Leaky Gut and Autoimmune Diseases

Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Clinical Reviews in Allergy & Immunology (Impact Factor: 5.46). 11/2011; 42(1):71-8. DOI: 10.1007/s12016-011-8291-x
Source: PubMed


Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.

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Available from: Alessio Fasano, Jan 06, 2014
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    • "The GI immune system is exposed to large amounts of countless pathogenic and nonpathogenic foreign substances including dietary proteins and intestinal bacteria. Therefore, in the GI tract, three independent elements, " immune function , " " mucosal barrier function, " and " intestinal bacterial balance, " are tightly orchestrated to protect the host from hazardous pathogenic substances [14] [34] [39] as illustrated in Figure 1. This tight regulation is exemplified by the fact that the GI mucosa is consistently interacting with intestinal bacteria and their components, which stimulate the immune system and induce a state of " controlled physiological inflammation " [40] under healthy conditions. "
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    ABSTRACT: Autoimmune diseases (ADs) are considered to be caused by the host immune system which attacks and destroys its own tissue by mistake. A widely accepted hypothesis to explain the pathogenic mechanism of ADs is “molecular mimicry,” which states that antibodies against an infectious agent cross-react with a self-antigen sharing an identical or similar antigenic epitope. However, this hypothesis was most likely established based on misleading antibody assay data largely influenced by intense false positive reactions involved in immunoassay systems. Thus reinvestigation of this hypothesis using an appropriate blocking agent capable of eliminating all types of nonspecific reactions and proper assay design is strongly encouraged. In this review, we discuss the possibility that low immune function may be the fundamental, common defect in ADs, which increases the susceptibility to potential disease causative pathogens located in the gastrointestinal tract (GI), such as bacteria and their components or dietary components. In addition to these exogenous agents, aberrations in the host’s physical condition may disrupt the host defense system, which is tightly orchestrated by “immune function,” “mucosal barrier function,” and “intestinal bacterial balance.” These disturbances may initiate a downward spiral, which can lead to chronic health problems that will evolve to an autoimmune disorder.
    04/2015; 2015:1-12. DOI:10.1155/2015/636207
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    • "Many factors can alter this balance, including alterations in the gut microflora, modifications of the mucus layer, and epithelial damage, leading to increased intestinal permeability and translocation of luminal contents to the underlying mucosa. The integrity of these structures is necessary for the maintenance of normal intestinal barrier function, and dysregulation of the aforementioned components has been implicated in the pathogenesis of not only inflammatory bowel disease but also many other disorders of the GI tract, including infectious enterocolitis, irritable bowel syndrome, small intestinal bowel overgrowth, and allergic food intolerance [46–49]. "
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    ABSTRACT: Background: Interleukin (IL) 33 is a recently identified pleiotropic cytokine that influences the activity of multiple cell types and orchestrates complex innate and adaptive immune responses. Methods: We performed an extensive review of the literature published between 2005 and 2013 on IL-33 and related cytokines, their functions, and their regulation of the immune system following Candida albicans colonization. Our literature review included cross-references from retrieved articles and specific data from our own studies. Results: IL-33 (IL-1F11) is a recently identified member of the IL-1 family of cytokines. Accumulating evidence suggests a pivotal role of the IL-33/ST2 axis in host immune defense against fungal pathogens, including C. albicans. IL-33 induces a Th2-type inflammatory response and activates both innate and adaptive immunity. Studies in animal models have shown that Th2 inflammatory responses have a beneficial role in immunity against gastrointestinal and systemic infections by Candida spp. Conclusions: This review summarizes the most important clinical studies and case reports describing the beneficial role of IL-33 in immunity and host defense mechanisms against pathogenic fungi. The finding that the IL-33/ST2 axis is involved in therapeutic target has implications for the prevention and treatment of inflammatory diseases, including acute or chronic candidiasis.
    07/2014; 2014:340690. DOI:10.1155/2014/340690
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    • "''Leaky gut'' syndrome ''Leaky Gut'' Syndrome is a term given to the condition where the epithelial barrier function of the small or large intestine is impaired , causing less discrimination in the numbers and types of molecules and cells that are able to pass from the gut to the circulatory system and vice versa [32] [33] [34]. Tight junctions are responsible for the epithelial barrier function, and consist of a system of several proteins in the paracellular space between each cell in the gut lining. "
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    ABSTRACT: Autism Spectrum Disorders are neurodevelopmental disorders with symptoms that include cognitive impairments, stereotyped behaviors, and impairments in social skills. The dramatic increase in incidence of autism in recent years has created an increased need to find effective treatments. This paper proposes a hypothesis for a systems model of the connections between Autism Spectrum Disorder pathogenesis routes observed in recent studies. A combination treatment option is proposed to combat multiple pathogenesis mechanisms at once. Autism has been cited as being linked to gastrointestinal symptoms and is thought to be caused by a combination of genetic predisposition and environmental factors. Neuroinflammation as a result of increased gastrointestinal permeability has been noted as being a likely cause of Autism Spectrum Disorders, with possible primary causes stemming from abnormal intestinal bacteria and/or sulfur metabolic deficiencies. Our pathogenesis model proposes a circular relationship: oxidative stress and sulfur metabolic deficiencies could cause changes in colonic bacterial composition; and environmental bacterial contaminants could lead to elevated oxidative stress in individuals. It would thus be a self-perpetuating process where treatment options with single targets would have short-lived effects. It is believed that bacterial toxins, oxidative stress and dietary allergens such as gluten could all lead to increased epithelial permeability. Therefore, we propose a combination treatment to combat intestinal permeability, abnormal bacteria and/or bacterial overgrowth, and sulfur metabolic deficiencies. It is our hope that the proposed model will inspire new studies in finding effective treatments for individuals with Autism Spectrum Disorders. We suggest possible future studies that may lend more credibility to the proposed model.
    Medical Hypotheses 12/2012; 80(3). DOI:10.1016/j.mehy.2012.11.044 · 1.07 Impact Factor
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