Recognizing the Leaky Gut as a Trans-diagnostic Target for Neuroimmune Disorders Using Clinical Chemistry and Molecular Immunology Assays

Background: Increased intestinal permeability with heightened translocation of Gramnegative bacteria, also known as “leaky gut”, is associated with the pathophysiology of neuroimmune disorders, such as Major Depressive Disorder (MDD), Chronic Fatigue Syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome. This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice. <p> Methods: We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words “diagnosis” or “biomarkers” and “leaky gut”, “bacterial translocation”, and “intestinal permeability” and focused on papers describing tests that may aid in the clinical recognition of leaky gut. <p> Results: To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated. The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B. Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG-mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed. Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, β-defensin, α- antitrypsin, lysozyme and lactoferrin. Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption. <p> Discussion: Here, we propose strategies to recognize “leaky gut” in a clinical setting using the most adequate clinical chemistry and molecular immunology assays.

Download Full-text

An Observational Study to Evaluate the Association between Intestinal Permeability, Leaky Gut Related Markers, and Metabolic Health in Healthy Adults

Healthcare ◽

10.3390/healthcare9111583 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1583

Author(s):

Hiroyuki Hoshiko ◽

Gertrude G. Zeinstra ◽

Kaatje Lenaerts ◽

Els Oosterink ◽

Renata M. C. Ariens ◽

...

Keyword(s):

Acetylsalicylic Acid ◽

Intestinal Permeability ◽

Density Lipoprotein ◽

Metabolic Health ◽

Lipoprotein Cholesterol ◽

Permeability Test ◽

Leaky Gut ◽

Gut Permeability ◽

Acid Challenge ◽

Health Parameters

We explored whether metabolic health is linked to intestinal permeability, using a multi-sugar (MS) permeability test, and whether intestinal permeability is correlated with the leaky gut-related markers (LGM) zonulin, LBP, and sCD14. Metabolically healthy (n = 15) and unhealthy subjects (n = 15) were recruited based on waist circumference, fasting glucose, and high-density lipoprotein cholesterol levels. Participants underwent an MS permeability test that assessed site-specific permeabilities of the gastroduodenum and small and large intestines. The test was performed with/without an acetylsalicylic acid challenge to measure and correlate the gut permeability, LGM, and metabolic health. At baseline, metabolic health showed no correlation with gut permeability. Significant correlations were found between the metabolic health parameters and LGM. In the acetylsalicylic acid challenged MS permeability test, low-density lipoprotein cholesterol was correlated with the sucralose/erythritol ratio, reflecting the whole intestinal permeability. Correlations between most metabolic health parameters and LGM during the acetylsalicylic acid challenge were less pronounced than at baseline. In both MS permeability tests, no significant correlations were found between LGM (plasma and serum) and gut permeability. Thus, correlations between LGM and metabolic health might not be linked with paracellular gut permeability. Transcellular translocation and/or lipoprotein-related transportation is a more likely mechanism underlying the association between LGM and metabolic health.

Download Full-text

Faculty Opinions recommendation of Recognizing the Leaky Gut as a Trans-diagnostic Target for Neuroimmune Disorders Using Clinical Chemistry and Molecular Immunology Assays.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734454631.793570032 ◽

2020 ◽

Author(s):

Alessio Fasano

Keyword(s):

Clinical Chemistry ◽

Leaky Gut ◽

Molecular Immunology

Download Full-text

Leaky Gut: Effect of Dietary Fiber and Fats on Microbiome and Intestinal Barrier

International Journal of Molecular Sciences ◽

10.3390/ijms22147613 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7613

Author(s):

Haruki Usuda ◽

Takayuki Okamoto ◽

Koichiro Wada

Keyword(s):

Intestinal Permeability ◽

Intestinal Tract ◽

Inflammatory Diseases ◽

Intestinal Barrier ◽

Short Chain Fatty Acids ◽

Systemic Circulation ◽

Mucosal Tissue ◽

Leaky Gut ◽

Exogenous Factors ◽

Intestinal Barrier Integrity

Intestinal tract is the boundary that prevents harmful molecules from invading into the mucosal tissue, followed by systemic circulation. Intestinal permeability is an index for intestinal barrier integrity. Intestinal permeability has been shown to increase in various diseases—not only intestinal inflammatory diseases, but also systemic diseases, including diabetes, chronic kidney dysfunction, cancer, and cardiovascular diseases. Chronic increase of intestinal permeability is termed ‘leaky gut’ which is observed in the patients and animal models of these diseases. This state often correlates with the disease state. In addition, recent studies have revealed that gut microbiota affects intestinal and systemic heath conditions via their metabolite, especially short-chain fatty acids and lipopolysaccharides, which can trigger leaky gut. The etiology of leaky gut is still unknown; however, recent studies have uncovered exogenous factors that can modulate intestinal permeability. Nutrients are closely related to intestinal health and permeability that are actively investigated as a hot topic of scientific research. Here, we will review the effect of nutrients on intestinal permeability and microbiome for a better understanding of leaky gut and a possible mechanism of increase in intestinal permeability.

Download Full-text

Bile Acid Malabsorption or Disturbed Intestinal Permeability in Patients Treated with Enzyme Substitution for Exocrine Pancreatic Insufficiency Is Not Caused by Bacterial Overgrowth

Pancreas ◽

10.1097/00006676-200303000-00007 ◽

2003 ◽

Vol 26 (2) ◽

pp. 130-133 ◽

Cited By ~ 16

Author(s):

Jan Lysgård Madsen ◽

Jesper Graff ◽

Else Kirstine Philipsen ◽

Ole Scharff ◽

Jüri Johannes Rumessen

Keyword(s):

Bile Acid ◽

Intestinal Permeability ◽

Pancreatic Insufficiency ◽

Bacterial Overgrowth ◽

Exocrine Pancreatic Insufficiency ◽

Bile Acid Malabsorption

Download Full-text

Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

10.1101/2020.09.19.304303 ◽

2020 ◽

Author(s):

Elke M. Muntjewerff ◽

Kechun Tang ◽

Lisanne Lutter ◽

Gustaf Christoffersson ◽

Mara J.T. Nicolasen ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Chromogranin A ◽

Intestinal Barrier ◽

Enteroendocrine Cells ◽

Leaky Gut ◽

Gut Permeability ◽

Gut Barrier ◽

Ultrastructural Studies ◽

New Findings

AbstractBackground and AimsA ‘leaky’ gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we asked how Chromogranin A (CgA), a major hormone produced by the enteroendocrine cells, and Catestatin (CST), the most abundant CgA-derived proteolytic peptide, affect the gut barrier.Methods and ResultsUltrastructural studies on the colons from Catestatin (CST: hCgA352-372) knockout (CST-KO) mice revealed (i) altered morphology of tight (TJ) and adherens (AJ) junctions and desmosomes, indicative of junctional stress and (ii) an increased infiltration of immune cells compared to controls. Flow cytometry studies confirmed these cells to be macrophages and CD4+ T cells. Gene expression studies confirmed that multiple TJ-markers were reduced, with concomitant compensatory elevation of AJ and desmosome markers. Consistently, the levels of plasma FITC-dextran were elevated in the CST-KO mice, confirming leakiness’ of the gut. Leaky gut in CST-KO mice correlated with inflammation and a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in a multitude of diseases. Supplementation of CST-KO mice with recombinant CST reversed this leakiness and key phenotypes. Supplementation of CgA-KO mice with either CST alone, or with the pro-inflammatory proteolytic CgA fragment pancreastatin (PST: CgA250-301) showed that gut permeability is regulated by the antagonistic roles of these two peptide hormones: CST reduces and PST increases leakiness.ConclusionWe conclude that the enteroendocrine cell-derived hormone, CgA regulates gut permeability. CST is both necessary and sufficient to reduce the leakiness. CST acts primarily via antagonizing the effects of PST.What you need to knowBackground and ContextThe intestinal barrier is disrupted in many intestinal diseases such as Crohn’s disease. Chromogranin A (CgA) is produced by enteroendocrine cells in the gut. CgA is proteolytically cleaved into bioactive peptides including catestatin (CST) and pancreastatin (PST). The role of CgA in the gut is unknown.New findingsCgA is efficiently processed to CST in the gut and this processing might be decreased during active Crohn’s disease. CST promotes epithelial barrier function and reduces inflammation by counteracting PST.LimitationsThe complete mechanism of intestinal barrier regulation by CST likely involves a complex interplay between the enteroendocrine system, metabolism, the epithelium, the immune system and the gut microbiota.ImpactOur findings indicate that CST is a key modulator of the intestinal barrier and immune functions that correlates with disease severity of Crohn’s disease. CST could be a target for therapeutic interventions in Crohn’s disease.

Download Full-text

The Onset of Enhanced Intestinal Permeability and Food Sensitivity Triggered by Medication Used in Dental Procedures: A Case Report

Case Reports in Gastrointestinal Medicine ◽

10.1155/2012/265052 ◽

2012 ◽

Vol 2012 ◽

pp. 1-3

Author(s):

Aristo Vojdani ◽

Jama Lambert

Keyword(s):

Intestinal Permeability ◽

Present Report ◽

Wheat Gluten ◽

Secretory Iga ◽

Dental Procedure ◽

Food Sensitivity ◽

Gut Dysfunction ◽

Dental Procedures ◽

Bacterial Endotoxins ◽

The Many

Enhanced intestinal permeability and food sensitivity are two of the many proven causes of gastrointestinal disorders. This present report describes a woman with no previous gastrointestinal (GI) complaints, who underwent dental root canal, bone graft, and implant procedures. Postsurgery she experienced an allergic reaction to the combined medications. In the weeks that followed, she presented with multiple food intolerances. Four weeks after the final dental procedure, she was assessed serologically for mucosal immune function, salivary, and blood-gluten reactivity, intestinal permeability, and other food sensitivities. Compared to her test reports from two months prior to her first dental procedure, the patient’s results showed high total secretory IgA (SIgA) and elevated salivary antibodies to alpha-gliadin, indicating abnormal mucosal immunity and loss of tolerance to gluten. Her serologic assessments revealed immunoglobulin G (IgG) and IgA antibodies to a range of wheat/gluten proteins and peptides, gut bacterial endotoxins and tight junction proteins. These test results indicate gut dysbiosis, enhanced intestinal permeability, systemic gluten-reactivity, and immune response to other dietary macromolecules. The present case suggests that patients who experience severe allergic or pseudoallergic reactions to medication should be assessed and monitored for gut dysfunction. If left untreated this could lead to autoimmune reactions to self tissues.

Download Full-text