Bacterial Lipopolysaccharide Increases Serotonin Metabolism in Both Medial Prefrontal Cortex and Nucleus Accumbens in Male Wild Type Rats, but Not in Serotonin Transporter Knockout Rats

Korte-Bouws, G.A.H.; Heesch, Floor van; Westphal, Koen G.C.; Ankersmit, Lisa M J; Oosten, Edwin M van; Güntürkün, Onur; Korte, S. Mechiel

doi:10.3390/ph11030066

Cited by 19 publications

(14 citation statements)

References 51 publications

(76 reference statements)

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“…As expected, TNF-α inhibition with etanercept reduced this SERT availability [84]. More about immune activity and monoamine transporter function can be found in the present Special Issue of Pharmaceuticals [85].…”

Section: Discussionsupporting

confidence: 54%

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

et al. 2019

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Juvenile idiopathic arthritis (JIA) represents joint inflammation with an unknown cause that starts before the age of 16, resulting in stiff and painful joints. In addition, JIA patients often report symptoms of sickness behavior. Recent animal studies suggest that proinflammatory cytokines produce sickness behavior by increasing the activity of indoleamine-2,3-dioxygenase (IDO) and guanosinetriphosphate–cyclohydrolase-1 (GTP–CH1). Here, it is hypothesized that inflammation in JIA patients enhances the enzymatic activity of IDO and GTP-CH1 and decreases the co-factor tetrahydrobiopterin (BH4). These compounds play a crucial role in the synthesis and metabolism of neurotransmitters. The aim of our study was to reveal whether inflammation affects both the GTP-CH1 and IDO pathway in JIA patients. Serum samples were collected from twenty-four JIA patients. In these samples, the concentrations of tryptophan (TRP), kynurenine (KYN), tyrosine (TYR), neopterin, and phenylalanine (PHE) were measured. An HPLC method with electrochemical detection was developed to quantify tryptophan, kynurenine, and tyrosine. Neopterin and phenylalanine were quantified by ELISA. The KYN/TRP ratio was measured as an index of IDO activity, while the PHE/TYR ratio was measured as an index of BH4 activity. Neopterin concentrations were used as an indirect measure of GTP-CH1 activity. JIA patients with high disease activity showed higher levels of both neopterin and kynurenine, and a higher ratio of both KYN/TRP and PHE/TYR and lower tryptophan levels than clinically inactive patients. Altogether, these data support our hypothesis that inflammation increases the enzymatic activity of both IDO and GTP-CH1 but decreases the efficacy of the co-factor BH4. In the future, animal studies are needed to investigate whether inflammation-induced changes in these enzymatic pathways and co-factor BH4 lower the levels of the brain neurotransmitters glutamate, noradrenaline, dopamine, serotonin, and melatonin, and consequently, whether they may affect fatigue, cognition, anxiety, and depression. Understanding of these complex neuroimmune interactions provides new possibilities for Pharma-Food interventions to improve the quality of life of patients suffering from chronic inflammation.

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Section: Discussionsupporting

confidence: 54%

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

et al. 2019

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“…LPS also modulates serotonin metabolism, for example, activating the serotonin transporter (SERT) and, consequently, serotonin reuptake 61 , 62 . Similar effect was observed here for LPS + fluoxetine, lowering serotonin levels (vs. chronic stress, fluoxetine, EPA and LPS), and also affecting serotonin turnover.…”

Section: Discussionmentioning

confidence: 99%

Modulation of behavioral and neurochemical responses of adult zebrafish by fluoxetine, eicosapentaenoic acid and lipopolysaccharide in the prolonged chronic unpredictable stress model

Demin

Колесникова

Galstyan

et al. 2021

Sci Rep

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Long-term recurrent stress is a common cause of neuropsychiatric disorders. Animal models are widely used to study the pathogenesis of stress-related psychiatric disorders. The zebrafish (Danio rerio) is emerging as a powerful tool to study chronic stress and its mechanisms. Here, we developed a prolonged 11-week chronic unpredictable stress (PCUS) model in zebrafish to more fully mimic chronic stress in human populations. We also examined behavioral and neurochemical alterations in zebrafish, and attempted to modulate these states by 3-week treatment with an antidepressant fluoxetine, a neuroprotective omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA), a pro-inflammatory endotoxin lipopolysaccharide (LPS), and their combinations. Overall, PCUS induced severe anxiety and elevated norepinephrine levels, whereas fluoxetine (alone or combined with other agents) corrected most of these behavioral deficits. While EPA and LPS alone had little effects on the zebrafish PCUS-induced anxiety behavior, both fluoxetine (alone or in combination) and EPA restored norepinephrine levels, whereas LPS + EPA increased dopamine levels. As these data support the validity of PCUS as an effective tool to study stress-related pathologies in zebrafish, further research is needed into the ability of various conventional and novel treatments to modulate behavioral and neurochemical biomarkers of chronic stress in this model organism.

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“…On the contrary, an intracerebroventricular injection of 10 mcg of 5-HT in the LPS-injected group reduced LPS-induced fever, plasma corticosterone, and plasma IL-6 release. Korte-Bouws et al [80] showed that LPS-induced 5-HT metabolism is significantly increased in both the Nucleus Accumbens (NAc) and Medial Prefrontal Cortex (mPFC) of homozygous (SERT+/+) male rats whereas this increase is partly or completely abolished in heterozygous (SERT+/-) or knockout (SERT-/-) male rats, respectively. The results of these studies suggested that bacterial LPS released by the intestine could interfere with the efficacy of drugs that act on the 5-HT receptor, potentially inducing adverse effects.…”

Section: Gut Motilitymentioning

confidence: 99%

The Relationship Between the Serotonin Metabolism, Gut-Microbiota and the Gut-Brain Axis

Stasi

Sadalla

Milani

2019

CDM

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Background:: Serotonin (5-HT) has a pleiotropic function in gastrointestinal, neurological/psychiatric and liver diseases. The aim of this review was to elucidate whether the gut-microbiota played a critical role in regulating peripheral serotonin levels. Methods:: We searched for relevant studies published in English using the PubMed database from 1993 to the present. Results: : Several studies suggested that alterations in the gut-microbiota may contribute to a modulation of serotonin signalling. The first indication regarded the changes in the composition of the commensal bacteria and the intestinal transit time caused by antibiotic treatment. The second indication regarded the changes in serotonin levels correlated to specific bacteria. The third indication regarded the fact that decreased serotonin transporter expression was associated with a shift in gut-microbiota from homeostasis to inflammatory type microbiota. Serotonin plays a key role in the regulation of visceral pain, secretion, and initiation of the peristaltic reflex; however, its altered levels are also detected in many different psychiatric disorders. Symptoms of some gastrointestinal functional disorders may be due to deregulation in central nervous system activity, dysregulation at the peripheral level (intestine), or a combination of both (brain-gut axis) by means of neuro-endocrine-immune stimuli. Moreover, several studies have demonstrated the profibrogenic role of 5-HT in the liver, showing that it works synergistically with platelet-derived growth factor in stimulating hepatic stellate cell proliferation. Conclusion:: Although the specific interaction mechanisms are still unclear, some studies have suggested that there is a correlation between the gut-microbiota, some gastrointestinal and liver diseases and the serotonin metabolism.

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Bacterial Lipopolysaccharide Increases Serotonin Metabolism in Both Medial Prefrontal Cortex and Nucleus Accumbens in Male Wild Type Rats, but Not in Serotonin Transporter Knockout Rats

Cited by 19 publications

References 51 publications

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

Modulation of behavioral and neurochemical responses of adult zebrafish by fluoxetine, eicosapentaenoic acid and lipopolysaccharide in the prolonged chronic unpredictable stress model

The Relationship Between the Serotonin Metabolism, Gut-Microbiota and the Gut-Brain Axis

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