Article

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

ABSTRACT

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
    • "function, leading to increased permeability – also known as leaky gut syndrome (LGS) – is supposed to be involved in several gut-related diseases (Groschwitz & Hogan, 2009), such as chronic fatigue syndrome (Maes & Twisk, 2009), metabolic disorders, type 1 diabetes (Vaarala, Atkinson, & Neu, 2008), allergies, asthma, alcoholic dependence (Hartmann et al., 2013) and autoimmune diseases (Fasano, 2012). LGS is also associated with strong mucosal inflammation as for example in inflammatory bowel diseases (IBD), a common digestive morbidity which affects nearly 5 million people worldwide, with a continuously increasing incidence (Chey, Maneerattaporn, & Saad, 2011; Heitkemper, Jarrett, & Jun, 2013). "
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    ABSTRACT: Impaired gut epithelium functionalities coupled with microbial dysbiosis contribute to the development of diseases such as inflammatory bowel disease (IBD). Functional foods represent an interesting possibility to modulate the gut microbiota and hence the gut barrier functionality. The effect of arabinogalactan (AG) and fructooligosaccharides (FOS) has been studied in a Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) – inoculated with faecal material from an IBD patient – coupled with co-cultures of enterocyte-like cells (Caco-2) and macrophages (THP1). AG and FOS showed a different fermentation profile in the colon (proximal for FOS, distal for AG) and both fibres exerted a potential positive effect on gut barrier and inflammation. AG showed a significantly higher transepithelial electrical resistance of Caco-2 cells, decreased NF-κB activity and increased IL-10 production. These results suggest that AG could be an interesting supplement for those conditions characterized by inflammation and increased permeability in the distal colon.
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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.
    Full-text · Article · Apr 2015
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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.
    Full-text · Article · Jul 2014
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