Abstract
Improved hygiene leading to reduced exposure to microorganisms has been implicated as one possible cause for the recent “epidemic” of chronic inflammatory diseases (CIDs) in industrialized countries. That is the essence of the hygiene hypothesis that argues that rising incidence of CIDs may be, at least in part, the result of lifestyle and environmental changes that have made us too “clean” for our own good, so causing changes in our microbiota. Apart from genetic makeup and exposure to environmental triggers, inappropriate increase in intestinal permeability (which may be influenced by the composition of the gut microbiota), a “hyper-belligerent” immune system responsible for the tolerance–immune response balance, and the composition of gut microbiome and its epigenetic influence on the host genomic expression have been identified as three additional elements in causing CIDs. During the past decade, a growing number of publications have focused on human genetics, the gut microbiome, and proteomics, suggesting that loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately influencing the close bidirectional interaction between gut microbiome and our immune system. This cross-talk is highly influential in shaping the host gut immune system function and ultimately shifting genetic predisposition to clinical outcome. This observation led to a re-visitation of the possible causes of CIDs epidemics, suggesting a key pathogenic role of gut permeability. Pre-clinical and clinical studies have shown that the zonulin family, a group of proteins modulating gut permeability, is implicated in a variety of CIDs, including autoimmune, infective, metabolic, and tumoral diseases. These data offer novel therapeutic targets for a variety of CIDs in which the zonulin pathway is implicated in their pathogenesis.
Highlights
Twenty-five hundred years ago, when Hippocrates stated that “All disease begins in the gut”, he had an incredible intuition that only recently has been fully appreciated because of new insights into the pathogenesis of many chronic inflammatory diseases (CIDs) afflicting humankind
Gliadin triggers zonulin release through the CXCR3 receptor activated by its engagement to MyD88 with a subsequent increase in gut permeability[27], suggesting that gluten is misinterpreted by the zonulin pathway as a potential harmful component of a microorganism. These data suggest that the activation of the zonulin pathway may represent a defensive mechanism that “flushes out” microorganisms, contributing to the innate immune response of the host against changes in microbiome ecosystem, bacterial colonization of the small intestine or changes in its composition or both. These findings are in line with the growing evidence on the role of changes in gut microbiome composition and function in causing functional changes in gut permeability, with subsequent increased Ag trafficking and break of tolerance leading to CID in genetically susceptible individuals (Figure 1)
Zonulin transgenic, junctional adhesion molecule (JAM)-A−/−, and NM IIA−/− mice all showed increased susceptibility to chemical-induced colitis[29,30,31]. These data suggest that gut permeability may contribute to the development of several CIDs provided that additional genetic components regulating immune response and an imbalanced microbiome are coexistent
Summary
F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Any comments on the article can be found at the end of the article
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