Front Immunol. 2017; 8: 598 May 23 2017 .
READ ENTIRE ARTICLE HERE https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440529/
Leaky Gut As a Danger Signal for Autoimmune Diseases
For digestion and absorption purposes, mammals have developed a very complicated and highly specialized gastrointestinal system maintained by the mucosal barrier (1). However, apart from absorbable nutrients, the intestinal mucosa also faces tremendous exterior antigens, including food antigens, commensal bacteria, pathogens, and toxins. Thus, a specialized barrier function is required to block the entry of diverse exterior antigens while absorbing nutrients. Impressively, in the intestine, the front line of this barrier is maintained by only a single layer of specialized epithelial cells that are linked together by tight junction (TJ) proteins. Many other factors aid in support of this barrier including mucins, antimicrobial molecules, immunoglobulins, and cytokines. If any abnormalities occur among these factors, the intestinal permeability may increase, which is termed a “leaky gut.” A leaky gut allows the entry of exterior antigens from the gut lumen into the host, which may promote both local and systemic immune responses. Multiple diseases may arise or be exacerbated due to a leaky gut, including autoimmune diseases such as inflammatory bowel disease, celiac disease, autoimmune hepatitis, type 1 diabetes (T1D), multiple sclerosis, and systemic lupus erythematosus (SLE) (2–6). Numerous factors can affect gut permeability, such as various diet-derived compounds, alcohol consumption, and gut microbiota dysbiosis. While this review is focused on chronic inflammation and gut barrier functions in mammals, it is worth noting that leaky gut is a phenomenon that is widespread in both mammalian and non-mammalian animals (7). Thus, studies in systems outside of mammals, such as zebrafish (7, 8), can be also helpful in our understanding of the relationship between inflammation and the intestinal barrier.
The gut microbiota has drawn intense attention in the past decade (9). Although scientists have studied gut microbiota for many years, recent advancements in molecular biology including next-generation sequencing technology has enabled researchers to gain new insight in this research field. While we are still far away from clearly understanding the exact roles and effecting modes of gut microbiota, growing evidence suggests that gut microbiota is important in modulating gut permeability and intestinal barrier functions. In this review, we summarize recent advances in the understanding of the leaky gut, bacterial translocation, and gut microbiota dysbiosis, with a particular focus on their association with extraintestinal autoimmune diseases, such as T1D and SLE….
…Reversing the Leaky Gut as a Potential Therapy
Considering the contributions of leaky gut and bacterial translocation to inflammation and multiple diseases, reversing gut leakiness appears to be an attractive therapeutic strategy. Prebiotics and probiotics, for example, can be used to reduce intestinal permeability (139). Diverse probiotic species have been uncovered that possess the properties to protect the intestinal barrier through targeting different components of the mucosal barrier system. The human commensal Bacteroides fragilis may serve as such a probiotic (140). In a mouse model, autism spectrum disorder (ASD) has been shown to be accompanied by intestinal barrier dysfunction, gut microbiota dysbiosis, and leakiness of 4-ethylphenylsulfate (4EPS), which originates from the commensal bacteria. When 4EPS was given to wild-type mice, it directly caused behavioral abnormalities similar to ASD mice. Treatment with B. fragilis reduced the translocation of disease-causative 4EPS, and significantly ameliorated the behavior defects. The therapeutic benefit of B. fragilis is believed to be due to its ability to alter microbial composition and enhance intestinal barrier function (140). B. fragilis is also known for its capability to induce the development of Foxp3+ regulatory T cells, a process regulated by another product of B. fragilis, polysaccharide A (PSA) (141, 142). B. fragilis and PSA are beneficial against inflammatory diseases, such as colitis and experimental autoimmune encephalomyelitis (141, 143). The application of B. fragilis to prevent the leaky gut and reverse autoimmunity warrants further investigation. In a practical point of view, probiotic candidates with different targets on reversing the leaky gut may synergistically act to attenuate disease as thus may serve as a probiotic cocktail. As probiotics are generally considered safe, it is anticipated that they will become cost-effective treatment options for people with autoimmune diseases in the foreseeable future. This is a very young but exciting field in which much still remains to be learned.