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

Massier, Lucas; Chakaroun, Rima; Kovacs, Peter; Heiker, John T.

doi:10.1136/gutjnl-2020-323026

Cited by 41 publications

(29 citation statements)

References 12 publications

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“…Nevertheless, recent reports have shown that zonulin is inappropriate as a biomarker for irritative bowel syndrome, functional dyspepsia and non-Coeliac wheat sensitivity (60). There was only a weak correlation between zonulin level and intestinal permeability (61). This could be due to the detection method; widely distributed ELISA for zonulin measurement fails to quantify zonulin levels correctly.…”

Section: Regulatory Mechanisms Of the Tj Barriermentioning

confidence: 94%

Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity

2021

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The intestinal surface is constitutively exposed to diverse antigens, such as food antigens, food-borne pathogens, and commensal microbes. Intestinal epithelial cells have developed unique barrier functions that prevent the translocation of potentially hostile antigens into the body. Disruption of the epithelial barrier increases intestinal permeability, resulting in leaky gut syndrome (LGS). Clinical reports have suggested that LGS contributes to autoimmune diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and celiac disease. Furthermore, the gut commensal microbiota plays a critical role in regulating host immunity; abnormalities of the microbial community, known as dysbiosis, are observed in patients with autoimmune diseases. However, the pathological links among intestinal dysbiosis, LGS, and autoimmune diseases have not been fully elucidated. This review discusses the current understanding of how commensal microbiota contributes to the pathogenesis of autoimmune diseases by modifying the epithelial barrier.

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Section: Regulatory Mechanisms Of the Tj Barriermentioning

confidence: 94%

Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity

2021

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“…However, in our opinion, studies employing biomarkers are generally lacking in strength due to various reasons: a) correlations with dynamic permeability tests such as dual sugar tests or Ussing chambers are not present or very weak; b) most of these markers are also acute phase proteins and are therefore increased in inflammation; c) their actions are not limited to the gut paracellular pathway; d) commercially available ELISAs are often not validated, as we and others recently demonstrated that the preferred ELISA for the most commonly used biomarker zonulin measures different products ( 197 , 198 ). Consequently, relevant literature should be interpreted carefully in this regard ( 199 ).…”

Section: Limitationsmentioning

confidence: 99%

Impaired Intestinal Barrier and Tissue Bacteria: Pathomechanisms for Metabolic Diseases

Massier¹,

Blüher²,

Kovacs³

et al. 2021

Front. Endocrinol.

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An intact intestinal barrier, representing the interface between inner and outer environments, is an integral regulator of health. Among several factors, bacteria and their products have been evidenced to contribute to gut barrier impairment and its increased permeability. Alterations of tight junction integrity - caused by both external factors and host metabolic state - are important for gut barrier, since they can lead to increased influx of bacteria or bacterial components (endotoxin, bacterial DNA, metabolites) into the host circulation. Increased systemic levels of bacterial endotoxins and DNA have been associated with an impaired metabolic host status, manifested in obesity, insulin resistance, and associated cardiovascular complications. Bacterial components and cells are distributed to peripheral tissues via the blood stream, possibly contributing to metabolic diseases by increasing chronic pro-inflammatory signals at both tissue and systemic levels. This response is, along with other yet unknown mechanisms, mediated by toll like receptor (TLR) transduction and increased expression of pro-inflammatory cytokines, which in turn can further increase intestinal permeability leading to a detrimental positive feedback loop. The modulation of gut barrier function through nutritional and other interventions, including manipulation of gut microbiota, may represent a potential prevention and treatment target for metabolic diseases.

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“…Furthermore, ZO-1 and occludin correlated positively with zonulin, which is considered as a biomarker for intestinal permeability (Camara-Lemarroy et al, 2019). However, the commercial ELISA kits used for the detection of zonulin have been criticized due to specificity problems (Massier et al, 2020); hence, the latter results must be interpreted with caution. Overall, occludin and ZO-1 has mainly been considered as biomarkers of the BBB integrity in MS patients and have primarily been assessed postmortem, in-vitro or in animal models of MS. Studies in other diseases such as inflammatory bowel diseases and neuromyelitis optica spectrum disorders (NMOSD) suggest that tight junction proteins also serve as biomarkers of permeability of the intestinal epithelial barrier (Wyatt et al, 1993;Landy et al, 2016;Cui et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Circulating levels of tight junction proteins in multiple sclerosis: Association with inflammation and disease activity before and after disease modifying therapy

Olsson¹,

Gustavsen²,

Langkilde³

et al. 2021

Multiple Sclerosis and Related Disorders

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Background: Tight junction proteins contribute to maintenance of epithelial and endothelial barriers such as the intestinal barrier and the blood brain barrier (BBB). Increased permeability of these barriers has been linked to disease activity in MS and there is currently a lack of easily accessible biomarkers predicting disease activity in MS. Aim: To investigate whether levels of circulating tight junction proteins occludin and zonula occludens-1 (ZO-1) are associated with biomarkers of inflammation and disease activity; and to determine whether they could serve as clinical biomarkers. Methods: We prospectively included 72 newly diagnosed patients with relapsing remitting MS or clinically isolated syndrome with no prior disease modifying therapy (DMT) use and 50 healthy controls (HCs). Patients were followed with blood samples, 3 tesla MRI, and clinical evaluation for 12 months. Occludin, ZO-1, calprotectin and soluble urokinase-type plasminogen activator receptor (suPAR) were measured by ELISA; serum neurofilament light (NfL) and IL-6 by single-molecule array (SIMOA). The mRNA expression of IFNG, IL1R1, IL10, IL1B, ARG1 and TNF was measured by quantitative real time polymerase chain reaction (qPCR) in whole blood. Results: Plasma occludin levels were higher in MS patients compared with HCs. After 12 months on DMT, occludin levels were reduced by approximately 25% irrespective of 1st or 2nd line DMT (p<0.001). Furthermore, NfL and calprotectin levels were significantly reduced by 31% and 29%, respectively. Occludin and ZO-1 did not correlate with biomarkers of inflammation and did not predict disease activity at baseline or after 12 months. Conclusions: Higher levels of occludin suggest an increased permeability of the BBB and/or the intestinal barrier in MS patients. The reduction of occludin after 12 months on DMTs might reflect repair of these barriers upon treatment. However, plasma levels of ZO-1 and occludin could not predict clinical or MRI disease activity as determined by regression and ROC-curve analysis. Our results do not indicate a clear clinically relevant role for circulating tight junction proteins as biomarkers of disease activity in MS and further investigations in larger cohorts are needed to clarify this issue.

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

Abstract: Table 1 Studies using zonulin ELISA and correlations with intestinal permeability Study Year Zonulin kit N Correlation Citation Halasa et al 2019 IDK 38 R=0.11, p>0.05 8 Linsalata et al 2018 IDK 71 R=0.17, p>0.05 9 Kuzma et al 2020 IDK (distributed by ALPCO) 24 R=0.033, p=0.79 10

Cited by 41 publications

References 12 publications

Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity

Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity

Impaired Intestinal Barrier and Tissue Bacteria: Pathomechanisms for Metabolic Diseases

Circulating levels of tight junction proteins in multiple sclerosis: Association with inflammation and disease activity before and after disease modifying therapy

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