Maes M, Kubera M, Leunis JC. 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. Neuro Endocrinol Lett 29: 117-124

M-Care4U Outpatient Clinics, Antwerp, Belgium.
Neuro endocrinology letters (Impact Factor: 0.8). 03/2008; 29(1):117-24.
Source: PubMed


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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    • "However its causative role has not been confirmed. Maes et al. (2008) reported that inflammatory response system activation , through an increased production of IFNγ and IL-6, is an essential factor in the loss of the intestinal epithelial barrier function allowing poorly invasive enterobacteria to cross the gut wall. This may induce an increased translocation of lipopolysaccharides (LPSs) of Gramnegative bacteria (leaky gut) with subsequent increase in their serum concentration which may underpin the link between intestinal mucosal dysfunction and MDD (Maes et al., 2012). "

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    • "Certain experimental protocols of stress induce an increased intestinal permeability resulting in bacterial translocation (Santos et al., 2001; Ponferrada et al., 2007) indicating that stress exposure could be able to cause the presence of circulating LPS from Gram-negative bacteria which in turn could induce a neuroinflammatory response by brain TLR-4 activation. This proposed mechanism known as " leaky gut " also takes place in patients with chronic depression, suggesting that depression could be accompanied by bacterial translocation, which would be related to the inflammatory pathophysiology of the disease (Maes et al., 2008, 2012b; Leonard and Maes, 2012). "
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    ABSTRACT: Recent studies have suggested that depression is accompanied by an increased intestinal permeability which would be related to the inflammatory pathophysiology of the disease. This study aimed to evaluate whether experimental depression presents with bacterial translocation that in turn can lead to the TLR-4 in the brain affecting the mitogen-activated protein kinases (MAPK) and antioxidant pathways. Male Wistar rats were exposed to chronic mild stress (CMS) and the intestinal integrity, presence of bacteria in tissues and plasma lipopolysaccharide levels were analyzed. We also studied the expression in the prefrontal cortex of activated forms of MAPK and some of their activation controllers and the effects of CMS on the antioxidant Nrf2 pathway. Our results indicate that after exposure to a CMS protocol there is increased intestinal permeability and bacterial translocation. CMS also increases the expression of the activated form of the MAPK p38 while decreasing the expression of the antioxidant transcription factor Nrf2. The actions of antibiotic administration to prevent bacterial translocation on elements of the MAPK and Nrf2 pathways indicate that the translocated bacteria are playing a role in these effects. In effect, our results propose a role of the translocated bacteria in the pathophysiology of depression through the p38 MAPK pathway which could aggravate the neuroinflammation and the oxidative/nitrosative damage present in this pathology. Moreover, our results reveal that the antioxidant factor Nrf2 and its activators may be involved in the consequences of the CMS on the brain.
    Full-text · Article · Dec 2015 · Neuropharmacology
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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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