Mechanistic evidence was systematically reviewed on how major metabolites produced during fermentation of foods modulate obesity through gut microbiota remodeling and multiorgan metabolic regulation, with emphasis on the gut-brain axis, immunometabolic pathways, and epigenetic mechanisms. Obesity remains a major global public health challenge, and conventional management strategies are frequently limited by poor long-term efficacy, low adherence, and undesirable side effects. Increasing evidence positions the gut microbiome as a central metabolic organ that profoundly influences host energy homeostasis and adiposity. Individuals with obesity commonly have a disrupted intestinal microbial ecosystem characterized by reduced microbial diversity, depletion of health-promoting taxa, and enrichment of facultative pathogens, which compromise intestinal barrier function, promote chronic low-grade inflammation, and disturb systemic metabolic regulation. Fermented foods, integral to traditional diets, provide a rich source of live microorganisms and a diverse repertoire of bioactive metabolites produced through fermentation. A narrative review was conducted by synthesizing evidence from experimental, mechanistic, and preclinical studies on fermented foods, gut microbial ecology, fermentation-derived metabolites, and obesity-related metabolic pathways. Current evidence indicates that the anti-obesity effects of fermented foods are mediated not only by transient microbial colonization but, more importantly, by fermentation-derived metabolites such as short-chain fatty acids, conjugated linoleic acid, and indole derivatives (eg, indole-3-propionic acid). These metabolites exert multiorgan physiological effects through the gut-brain axis, immunometabolic pathways, and epigenetic regulation. Collectively, they modulate key processes, including enteroendocrine hormone secretion, hepatic glucose and lipid metabolism, browning of white adipose tissue, and central appetite control, ultimately contributing to metabolic restoration. This review provides a systematic and mechanistic evaluation of how major fermentation-derived metabolites counteract obesity by reshaping gut microbiota composition and functional activity across interconnected organ systems. The insights provide a strengthened conceptual framework for designing microbiota-directed nutritional strategies to sustain body-weight regulation.
