Work

Trimethylamine N-oxide (TMAO) in heat stroke: molecular mechanisms from gut dysbiosis to multi-organ injury

Year: 2026

Type: article

Abstract: Heat stroke, a life-threatening condition characterized by core hyperthermia (≥40 °C), central nervous system dysfunction, and multi-organ failure with mortality rates of 20–70%, is increasingly recognized as a systemic inflammatory and hemodynamic disorder rather than a purely thermoregulatory collapse. Among the emerging mediators of its pathophysiology, trimethylamine N-oxide (TMAO)—a gut microbiota-derived metabolite generated from dietary choline, L-carnitine, and betaine—has attracted growing attention as a molecular link between heat-induced gut dysbiosis and multi-organ injury. This review synthesizes current evidence on the physiological and molecular mechanisms whereby TMAO is proposed to aggravate heat stroke pathology, including: (1) NLRP3 inflammasome activation via ROS-TXNIP, SIRT3-SOD2-mtROS, and cathepsin B-mediated pathways; (2) endothelial dysfunction through tight junction disruption, eNOS/NO suppression, and ALDH2/ROS/GSDMD-dependent pyroptosis; (3) platelet hyperreactivity and thrombosis through enhanced Ca 2+ mobilization and IP 3 signaling; (4) mitochondrial oxidative stress and bioenergetic failure; and (5) neuroinflammation via the gut–brain axis. We further discuss the concentration-dependent duality of TMAO as a chemical chaperone versus a pathological mediator, and evaluate translational strategies targeting TMAO metabolism, including gut microbiota modulation, TMA lyase inhibition, and NLRP3 blockade. Importantly, the majority of the mechanistic evidence synthesized herein derives from disease models other than heat stroke (e.g., atherosclerosis, chronic kidney disease, obesity, aging, preeclampsia, and ischemic stroke); direct evidence obtained in heat-stroke settings remains limited, and several proposed pathways should be regarded as hypotheses awaiting heat-stroke-specific validation. Elucidating TMAO-dependent mechanisms may therefore inform future biomarker development and therapeutic investigation—both of which require clinical validation in heat-stroke patients—in this increasingly prevalent climate-sensitive disease.

Source: Frontiers in Physiology

DOI: 10.3389/fphys.2026.1983362

Authors: Qiong Wu, Guodong Lin, Yuanyuan Ou, Bo Ji, Zhiguo Pan, Yu Shao

Institutions: Chinese People's Liberation Army, Southern Medical University, Guangzhou University of Chinese Medicine

Language: English

Topic: Thermoregulation and physiological responses

Subfield: Physiology (medical)

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801