Nutrition as a Regulator of Tissue Crosstalk: Implications for Metabolic Health and Disease

Objectives To summarize evidence on the role of nutrition in regulating tissue crosstalk and to identify key knowledge gaps relevant to metabolic health and disease. Background Tissues continuously communicate to maintain metabolic balance. This inter-organ communication, referred to as tissue crosstalk, enables organs such as the liver, adipose tissue, skeletal muscle, gut, and immune system to coordinate responses to nutritional and environmental signals. Disruption of these pathways is increasingly recognized as a central feature of metabolic disorders, including obesity, type 2 diabetes, and non-alcoholic fatty liver disease. Nutrition plays a critical role in shaping tissue crosstalk beyond its role as a source of energy and building blocks. Dietary signals transmitted through hormones, cytokines, metabolites, and other mediators are strongly influenced by macronutrient quality and food matrix characteristics, thereby modifying metabolic and inflammatory signaling across organs. Methods This narrative review synthesizes evidence from human and experimental studies examining how nutrition regulates tissue crosstalk, with emphasis on macronutrient quality and gut microbiota–mediated mechanisms. Results The gut microbiota represents a key link between diet and systemic metabolic regulation. Dietary patterns influence microbial composition and activity, leading to the production of metabolites such as short-chain fatty acids, bile acid derivatives, and tryptophan-related2compounds. These microbial products act as signaling molecules that affect distant tissues and support coordinated metabolic responses. Evidence suggests that whole foods and food matrices may modulate these interactions more effectively than isolated nutrients or supplements. Conclusion Macronutrient quality and diet–microbiota interactions emerge as central regulators of inter- organ communication. Important gaps remain regarding the context-dependent effects of dietary protein quality and the influence of plant-based dietary patterns under conditions of positive energy balance. Addressing these gaps may help inform nutritional strategies aimed at supporting metabolic health beyond weight loss alone.