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The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression

M-Care4U Outpatient Clinics, Antwerp, Belgium.
Neuro endocrinology letters (Impact Factor: 0.94). 03/2008; 29(1):117-24.
Source: PubMed

ABSTRACT There is now evidence that major depression (MDD) is accompanied by an activation of the inflammatory response system (IRS) and that pro-inflammatory cytokines and lipopolysacharide (LPS) may induce depressive symptoms. The aim of the present study was to examine whether an increased gastrointestinal permeability with an increased translocation of LPS from gram negative bacteria may play a role in the pathophysiology of MDD. Toward this end, the present study examines the serum concentrations of IgM and IgA against LPS of the gram-negative enterobacteria, Hafnia Alvei, Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in MDD patients and normal controls. We found that the prevalences and median values for serum IgM and IgA against LPS of enterobacteria are significantly greater in patients with MDD than in normal volunteers. These differences are significant to the extent that a significant diagnostic performance is obtained, i.e. the area under the ROC curve is 90.1%. The symptom profiles of increased IgM and IgA levels are fatigue, autonomic and gastro-intestinal symptoms and a subjective feeling of infection. The results show that intestinal mucosal dysfunction characterized by an increased translocation of gram-negative bacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. It is suggested that the increased LPS translocation may mount an immune response and thus IRS activation in some patients with MDD and may induce specific "sickness behaviour" symptoms. It is suggested that patients with MDD should be checked for leaky gut by means of the IgM and IgA panel used in the present study and accordingly should be treated for leaky gut.

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Available from: Michael Maes, Aug 11, 2014
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    • "This suggests that peripheral inflammation in depressed patients, perhaps especially when associated with increases in somatization symptoms, will modulate not only cognitive functioning but also central immune and glia reactivity threshold, as well as BBB permeability, thereby having modulatory effects on leukocyte extravasation, central inflammatory levels, neuroprogression and processes classically associated with neurodegenerative disorders. Recent data has shown a role for increased gut permeability in the aetiology and course of depression [100]. The above would be some of the likely downstream mechanisms whereby increased gut permeability, by inducing immune inflammatory activity, contributes to the changes occurring in depression. "
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    • "The gut microbiome plays essential roles in neurological diseases, such as autism and Parkinson's disease (Collins and Bercik 2009; Finegold et al. 2010; Hsiao et al. 2013). A leaky gut with an increased translocation of LPS from gram-negative enterobacteria also plays a role in the inflammatory pathophysiology of depression (Maes et al. 2008). Our data provide evidence regarding dysbiosis, a shift of bacterial populations, in an ALS mouse model. "
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    ABSTRACT: Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3–5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1G93A), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.
    04/2015; 3(4). DOI:10.14814/phy2.12356
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    • "The degree and nature of this passive movement of molecules across the intestinal mucosal layer depend on the structure of the intestinal mucosal membrane (intestinal epithelial layer and paracellular junctions), the physicochemical properties of the solute, and its interaction with the media that determines the level of permeability of the intestinal epithelial layer. It is not surprising that abnormal intestinal permeability ( " leaky gut " ) has been proposed as one of the key pathological events, not only for gastrointestinal diseases like inflammatory bowel disease [10], irritable bowel syndrome [11], celiac disease [12], colon cancer [13], and liver diseases [14] [15], but also in systemic disorders like obesity and metabolic syndrome [16], diabetes [17], neurodegenerative diseases like Parkinson's disease [18], and even psychological disorders like depression, anxiety and PTSD [2] [19] [20], just to name a few. Clinica Chimica Acta 442 (2015) 24–32 Abbreviations: L/M ratio, lactulose to mannitol ratio; PD, Parkinson's disease; PTSD, post-traumatic stress disorder; RF, response factor; S/L ratio, sucralose to lactulose ratio; TFA, trifluoroacetic acid. "
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    ABSTRACT: Measurement of intestinal permeability is important in several diseases but currently several methods are employed. We sought to: (1) develop a new GC based method to measure urinary mannitol, lactulose and sucralose to assess regional and total gut permeability; (2) analyze the kinetics of these sugars in the urine to determine which ratio is useful to represent intestinal permeability; and (3) determine whether age, gender, race and BMI impact these values. Subjects drank a cocktail of sucrose, lactulose, mannitol and sucralose and these sugars were measured in the urine at 5, 12 and 24h with gas chromatography. Urinary mannitol exhibited significantly different kinetics than lactulose and sucralose which were similar to each other and varied little over the 24h. No permeability differences were observed for renal function, age, race, sex, or BMI. Our data do not support the use of the widely used L/M ratio as an accurate estimate of intestinal permeability. Our data support the use of: The sucralose/lactulose (S/M) ratio to measure: small intestine permeability (first 5h); small and large intestine (first 12hours), and total gut permeability (24h). This was also found to be true in a Parkinson's disease model. Copyright © 2015 Elsevier B.V. All rights reserved.
    Clinica Chimica Acta 01/2015; 442. DOI:10.1016/j.cca.2014.12.040 · 2.82 Impact Factor
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