Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis

Abstract

Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.

Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis

“…Finally, a study presented in 2018 (currently available only as an abstract) provided strong evidence of gut-joint trafficking in SpA, by use of photoconversion technology to demonstrate that cells labelled in the gut could be found in the enthesis of arthritic TNF ΔARE mice 126 . The same technology has been used in autoantibody-dependent arthritis models to demonstrate trafficking of gut-derived α4β7 + T follicular helper cells to secondary lymphoid organs in K/B×N mice when infected with segmented filamentous bacteria 127 and more recently to show small intestine immune cell trafficking to synovial tissue in collagen-induced arthritis 128 .…”

Blurring the picture in leaky gut research: how shortcomings of zonulin as a biomarker mislead the field of intestinal permeability

“…Until then, researchers are strongly encouraged to circumvent the unspecific measurement of zonulin and instead apply rigorous tests of intestinal permeability such as dual-sugar assays, and use immunohistochemistry and expression profiles of zonula occludens proteins. 3…”

“…This renders measurements of serum zonulin in rodent models highly questionable and potentially misleading. 3 Along these lines, differential ELISA signals obtained in mouse sera further indicate detection of unspecific and unknown proteins by the ELISA. 3 For translational research, assessing zonulin levels in mouse models does only become relevant when using zonulin-specific assays in 'humanised mice' genetically modified to express human HP2, as has been previously described.…”

“…2 A recent study showed that zonulin-mediated intestinal barrier integrity is an important mechanism by which gut microbial dysbiosis affects the transition from asymptotic autoimmunity to inflammatory disease associated with increased circulating zonulin in patients with arthritis. 3 In all of these studies, zonulin measurements are based on commercial ELISA.…”

Dietary Short-Term Fiber Interventions in Arthritis Patients Increase Systemic SCFA Levels and Regulate Inflammation

“…The different mechanisms of SCFA acting on inflammation were recently comprehensively reviewed by Vinolo et al [ 4 ]. Furthermore, we and others could recently also expand the beneficial effect of SCFA to inflammatory arthritis and bone health, both in preclinical models [ 23 , 32 , 33 , 34 , 35 ] and in a first feasibility study in RA patients [ 36 ]. The Firmicutes/Bacteroidetes ratio has been shown to be associated with different diseases.…”