Leaky brain in neurological and psychiatric disorders: Drivers and consequences

Morris, Gerwyn; Fernandes, Brisa Simões; Puri, Basant K.; Walker, Adam J.; Carvalho, André F.; Berk, Michael

doi:10.1177/0004867418796955

Cited by 105 publications

(62 citation statements)

References 407 publications

(515 reference statements)

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“…This observation is supported by other lines of evidence suggesting that manipulation of the gut commensal population can exert positive effects on glutamatergic neurotransmission, which is compromised in patients with intractable epilepsy and neuroprogressive disorders [331][332][333]. In addition, the reduction of dysbiosis or positive changes to the composition of the microbiota can exert a number of additional neuroprotective effects mediated via the enteric nervous system and the vagus nerve (reviewed by [326]). Thus, the positive effects on seizure control effected by the KD associated with changes in the microbiota are likely underpinned by multifactorial mechanisms.…”

Section: Caveats and Uncertaintysupporting

confidence: 55%

“…Elevated levels of BHB also result in the suppression of peripheral inflammation via the inhibition of NF-κB and the NLRP3 inflammasome (reviewed by [1]). This latter point is important because peripheral inflammation is also a driver of pro-inflammatory dysbiosis via mechanisms explained in [326] and [321]. Hence, the reduction in peripheral inflammation seen in individuals following protracted consumption of a KD could potentially explain the positive effects on the composition of the gut population seen above, which in turn could make an independent contribution to the reduction of peripheral inflammation.…”

Section: Caveats and Uncertaintymentioning

confidence: 99%

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Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

et al. 2020

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Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

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Section: Caveats and Uncertaintysupporting

confidence: 55%

Section: Caveats and Uncertaintymentioning

confidence: 99%

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

et al. 2020

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“…Evidence suggests that dysbiosis and altered gut permeability play a pathogenic role allowing the input of molecules (e.g. pro-inflammatory cytokines IL-6, TNF-α and IL-1β and several chemokines including MCP-1, CXCL-1 and MIP-1α) potentially neurotoxic in the blood stream and activating the immune system in an abnormal way [48]. Indeed, as mentioned, the gut microbiota has shown to have a direct influence on the brain by modulating the immune system; a ultra-low state of immune activation is always present in gut due to microbial cells that continually stimulate the immune system which, in turn, controls microbial populations.…”

Section: Mgb Axis In Neuropsychiatric Disordersmentioning

confidence: 99%

Microbiota-gut brain axis involvement in neuropsychiatric disorders

Iannone

Preda

Blottière

et al. 2019

Expert Review of Neurotherapeutics

123

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Microbiota-gut brain axis involvement in neuropsychiatric disorders Background The microbiota-gut brain (MGB) axis is the bidirectional communication between the intestinal microbiota and the brain. An increasing body of preclinical and clinical evidence has revealed that the complex gut microbial ecosystem can affect neuropsychiatric health. However, there is still a need of further studies to elucidate the complex gene-environment interactions and the role of the MGB axis in neuropsychiatric diseases, with the aim of identifying biomarkers and new therapeutic targets, to allow early diagnosis and improving treatments. Areas covered To review the role of MGB axis in neuropsychiatric disorders, prediction and prevention of disease through exploitation, integration and combination of data from existing gut microbiome/microbiota projects and appropriate other International "-Omics" studies. We also evaluated the new technological advances to investigate the microbiome and evidence-based treatment modulating the gut microbiota through nutritional and other interventions. Expert Opinion The clinical studies have documented an association between alterations in gut microbiota composition and/or function, whereas the preclinical studies support a role for the gut microbiota in impacting behaviours which are of relevance to psychiatry and other central nervous system (CNS) disorders. Targeting MGB axis could be an additional approach for treating CNS disorders and all conditions in which alterations of the gut microbiota are involved.

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“…Zonulin causes a dysregulation of the endothelial tight junctions of these barriers [10]. As a consequence of the altered permeability, the development of depressive symptoms may be triggered by microbiotaderived degradation products (i.e., neurotransmitters, TMAO, and toxic bacterial metabolites) [31].…”

Section: Disease Markersmentioning

confidence: 99%

Sex-Specific Associations of Trimethylamine-N-Oxide and Zonulin with Signs of Depression in Carbohydrate Malabsorbers and Nonmalabsorbers

et al. 2020

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Background. The microbiome-derived trimethylamine-N-oxide (TMAO) and the intestinal permeability marker zonulin are considered to be linked with depression. Moreover, carbohydrate malabsorption (CMA) was shown to be associated with signs of depression. This study is aimed at investigating possible sex-specific associations between TMAO and zonulin and the presence of depressive signs in individuals with and without CMA. Methods. Serum concentrations of TMAO and zonulin were determined in 115 and 136 individuals with the presence or absence of CMA. All 251 study participants underwent lactase gene C/T-13910 polymorphism genotyping and fructose H2/CH4 breath testing. Additionally, they filled in the Beck Depression Inventory (BDI-II) questionnaire. Results. The median TMAO and zonulin serum concentrations were 2.66 (1.93–4.14) μmol/L and 40.83 (34.73–47.48) ng/mL. Serum TMAO levels were positively correlated with depressive symptoms (P=0.011, ρ=0.160). The strongest correlations were observed in 87 females (P=0.010, ρ=0.274) and 49 males (P=0.027, ρ=0.315) without CMA, whereas 115 patients with CMA showed no significant correlations. Zonulin tended to be negatively correlated with the BDI-II score in 49 males without CMA (P=0.062, ρ=−0.269). Conclusion. This study demonstrates a positive correlationship between the serum TMAO concentrations and the severity of depressive symptoms in females and males without CMA. Serum zonulin levels were negatively correlated with signs of depression in males without CMA. These findings suggest a gender-specific relationship between the serum TMAO and zonulin concentrations, depression, and CMA.

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Leaky brain in neurological and psychiatric disorders: Drivers and consequences

Cited by 105 publications

References 407 publications

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

Microbiota-gut brain axis involvement in neuropsychiatric disorders

Sex-Specific Associations of Trimethylamine-N-Oxide and Zonulin with Signs of Depression in Carbohydrate Malabsorbers and Nonmalabsorbers

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