The interplay between the microbiome and immune cells in metabolic homeostasis and disease.

Microbiome-derived metabolites, including short-chain fatty acids, bile acids, indoles, and lipopolysaccharides, among other bioactives, modulate mammalian immune cells through a variety of molecular processes, including epigenetic remodeling, mitochondrial metabolic reprogramming, and regulation of mTOR and AMPK signaling pathways. These diverse signals shape inflammatory programs that influence metabolic outcomes in a context-dependent manner, which may sustain metabolic health or drive chronic inflammation impacting obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular diseases. Here, we review these metabolite-driven immune-metabolic influences and highlight innovative directions in their exploration, including integration of spatial and single-cell multi-omics to deconvolute microbiome-derived signaling networks within metabolic tissues. We further outline emerging microbiome-based therapeutic strategies targeting immune pathways in cardiometabolic disease, ranging from personalized nutrition, precision probiotics, and microbial consortium transplantation to metabolite-based postbiotics. Collectively, advancing our understanding of host immune-microbiome-metabolic interactions may support the development of targeted interventions for the prevention and treatment of cardiometabolic diseases.