The gut-thyroid axis: physiological regulation of barrier function, microbiota, endocrine signaling and the consequences on energy metabolism

The gut-thyroid axis is a bidirectional physiological network in which intestinal barrier function, microbiota composition, micronutrient absorption, and Thyroid Hormone (TH) homeostasis are closely interconnected. Growing evidence indicates that alterations in intestinal integrity and microbial metabolism can significantly influence TH bioavailability and systemic endocrine regulation, while THs themselves actively shape intestinal structure and function. In this review, we summarize current knowledge on the physiological mechanisms underlying the gut-thyroid crosstalk. We first describe the organization of the intestinal barrier, focusing on epithelial transporters, tight junction dynamics, immune-epithelial interactions, and their role in controlling permeability and nutrient absorption. We then discuss how THs, via TRα1 signaling, regulate intestinal epithelial differentiation, stem-cell activity, barrier maintenance, and innate immune defenses, including the induction of intestinal alkaline phosphatase. Conversely, we examine how the intestine contributes to TH homeostasis by modulating hormone absorption, transporter-mediated uptake, deiodinase-dependent activation and inactivation, microbial deconjugation, and enterohepatic recycling. We also review the intestinal handling of iodine and selenium, emphasizing how epithelial and microbial mechanisms influence TH synthesis and peripheral metabolism. Finally, we integrate these processes into a systemic framework linking gut-thyroid interactions to energy metabolism, inflammatory status, and metabolic flexibility. Overall, this review delineates the gut-thyroid axis as a key physiological interface coordinating endocrine and gastrointestinal function and discusses emerging perspectives for therapeutic strategies targeting intestinal health to optimize TH action.