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.