFA-mediated host signaling, in vitro host-microbe models, and clinical evidence within the context of precision nutrition. This framework provides a systematic basis for understanding variable responses to prebiotics and for developing more personalized interventions. Future research should prioritize standardized analytical methods, well-designed stratified clinical trials, multi-omics integration, and computational approaches to identify responder phenotypes and optimize targeted prebiotic interventions.