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Probiotics and their Potential Effects on Schizophrenia Symptoms
Published in Martin Colin R, Derek Larkin, Probiotics in Mental Health, 2018
Mick P Fleming, Colin R Martin
O’Mahony et al. (2011) describe the gut-brain axis as a complex reflex network that is made up of receptors, neurotransmitters, afferent and efferent fibres that project into different parts of the autonomic nervous system such as integrative central areas and smooth muscle and glands. The bi-directional nature of the communication suggests that the brain can influence gastro intestinal functioning and vice versa in terms of the gastro intestinal system influencing reflex responses and regulation (O’Mahony et al., 2011). This model of communication within the axis implies that psychological processes, particularly stress responses, can influence gastro-intestinal functioning and gastro-intestinal functioning can influence cognitions, emotional response and behaviour. The Hypothalamic-pituitary axis (HPA) is activated by chronic stress and is made up of three main structures; (1) the hypothalamus, (2) the pituitary gland, and (3) the adrenal glands. The HPA regulates the immune system and is the mechanism that regulates the bio-psychological stress response in humans. Corticotrophin-releasing factor receptors produced as part of the HPA function are found in both the central nervous system and the gastro-intestinal tract. Secretion of corticotrophin-releasing factor (CRF) within the gastro-intestinal tract has been found to influence a number of functions of gut-brain axis such as transit, visceral sensation and permeability of the intestinal wall (O’Mahony et al., 2011). Providing evidence of the central role played by the HPA and its products within the gut- brain axis (McKeman et al., 2010; Neufeld et al., 2011). A number of mechanisms and study findings have been identified as evidence supporting this gut-brain axis (O’Mahony et al., 2011).The high co-morbidity found in clinical studies between stress related conditions and gastrointestinal disorders (Bercik et al., 2011; Cryan and O’Mahony, 2011).Links between chronic stress and anxiety, immune response and the development of inflammatory conditions such as irritable bowel syndrome (McKernan et al., 2010; Neufeld et al., 2011).Implication of the action of chronic stress on the regulation of stress response hormones initiated by the hypothalamic-pituitary-adrenal axis and its association with the development of irritable bowel syndrome (McKernan et al., 2010).Associations between gastro-intestinal infections and changes in behaviour and central nervous system biochemistry such as changes in tryptophan metabolism causing and increasing levels of anxiety inducing kynurenin (Bercik et al., 2011). Alterations in the level of kynurenine 3-monooxygenase enzymes within the kynurenine pathway leading to increased concentrations of cortical kynurenic acid in the cerebrospinal fluid have been associated with the development of neuro-cognitive deficits found in people with schizophrenia (Wonodi et al., 2011).
Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease
Published in Expert Opinion on Therapeutic Targets, 2021
Fanni Annamária Boros, László Vécsei
The first step of the KP is the conversion of Trp into N-formyl-L-kynurenine in a reaction catalyzed by indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO) enzymes. N-formyl-L-kynurenine is then metabolized into L-kynurenine (KYN) by formamidase. KYN is situated at an important branch point of the KP, since it can be converted into i) kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), ii) anthranilic acid (AA) by kynureninase (KYNU), and iii) 3-hydroxykynurenine (3-HK) via a reaction catalyzed by kynurenine 3-monooxygenase (KMO). 3HK can further be metabolized into xanthurenic acid (XA) by KATs or can form 3-hydroxyanthranilate (3-HAA), which is further converted into 2-amino-3-carboxymuconate semialdehyde (ACMS) in a reaction catalyzed by 3-hydroxyanthranilate 3,4-dioxygenase. ACMS can be further processed by aminocarboxymuconate-semialdehyde decarboxylase (ACMSD) for the synthesis of 2-aminomuconate semialdehyde, which is then further metabolized into picolinic acid (PIC). ACMS can also undergo non-enzymatic cyclization and form quinolinic acid (QUIN), which is then ultimately metabolized into nicotinamide adenine dinucleotide (NAD+), a crucial molecule for cellular energy production and metabolism.
Exercise-mediated improvement of depression in patients with gastro-esophageal junction cancer is linked to kynurenine metabolism
Published in Acta Oncologica, 2019
Anita Herrstedt, Marie L. Bay, Casper Simonsen, Anna Sundberg, Charlotte Egeland, Sarah Thorsen-Streit, Sissal S. Djurhuus, Per Magne Ueland, Øivind Midttun, Bente K. Pedersen, Lars Bo Svendsen, Pieter de Heer, Jesper F. Christensen, Pernille Hojman
As an alternative to the conversion of Kyn to KA, Kyn may be metabolized to 3-hydroxykynurenine (HK) and its downstream products leading to accumulation of neurotoxic metabolites (Figure 3a). We found normal plasma level of HK in both groups at baseline (Figure 3b), but across the intervention period, plasma HK increased significantly in the control group (21.5 µmol/l [5.61; 37.35], p < 0.001), while this induction was attenuated in the exercise group across the intervention period (6.42 µmol/l [−0.15; 12.98], p = 0.07) (Figure 3b). Accordingly, the ratio of HK/Kyn increased significantly in the control group (8.80 [0.21; 17.39], p = 0.01), but not in the exercise group (3.38 [−0.46; 7.21], p = 0.12) (Figure 3c). The conversion of Kyn to HK is catalyzed by kynurenine 3-monooxygenase (KMO), an enzyme that is induced by pro-inflammatory cytokines. We, therefore, evaluated the expression level of KMO in muscle biopsies taken post-intervention in both groups and found that KMO expression was higher in the control group compared with the exercise group (p = 0.05) (Figure 3d). Across the intervention period, we observed high inter-individual variations in the paired muscle biopsies and thus no significant differences in either group (Figure 3e). HK is either converted to xanthurenic acid (XA) or 3-hydroxyanthranilic acid (HAA), which is formed based on anthranilic acid (AA) (Figure 4a). We did not observe any effects on plasma XA or HAA levels across the intervention period (Figure 3h). In contrast, the HAA intermediate, AA, increased significantly during the intervention period in both the exercise group (3.70 [1.64; 5.77], p = 0.003) and the control group (4.21 [1.42; 7.00], p = 0.002) (Figure 3g). HAA is further converted to quinolinic acid (QA), and across the intervention period, mean QA levels increased in the control group (60.8 [−35.3; 156.9], p = 0.045), while no further increases were observed in the exercise group (Figure 3i).