Leaky Gut As a Danger Signal for Autoimmune Diseases

Abstract

The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the blood stream creating a “leaky gut.” In individuals with a genetic predisposition, a leaky gut may allow environmental factors to enter the body and trigger the initiation and development of autoimmune disease. Growing evidence shows that the gut microbiota is important in supporting the epithelial barrier and therefore plays a key role in the regulation of environmental factors that enter the body. Several recent reports have shown that probiotics can reverse the leaky gut by enhancing the production of tight junction proteins; however, additional and longer term studies are still required. Conversely, pathogenic bacteria that can facilitate a leaky gut and induce autoimmune symptoms can be ameliorated with the use of antibiotic treatment. Therefore, it is hypothesized that modulating the gut microbiota can serve as a potential method for regulating intestinal permeability and may help to alter the course of autoimmune diseases in susceptible individuals.

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

“…. We also measured the bacteria-specific IgA levels in the serum as an index of gut permeability due to loss of gut tolerance (48)(49)(50). While there was a systemic decrease in total IgA ( Figure 3I), we observed that B cell-specific GARP-KO mice had a significant increase in IgA level against gut bacteria ( Figure 3J).…”

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

“…The gut barrier comprises a physical barrier, a biochemical barrier and an immune system barrier 28. The physical barrier is supported mainly by the mucus layer, microbes and a single layer of intestinal epithelial cells that are linked by tight junction proteins.…”

“…Molecules with antimicrobial properties, such as bile acids and antimicrobial proteins (including α-defensins and β-defensins, C-type lectins, cathelicidin, lysozyme and intestinal alkaline phosphatase) support and mediate the biochemical barrier 29. Secretory immunoglobulin A and lymphoid follicles that contain a variety of immune cells, including B cells, T cells, dendritic cells and neutrophils, are the components of immune system barrier 28. Gut barrier dysfunction results in translocation of microbes, their secreted metabolites and other microbial products from the gut lumen into blood and lymphatics, allowing them to reach other tissues and organs including the liver 30 31…”

Individual combinations of danger signals synergistically increase FVIII product immunogenicity

“…The combination of poly(I:C) and R848 with FVIII in absence of LPS resulted in less DC activation ( Figure S1B). 21 We show here that under in vitro conditions a combination of 1000 pg/mL LPS plus a second danger signal and FVIII is sufficient to induce a strong DC and subsequent T cell activation. 20 These plasma endotoxin levels can increase in different clinical setting for example upon (sub-) clinical infections or in patients with a leaky-gut syndrome.…”