From cooperation to collapse: the diet-microbiota-host gene triad in disease and aging.

Symbiotic relationships are the basis of biological complexity. It can be traced back from ancient mitochondrial acquisition to modern host-microbiota interactions. In this review, we explore aging and disease susceptibility through the lens of a diet-microbiota-host gene triad, a dynamic symbiotic network in which dietary inputs, the gut microbiota, and the host genome co-regulate physiological equilibrium. The symbiotic triad evolved as nutrition was outsourced, with dietary and microbial components internalized by the host. Dietary components modulate microbial composition and metabolic activity. In contrast, microbial fermentation of nutrients produces short-chain fatty acids, vitamins, bile acids, and neuroactive compounds, which, in turn, influence host gene expression, immune responses, barrier integrity, nutrient preferences, and health. Host genes have also co-evolved as critical modulators of this triad, encoding nutrient sensors, immune effectors, and proteins that maintain microbial balance and prevent dysbiosis. Polymorphisms in key metabolic and immune genes fine-tune responses to dietary and microbial adaptations, building resilience across different contexts. As organisms age, this triadic equilibrium destabilizes, leading to reduced microbial diversity, compromised barrier integrity and function, and chronic inflammation that accelerates age-related pathologies. Therefore, understanding dietary, microbial, and genetic interdependencies and viewing aging and disease from this perspective offers a blueprint for developing personalized nutrition- and microbiome-targeted therapies to combat age-associated diseases and promote health and longevity.