Gut microbial metabolism in aging: from metabolite production to organ-specific immunometabolic effects

Abstract

Age-related changes in gut microbiota metabolism are heterogeneous across populations and pathways, and their relationships with immunometabolism and organ phenotypes should be interpreted in the context of health status and disease. Microbial abundance or the concentration of a single metabolite does not, by itself, capture microbial production, host exposure, or effects in target tissues. This narrative review summarizes upstream influences, including gastrointestinal physiology, dietary substrates, comorbidities, and medications, and discusses the origins and host processing of major metabolites, their immunometabolic effects, and associated organ phenotypes. Studies in some older populations report lower fecal short-chain fatty acid concentrations. Microbiota-derived indole derivatives and host-synthesized, microbiota-modified bile acids show molecule- and population-specific patterns. Circulating concentrations of some host–microbe co-metabolites are higher in selected older or disease populations, but are also shaped by host biotransformation and clearance. Human evidence is predominantly observational and links metabolic features to health status or clinical phenotypes, whereas animal and cell studies support effects on barrier function, inflammation, and cellular metabolism under specific experimental conditions. Personalized nutrition, metabolite supplementation, selective targeting of microbial enzymes, and multi-omics-based responder stratification are promising research directions; prospective evidence that these strategies improve functional outcomes in older adults remains limited.