Systemic Remodeling Under Cold Stress: From Gut Microbiota-Metabolite-Bloodstream Axis Dysregulation to Precision Microbiota Intervention

Background Cold stress imposes significant physiological challenges on mammalian homeostasis, demanding coordinated reorganization across neuroendocrine, metabolic, and immune systems. Classical thermal biology has focused predominantly on host-intrinsic thermogenic mechanisms, including shivering and uncoupling protein 1 (UCP1)-mediated non-shivering thermogenesis in brown adipose tissue (BAT). However, sustained cold exposure drives mitochondrial cataplerosis through excessive lipid mobilization and gluconeogenic TCA cycle intermediate depletion, exposing metabolic constraints within host-intrinsic pathways. Scope and Approach While previous literature has predominantly focused on general health implications or host-intrinsic thermogenic shifts, this review fills a critical knowledge gap by redefining cold adaptation as a barrier-constrained metabolic rescue operation. We distinguish our approach from existing reviews by explicitly targeting the host's "cataplerosis" deadlock and positioning the gut-vascular barrier (GVB) as the pivotal physical gatekeeper. Integrating evidence from microbiology, metabolomics, vascular biology, and synthetic biology, we critically examine cold-induced non-occlusive mesenteric ischemia (NOMI), GVB disruption marked by pathological PV1 overexpression, and the consequent cascade of systemic endotoxemia and thermogenic blunting. We further decode the dynamic succession of gut anaerobic communities, dissect secondary bile acid–TGR5 and SCFA–GPR43/41 signaling in driving anaplerotic compensation and adipose browning, and evaluate dietary and host heterogeneity as confounding modulators of microbiota-mediated thermogenesis. Key Findings and Conclusions The gut microbiota operates as a critical metabolic compensatory hub during cold stress, providing anaplerotic substrates to resolve host cataplerotic bottlenecks. However, this metabolic rescue is strictly contingent upon GVB integrity, as its ischemia-induced disruption allows endotoxin translocation that triggers an NF-κB-driven "thermogenic blunting" loop. Decoding this microbiota-driven thermogenic network not only supports the development of AI-guided, synthetic biology-engineered probiotics for extreme-environment protection, but also introduces a novel "thermal-mimetics" framework. This framework addresses the "evolutionary mismatch" associated with reduced natural cold exposure, offering promising therapeutic strategies for widespread metabolic conditions such as obesity and metabolic dysfunction-associated steatotic liver disease.