Neural circuits and gut microbiota axis in heat acclimation: mechanistic insights and potential value

Heatstroke (HS) is a life-threatening heat-related syndrome whose pathogenesis involves disruption of central temperature regulation, cellular stress, and multi-organ dysfunction. As global warming intensifies and extreme heat events become more frequent, high-risk groups such as outdoor workers, firefighters, athletes, and the elderly face increasingly serious health threats. Currently, this condition is prevalent worldwide, and there is a lack of effective prevention strategies. This review focuses on the latest research advances in heat acclimation (HA) and systematically examines its protective effects in enhancing the body’s heat tolerance and preventing the onset of HS through multiple mechanisms. As is well known, the medial preoptic area (MPO) of the hypothalamus is the central hub of thermoregulation in mammals. Under repeated heat stimulation, the body initiates plastic remodeling of the MPO BDNF and MPO TRPV1 neuronal circuits in the medial preoptic area of the hypothalamus, and improve heat dissipation and alleviate anxiety via the MPO BDNF → DMH/rRPa and MPO TRPV1 → DMH/rRPa circuits, among these, the dorsomedial hypothalamus (DMH), as the core brain region involved in thermogenesis regulation, plays a key role in this descending pathway; simultaneously, the upregulation of heat shock protein 70 (HSP70) exerts anti-inflammatory effects and protects the intestinal barrier; HA also maintains intestinal barrier integrity by reshaping the gut microbiota and may modulate the central body temperature set point via the gut-microbiota-brain axis. We further discuss potential key targets of heat acclimation in the prevention of human heat stress, including MPO neuron circuits plasticity, HSP70 induction, and gut microbiota metabolites, and summarizes the current status of HA applications among specific populations, providing an in-depth analysis of the challenges faced in the practical implementation of HA programs. By integrating the neuro-immune-metabolic physiology mechanism, we propose a conceptual framework centered on “thermal endurance reconstruction.” This model integrates central thermoregulatory control, cellular stress responses, and the gut-microbiota axis, thereby filling a long-standing gap in our understanding of heat adaptation and identifying potential targets for future translational research on thermoregulatory resilience.