Original Article: Bile Acids Combat Heat Waves – Heat Stress, Retreat! Retreat! Retreat!

Heat Waves Strike: The Devastating Impacts of Heat Stress

Thermal oxidative stress is a pathological process in animals under high-temperature conditions, characterized by redox imbalance caused by heat accumulation, excessive accumulation of reactive oxygen species (ROS), cellular damage, and multiple organ dysfunction.

The pathological cascade proceeds as follows:Elevated environmental temperature → increased core body temperature → ROS burst → collapse of the antioxidant system → damage to biological macromolecules → activation of apoptotic pathways → multiple organ dysfunction (intestinal, immune, reproductive).

Initiation of heat stress and heat imbalanceWhen the ambient temperature exceeds an animal’s thermoneutral zone, heat dissipation efficiency falls behind heat production (e.g., metabolic heat, exercise-induced heat), leading to a rise in core body temperature.

Triggering of oxidative stressHeat stress disrupts the pro-oxidant/antioxidant balance through ROS explosion and collapse of the antioxidant system.

First, the activities of key antioxidant enzymes (SOD, CAT, GSH-Px) are inhibited, accompanied by depletion of reduced glutathione (GSH).

Second, insufficient activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway reduces the expression of downstream antioxidant genes (e.g., HO-1, SOD1), impairing efficient ROS scavenging.

Cellular injury and apoptosis Excessive ROS directly attack biological macromolecules via lipid peroxidation and protein denaturation, and induce programmed cell death through multiple signaling pathways, including the mitochondrial pathway, lipid metabolism-mediated pathway, and endoplasmic reticulum stress pathway.

System-level pathological effectsThermal oxidative stress causes systemic damage via inter-organ crosstalk, including metabolic disorders (abnormal glucose and lipid metabolism, acidosis), intestinal barrier disruption, immune dysfunction, reproductive impairment, amplified thermal inflammation, reduced feed intake, and declined production performance (growth arrest, decreased milk/egg yield).

The Antioxidant Defense System in Animals

Under physiological conditions, animals maintain a dynamic redox balance via a sophisticated regulatory network: oxidation provides energy and supports physiological functions, while reduction prevents stress injury caused by excessive oxidation. This balance relies on a multi-level defense system.

Biomarkers of oxidative damageThe severity of lipid peroxidation and cellular injury can be reflected by malondialdehyde (MDA) content. MDA is a stable aldehyde produced from the breakdown of lipid peroxides, with strong cytotoxicity. It can crosslink with proteins and DNA, exacerbating cellular damage.Elevated MDA content = attack on the cell membrane system + vicious cycle of oxidative damage.

Synergistic defense of antioxidant enzymesThe body clears ROS through enzymatic cascade reactions. Superoxide dismutase (SOD) catalyzes the dismutation of superoxide anion (·O₂⁻) into hydrogen peroxide (H₂O₂). Glutathione peroxidase (GSH-Px) reduces H₂O₂ to water using reduced glutathione (GSH). GSH contains a reactive -SH group that directly scavenges free radicals and protects sulfhydryl proteins from oxidative damage.

Total antioxidant capacity (T-AOC) is a key indicator for evaluating the overall antioxidant potential of all enzymatic and non-enzymatic antioxidants in vivo.Under heat stress, however, hepatic SOD activity and GSH content are significantly inhibited in animals, which is closely related to oxidative stress induced by heat exposure.

The Nrf2 signaling pathwayThe Nrf2-mediated signaling pathway plays a critical role in protecting against oxidative stress injury. Numerous studies confirm that Nrf2 activation markedly alleviates heat stress damage in animals.

Under normal conditions, Nrf2 resides mainly in the cytoplasm, forming an inactive complex with its chaperone protein Keap1. Stimuli such as heat stress trigger dissociation of the Keap1–Nrf2 complex, allowing Nrf2 to translocate into the nucleus. Nrf2 then binds to the antioxidant response element (ARE) and initiates the transcription of downstream genes (e.g., HO-1, NQO1, SOD, GSH synthetase), enhancing detoxification and antioxidant capacity.Activation of the Nrf2 pathway is a key target for nutritional intervention to relieve heat stress injury.

 Figure 1. Bile Acids Alleviate Thermal Oxidative Stress via the Nrf2 Pathway

A Game-Changer for Heat Stress: The Remarkable Effects of Bile Acids

Wang Shoukai (2019) reported that 100 mg/kg chenodeoxycholic acid (CDCA) significantly increased hepatic SOD activity and GSH content in heat-stressed mice, improving hepatic antioxidant capacity and exerting protective effects against hepatic oxidative damage caused by heat stress. Meanwhile, CDCA extremely significantly upregulated the protein expression of Nrf2, HO‑1 and NQO1 to exert anti‑heat stress effects, indicating strong application potential of CDCA in alleviating heat stress.

Long Wenhao (2025) found that bile acid supplementation significantly increased GSH content and T‑AOC activity, markedly reduced MDA content, and tended to increase CAT and SOD activities in Mystus wyckioides.

SuCetal. (2022) demonstrated that dietary bile acids significantly enhanced GSH content, T‑AOC and SOD activity in the hepatopancreas of Litopenaeus vannamei.

LEIWetal. (2023) observed that bile acids positively regulated the nuclear factor erythroid 2‑related factor 2 (Nrf2)–Kelch‑like ECH‑associated protein 1 (Keap1) pathway at the antioxidant gene level in ricefield eels (Monopterus albus).

First, in response to the reactive oxygen species (ROS) burst induced by high temperature, bile acids strongly activate the Nrf2 pathway, sharply increase the production of antioxidant enzymes including SOD and glutathione, decrease the level of the oxidative damage marker MDA, and effectively block lipid peroxidation injury of cell membranes.

Second, under stress conditions, the liver bears an excessive detoxification burden. Bile acids significantly enhance hepatic detoxification enzyme activity by activating the FXR receptor, accelerate toxin metabolism, and restore the liver from an overloaded state to efficient function.

Third, by promoting fat emulsification and absorption, bile acids enable animals to efficiently obtain energy even under reduced appetite, thus avoiding declines in production performance.