Intestinal barrier permeability: the influence of gut microbiota, nutrition, and exercise

Abstract

The intestinal wall is a selectively permeable barrier between the content of the intestinal lumen and the internal environment of the body. Disturbances of intestinal wall permeability can potentially lead to unwanted activation of the enteric immune system due to excessive contact with gut microbiota and its components, and the development of endotoxemia, when the level of bacterial lipopolysaccharides increases in the blood, causing chronic low-intensity inflammation. In this review, the following aspects are covered: the structure of the intestinal wall barrier; the influence of the gut microbiota on the permeability of the intestinal wall via the regulation of functioning of tight junction proteins, synthesis/degradation of mucus and antioxidant effects; the molecular mechanisms of activation of the pro-inflammatory response caused by bacterial invasion through the TLR4-induced TIRAP/MyD88 and TRAM/TRIF signaling cascades; the influence of nutrition on intestinal permeability, and the influence of exercise with an emphasis on exercise-induced heat stress and hypoxia. Overall, this review provides some insight into how to prevent excessive intestinal barrier permeability and the associated inflammatory processes involved in many if not most pathologies. Some diets and physical exercise are supposed to be non-pharmacological approaches to maintain the integrity of intestinal barrier function and provide its efficient operation. However, at an early age, the increased intestinal permeability has a hormetic effect and contributes to the development of the immune system.

Keywords: HIF-1α; NF-κB; ROS; TLR4; inflammation; tight junction proteins.

FIGURE 1

The schematic structure of the intestinal barrier. For details see the text.

FIGURE 2

Potential mechanism of early and late activation of NF-κB-mediated pro-inflammatory response and bacterial translocation due to the disruption of the intestinal wall integrity. For details see the text. Abbreviations: NF-κB, nuclear factor κB; LPS, lipopolysaccharide; TLR4, toll-like receptor 4; TIRAP, toll/interleukin-1 receptor domain-containing adapter protein; MyD88, myeloid differentiation factor 88; IRAK 2/4, interleukin-1 receptor-associated kinase 2/4; TRAF6, TNF receptor-associated factor 6; TAK1, TGFβ-activating kinase 1; IκB, inhibitor of NF-κB; TRAM, TRIF-related adapter molecule; TRIF, TIR-domain-containing adapter-inducing interferon-β; P, phosphate; Ub, ubiquitin.

FIGURE 3

Influence of exercise-induced hypoxia on intestinal permeability. For details see the text. Abbreviations: HIF-1α/β, hypoxia-inducible factor 1α/β; HRE, hypoxia responsive element; DNA, deoxyribonucleic acid; TJ, tight junction; PHD, prolyl hydroxylase domain protein.

FIGURE 4

Potential consequences of acute intense exercise, unhealthy diet (e.g., high-fat diet) or dysbiosis on the intestinal barrier. Acute intense exercise contributes to the development of heat stress that the body cannot cope with, as well as a decrease in oxygen concentration, which causes hypoxia and the associated activation of HIF-1α. At the same time, hypoxia-related oxidative stress caused by an increase in the level of ROS can be observed. In general, these changes can cause the development of dysbacteriosis that can be associated with decreased expression of tight junction proteins and mucus degradation probably due to overgrowth of mucolytic bacteria. A high-fat diet also contributes to a decrease in tight junction proteins in combination with an increase in ROS production and the development of dysbacteriosis. In general, this contributes to a decrease in mucus thickness, an increase in the distance between neighboring epithelial cells and, as a result, an increase in the permeability of the intestinal barrier. This causes the development of an immune imbalance. Bacterial lipopolysaccharides are available as a result of increased permeability of the intestinal barrier and are recognized by TLR4 of the host’s epithelial and immune cells. This leads to the activation of NF-κB and production of pro-inflammatory cytokines such as IL-1β, IL-2, IL-6 triggering the development of inflammation. Abbreviations: ROS, reactive oxygen species; HIF-1α, hypoxia-inducible factor 1α; TLR4, toll-like receptor 4; NF-κB, nuclear factor κB; IL-1β/2/6, interleukin 1β/2/6. ↓, decreasing; ↑, increasing. Details of the structure of the intestinal barrier are shown in Figure 1.