Endotoxin, also known as lipopolysaccharide (LPS), is a major component of the outer leaflet of intestinal Gram-negative bacteria and consists of carbohydrate-containing glycolipids and lipid A moieties. Several critically ill patients with non-gram-negative bacterial infections and patients in stress states suffer from endotoxemia, and endotoxin in plasma mainly results from the absorption of intestinal endotoxin, so intestinal endotoxemia is almost universal. It is often the main cause of death in critically ill patients and is a pathophysiological process they experience. One of the major functions of the gut is to prevent the translocation of bacteria and endotoxins within the gut lumen to other tissues. Known as bacterial translocation or endotoxin translocation, the loss of intestinal shielding functions can lead to a large migration of bacteria and endotoxins into extraintestinal tissues. Toxins originate from the translocation of intestinal endotoxins, which is called gut-derived endotoxemia. The pathogenesis of gut-derived endotoxemia may be related to the increased production and uptake of intestinal endotoxins (translocation of intestinal microorganisms).
Figure 1. Comparison between a healthy and "leaky gut". (Mohammad S, et al., 2021)
The human gut has several lines of defense that prevent the transfer of microorganisms or microbial products into the blood, and this multilayered barrier constitutes the largest interface between the external environment and the host. The gut is the organ that digests food and absorbs nutrients and is where a large number of debris passes or lodges, including unabsorbed food components, resident bacteria, and pathogens. Therefore, the gut wall has a special barrier system that allows nutrients to be absorbed while blocking substances that should not enter the body. The barrier system is physically supported by the epithelial cells that make up the intestinal wall, and the spaces between the epithelial cells are tightly sealed by tight junctions (made up of proteins). This barrier contains mucin-like sticky glycoproteins from epithelial cells and releases antimicrobial substances that keep pathogens away.
If the tight junctions that seal the gaps between epithelial cells loosen for any reason, the barrier system collapses, and material from the gut can pass through the gaps between epithelial cells into the body, a phenomenon known as a leaky gut. The LPS in Gram-negative bacteria strongly induces inflammation if Gram-negative bacteria enter the body. Gut microbiota is considered to be the main source of LPS in metabolic endotoxemia. A leaky gut occurs as a result of LPS altering the tight junction protein assembly of the intestinal epithelium, leading to endotoxemia and overproduction of proinflammatory cytokines. Studies have shown that the intact intestinal mucosa has little absorption of endotoxin, but in the following cases, it leads to increased production and uptake of intestinal endotoxin.
Long-term use of glucocorticoids, protein malnutrition, intensive care patients, severe trauma, and starvation can impair the body's general immune function, destroy the intestinal mucosal immune barrier, and allow endotoxin to enter the bloodstream.
Mucosa ischemia, atrophy, damage, and shedding caused by various trauma, shock, ionizing radiation, various inflammations, and vascular factors can all cause endotoxin displacement and intestinal-derived endotoxemia.
The normal intestinal flora is dominated by obligate anaerobic bacteria, which limits the contact of pathogenic intestinal microorganisms and endotoxins with the intestinal mucosa. The long-term application of broad-spectrum antibiotics reduces the number of antibiotic-sensitive anaerobic bacteria, leading to the proliferation of Gram-negative bacteria, breaking through the mucosal barrier and translocating into the blood circulation.
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