Stress-induced sympathetic overactivation as the critical risk for gastrointestinal inflammation: 3PM-guided conceptual innovation

The gastrointestinal tract is a major interface between the body and its external environment. The maintenance of intestinal homeostasis relies on the coordination of several systems, including the epithelial barrier, immune cells, enteroendocrine cells, and the autonomic nervous system (ANS). The loss of this balance can lead to chronic gastrointestinal disorders, among which inflammatory diseases represent major clinical and socioeconomic challenges. In this context, the ANS is known to influence gastrointestinal function, although the mechanisms through which it contributes to gut pathophysiology are not fully understood. This narrative review focuses specifically on the molecular and cellular pathways through which stress-associated sympathetic signals modulate intestinal inflammation, addressing, therefore, the complex interplay between sympathetic neurotransmitters, adrenergic receptor subtypes, immune cell populations, vascular and mitochondrial homeostasis, amongst other actors. To this end, the sympathetic overdrive phenotype (SOP), characterized by chronic sympathetic predominance, emerges as a powerful contributor to alterations in gut homeostasis through mechanisms involving excessive vasoconstriction associated with systemic ischemic lesions, oxidative stress overload, shifted mitochondrial homeostasis, and myriads of metabolic pathways. Recent pre/clinical experimental findings clearly demonstrate that sympathetic dominance influences the appearance and extent of gut inflammation in a context-dependent manner, including gender, hormonal status, age, environmental risks, genetic predisposition, suboptimal health conditions, stage of relevant pathologies, comorbidities, etc. In addition, clinical studies reported signs of autonomic dysfunction in patients with intestinal inflammation, suggesting the potential therapeutic value of ANS-based interventions. Contextually, here we propose that better understanding the SOP-mediated inflammatory mechanisms could enable a paradigm shift from the less effective reactive medical services to a proactive approach aiming to advance the overall management of gastrointestinal disorders and to benefit vulnerable subpopulations in primary care and affected patient cohorts in secondary care. To this end, highly dynamic mitochondrial homeostasis acts as the natural systemic biosensor and allows for proactive medical services such as predictive diagnostics and real-time treatment monitoring in the overall management of health conditions. The mitochondria-based treatments of compromised health conditions are systemic and complex, including rejuvenation of the mitochondrial population, reactive oxygen species (ROS) and liver detoxification, stabilised mitochondrial homeostasis and activated repair machinery under stress conditions, adequate energy supply and stress response, suppression of sterile chronic inflammation, optimal lifestyle, dietary habits, physical activity, sleep duration and quality, etc. – all strictly tailored to individualised patient profiles. Key research priorities are envisaged for developing 3PM-guided strategies discussed in this article.