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Review
. 2020 Jan 31:9:F1000 Faculty Rev-69.
doi: 10.12688/f1000research.20510.1. eCollection 2020.

All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases

Alessio Fasano  1   2
Affiliations
Review

All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases

Alessio Fasano. F1000Res. .

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.

Keywords: Chronic inflammatory diseases; Gut permeability; microbiome; zonulin.

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Conflict of interest statement

Competing interests: The author is co-founder and stock holder of Alba Therapeutics, a company developing treatments complementary to the gluten-free diet by exploiting gut permeability.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Proposed chain of events leading to chronic inflammatory disease.
( 1) Under physiological circumstances there is a tightly control of mucosal antigen trafficking (antigen sampling) that, in concert with specific immune cells and chemokine and cytokine mediators lead to anergy and therefore to mucosal tolerance. ( 2) Gut dysbiosis causes inappropriate production of increased amount of zonulin with subsequent functional loss of gut barrier function, followed by microbiota-derived antigen and endotoxin trafficking from the lumen to the lamina propria triggering innate and immunoregulatory responses causing a pro-inflammatory micromilieu. ( 3) If this process continues, an adaptive immune response is mounted, causing production of pro-inflammatory cytokines, including interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) that cause further opening of the paracellular pathway to the passage of antigens, creating a vicious cycle. ( 4) Ultimately, these processes lead to break of tolerance with subsequent onset of chronic inflammatory disease whose nature is influenced by the specific host genetic background that dictates which organ or tissue will be targeted by the inflammatory process. DC, dendritic cell; IL-10, interleukin 10; TGF-β, transforming growth factor beta; Tregs, regulatory T cells. This figure was re-used from Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. doi:10.1080/21688370.2016.1251384 with permissions .
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