Gut leakage
Emerging studies have showed different causes of gut leakage(Figure 2), however, altered gut microbiota (dysbiosis) is the underlying fundamental cause in all conditions. The intestinal epithelium, which is mainly made up of a single layer of intestinal cells, is tightly connected with adjacent cells to form a critical, continuous physical barrier, which regulates the selective permeability of luminal content [30] [31]. Disruption of this epithelial barrier increases intestinal permeability, resulting in leaky gut syndrome: an acute inflammatory condition characterized by functional and structural losses and disruption of epithelial integrity the basement membrane, which lead to the efflux of bacterial toxins and other pro-inflammatory mediators into systemic circulation [32]. During intestinal epithelial cell injury, loss of tight junction integrity and apoptosis drive increased permeability and, in severe cases, eventually to a denuded basement membrane. During microbial dysbiosis, unfavorable inflammatory cascades are activated in the gut lumen that trigger the proinflammatory cytokine storm leading to intestinal epithelial membrane damage. Despite increasing insights into disease pathogenesis from experimental and clinical studies, dysbiosis remains a leading cause of several diseases among patients in critical care, with multi-organ failure and increasing mortality rates [33]. Increasingly, the body of evidence implies a link between dysbiosis-induced intestinal barrier dysfunction and development of several pathogenic conditions such as inflammatory bowel disease[34], obesity [35], bone diseases [34], liver diseases [36], autoimmune diseases [37], and neuroinflammation [32]. Intestinal pathobionts are observed to be increased in patients with inflammatory disorders, where they accelerate systemic inflammation by translocating across the epithelial barrier to reach extraintestinal tissue (Figure 2). Gut microbiota can regulate host immune cells including intestinal macrophages [38]. Other periodontopathic bacteria’s like Porphyromonas gingivalis andFusobacterium nucleatum can induce gut dysbiosis and damage epithelial cells [39, 40]. To date, no satisfactory, specific treatments have been developed to treat leaky gut syndrome. Moreover, several probiotic agents from successful trials, showing promise in both experimental and preclinical studies, failed to show an overall improvement in mortality during clinical trials, due to adverse effects and unfavorable alterations in the gut dysbiosis [41]. Therefore, there is an urgent medical need for the development of novel therapies to further improve clinical outcomes.