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 presented facts can give some clues for biological investigation of the me­ chanism of T1D development, but hardly any as­ sumption about the top trigger's identity. There is no other food type found having conclusive causative relations with T1D (Knip, Simel, 2012), although theories exist that wheat proteins may much contribute to the leaky gut (intestinal per­ meability), allowing protein macromolecules to pass through the intestinal epithelium into the bloodstream (Fasano, 2012). Additionally, a simple fact that T1D is com­ mon among the youngest population (0 + years) helps to further confine the description of the trig­ ger, as more likely bringing an occasional sharply affecting encounter than systemically accumulated through life exposure series. "
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    ABSTRACT: The article attempts to contribute to the whole momentum of finding the cause of type 1 diabetes (T1D), exhibiting the global growth in the incidence of 3% per year, but more intense in developing economies of Europe. As there is still no conclusion about the real cause of T1D, although a number of environmental factors in a focus, a hypothesis was raised that the possible main trigger is still not identified. The main method applied was screening of the scientific publications presenting geographical, epidemiological and etiological studies of T1D. The geographical, migrant, etiological and other facts suggesting a direct implication (deduced assumption) about the features of the top trigger of T1D were collected, discussed and used for deduction of assumptions, organized in a hierarchical order. The final assumption was drawn indicating the discussable candidate for the top trigger of T1D as a synthetic medicine administrated in times of viral infections with increasing popularity among the youngest population.
    05/2015; 1(1):56-64. DOI:10.6001/geol-geogr.v1i1.3072
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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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