Beyond Heat Stress: Intestinal Integrity Disruption and Mechanism-Based Intervention Strategies

Abstract

The current climate changes have increased the prevalence and intensity of heat stress (HS) conditions. One of the initial consequences of HS is the impairment of the intestinal epithelial barrier integrity due to hyperthermia and hypoxia following blood repartition, which often results in a leaky gut followed by penetration and transfer of luminal antigens, endotoxins, and pathogenic bacteria. Under extreme conditions, HS may culminate in the onset of "heat stroke", a potential lethal condition if remaining untreated. HS-induced alterations of the gastrointestinal epithelium, which is associated with a leaky gut, are due to cellular oxidative stress, disruption of intestinal integrity, and increased production of pro-inflammatory cytokines. This review summarizes the possible resilience mechanisms based on in vitro and in vivo data and the potential interventions with a group of nutritional supplements, which may increase the resilience to HS-induced intestinal integrity disruption and maintain intestinal homeostasis.

Keywords: heat stress (HS); intestinal integrity; nutritional supplements; reactive oxygen species (ROS); resilience pathways.

Figure 1

The sequence of events leading to heat stress-induced intestinal barrier damage. Hyperthermia induced by environmental or exertional heat stress (HS) stimulates the thermoregulatory mechanisms. (a) In the whole body, the thermoregulatory response shifts the splanchnic blood flow to the peripheral blood circulation, resulting in hypoxia in intestines and intestinal barrier dysfunction. (b) At the cellular level, hyperthermia leads to disruption of intestinal epithelial integrity, mainly by affecting the tight junctions (TJs) and adherens junctions (AJs), which are responsible for sealing the paracellular space between adjacent cells. Damage to TJs and AJs facilitates the transfer of luminal toxins and pathogens (light blue bodies) through the epithelial barrier into the lamina propria, harboring numerous immune cells that are activated and contribute to the exaggeration of the inflammatory reactions, which may further worsen the intestinal damage. ZO: zonula occludens protein.

Figure 2

Schematic illustration of the heat stress (HS)-induced heat shock response and oxidative stress response. (a) Cells under HS conditions activate the heat shock response pathway, which is initiated by translocation and trimerization of heat shock factor-1 (HSF1) into the nucleus, where it binds to the regulatory heat shock elements (HSE) in the promoter regions of heat shock protein (HSP) genes. (b) Oxidative stress induced by HS results in the liberation of nuclear factor erythroid 2 related factor 2 (Nrf2) from Kelch-like ECH-associated protein 1 (Keap1) and the translocation of Nrf2 into the nucleus where it binds to the antioxidant response element (ARE) in the promotor region of antioxidant target genes, driving their expression.

Figure 3

The pathways behind the protective effects of nutritional supplementation on HS-induced intestinal integrity disruption, inflammation, and oxidative stress. Pre-/probiotics (yellow square ⬜), α-lipoic acid (blue star ⭐), resveratrol (red circle ⚪), DHA/EPA (grey triangle 🔺) and amino acids (green diamond 🔷) not only restore intestinal epithelial integrity by increasing TJ/AJ protein and mucin expression, but also participate in anti-inflammation and stress resilience pathways. Normal arrow: enhancement or activation; bar-headed arrow: reduction or inhibition.