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Kynurenines, Neuronal Excitotoxicity, and Mitochondrial Oxidative Stress: Role of the Intestinal Flora.
The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into the gastrointestinal aspects but also the pathomechanism of other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial disorders are the most common type of inheritable metabolic illness caused by mutations of mitochondrial and nuclear DNA. Despite the intensive research, its diagnosis is usually difficult, and unfortunately, treating it challenges physicians. Metabolites of the kynurenine pathway are linked to many disorders, such as depression, schizophrenia, migraine, and also diseases associated with impaired mitochondrial function. The kynurenine pathway includes many substances, for instance kynurenic acid and quinolinic acid. In this review, we would like to show a possible link between the metabolites of the kynurenine pathway and mitochondrial stress in the context of intestinal flora. Furthermore, we summarize the possible markers of and future therapeutic options for the kynurenine pathway in excitotoxicity and mitochondrial oxidative stress.
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Addition of fermented and unfermented grape skin in broilers' diets: effect on digestion, growth performance, intestinal microbiota and oxidative stability of meat.
Grape skin is a source of polyphenols with antioxidant and antimicrobial properties. Little information is available regarding its application in animal feeding. The present study investigated the effect of inclusion of fermented (FS) and unfermented (UFS) grape skin at two different doses (30 g/kg, FS30 and UFS30, and 60 g/kg, FS60 and UFS60) and 200 mg/kg vitamin E (α-tocopheryl acetate) in a corn-soybean diet on growth performance, ileal protein digestibility, ileal and excreta total extractable polyphenols content and digestibility, intestinal microbiota and thigh meat oxidation in broiler chickens. Growth performance was depressed in chickens fed UFS and FS diets. A reduction in ileal protein digestibility was also observed in birds fed UFS, being this effect more pronounced in those fed 60 g/kg. The dietary inclusion of grape skin increased both ileal and excreta polyphenols contents, being higher in birds fed UFS than in those fed FS. Excreta moisture content increased in birds fed UFS and FS diets. No effect of dietary inclusion of grape skin was observed on ileal counts of lactic-acid bacteria and Clostridium, but UFS inclusion in the diet reduced ileal count of Escherichia coli as compared with FS dietary inclusion. After 7 days of refrigerated storage, values of thiobarbituric acid reactive substances (TBARS) were lower in chicken meat when grape skin was added in the diet at 60 g/kg instead of 30 g/kg, and meat from birds fed 60 g/kg of grape skin reached TBARS values similar to those of birds supplemented with vitamin E. In conclusion, high doses of grape skin polyphenols depressed growth performance and protein digestibility, and increased excreta moisture content. Unfermented grape skin contained more polyphenols than FS, and its inclusion in the diet led to higher ileal and excreta polyphenols contents and to a lower ileal count of E. coli. Furthermore, the antioxidant potential of the polyphenols present in grape skin was observed after 7 days of meat storage, with the dose of 60 g/kg of grape skin being as effective as vitamin E supplementation in maintaining oxidative stability of meat.
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Probiotaceuticals: Back to the future?
Probiotic research has undergone some exciting and unanticipated changes in direction since the 2010 commentary by GSH, which speculated on probiotics being ultimately utilized as "factories" capable of releasing pharmaceutical-grade metabolites with therapeutic potential for a wide range of primarily gastrointestinal disorders. Indeed, the unrelenting search for new alternatives to antibiotics has further stimulated the development of "next-generation" probiotics. Postbiotics, defined as inanimate microorganisms and/or their components that confer a health benefit on the host, remain at the forefront of current probiotic research, with increasing numbers of probiotic species, strains, and substrains now being identified and further exploited as pharmabiotics; probiotics with a proven pharmacologic role in health and disease that have been subjected to clinical trial prior to approval by regulatory bodies. However, perhaps the most unanticipated probiotic development over the past 15 y has been the emergence of psychobiotics with the potential to improve aspects of mental health, such as depression and anxiety, through the release of bioactive metabolites. Moreover, the recent identification of pharmacobiotics, probiotics capable of facilitating the effectiveness of conventional pharmaceutical drugs, is opening new avenues for probiotic applications to combat a range of diseases, including cancers of the digestive system. Although in its infancy, recent reports of oncobiotics with antineoplastic properties are further expanding the potential for certain next-generation probiotics to impact current cancer treatment regimens and possibly even contribute to cancer prevention. Looking to the next 15 y of probiotic development, one could perhaps predict the ultimate development of regulatory-approved xenopostbiotic formulations comprising metabolites with the capacity to improve digestive health, decrease the severity of intestinal disease, and increase the effectiveness of conventional pharmaceuticals, whilst simultaneously improving cognitive functioning and mental welfare. Although speculative, these xenopostbiotic formulations could prove especially effective for the adjunctive treatment of serious chronic diseases such as cancer.
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Exposure to polystyrene nanoplastics causes immune damage, oxidative stress and intestinal flora disruption in salamander (Andrias davidianus) larvae.
The toxic effects of nanoparticles have been increasingly investigated, but there has been limited research on amphibians, especially those of conservation value. This study examined the effects of different concentrations (0, 0.04, 0.2, 1, 5 mg/L) of polystyrene nanoplastics (PS-NPs, 80 nm) on the short-term exposure (7 d) of Andrias davidianus. Results demonstrated the concentration-dependent enrichment of PS-NPs in the intestine. Histological lesions displayed increased hepatic macrophages with cellular rupture, broken intestinal villi, decreased cuprocytes and crypt depression. Antioxidant- and inflammation-related enzyme activities were analysed, and it was found that hepatic and intestinal MDA content and CAT activity were highest in the N-1 group and SOD activity was highest in the N-0.2 group (p < 0.05). AKP activity continued to decline, and iNOS activity was highest in the N-0.2 group (p < 0.05). il-10, tgf-β, bcl-w and txnl1 were significantly downregulated in the N-0.2 group, while il-6 and il-8 were markedly upregulated in the N-0.2 group (p < 0.05). Exposing to PS-NPs decreased probiotic bacteria (Cetobacterium, Akkermansia) and increased pathogenic bacteria (Lachnoclostridium). Our results suggest that NPs exposure can have deleterious effects on salamanders, which predicts that NPs contamination may lead to continued amphibian declines. Therefore, we strongly recommend that attention be paid to amphibians, especially endangered species, in the field of NPs.
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Nutrition and schizophrenia: associations worthy of continued revaluation.
BACKGROUND: Accumulating evidence have shown that diet and nutrition play significant roles in mental illness, such as depression, anxiety and bipolar disorder. However, comprehensive evaluation of the relationship between nutrition and schizophrenia is lacking. OBJECTIVE: The present review aims to synthetic elaborate the associations between nutrition and schizophrenia. Relevant studies on dietary patterns, macronutrients, micronutrients were performed through a literature search to synthesize the extracted data. SUMMARY: Dietary interventions may help prevent the occurrence of schizophrenia, or delay symptoms: Healthy diets like nutritious plant-based foods and high-quality protein, have been linked to reducing the risk or symptoms of schizophrenia. Moreover, diet high in saturated fat and sugar is linked to more serious outcomes of schizophrenia. Additionally, when N-acetylcysteine acts as an adjuvant therapy, the overall symptoms of schizophrenia are significantly reduced. Also nascent evidence showed mental disorders may be related to intestinal microbiota dysfunction. Our study offered important insights into the dietary habits of patients with schizophrenia and the potential impact of nutritional factors on the disease. We also emphasized the need for further research, particularly in the form of large randomized double-blind controlled trials, to better understand the effects of nutrients on schizophrenia symptoms in different populations and disease types.
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Efficacy of a curcumin extract (Curcugen™) on gastrointestinal symptoms and intestinal microbiota in adults with self-reported digestive complaints: a randomised, double-blind, placebo-controlled study.
BACKGROUND: There is preliminary evidence to suggest curcumin can alleviate digestive symptoms in adults with self-reported digestive complaints and irritable bowel syndrome. However, in all these trials, curcumin was used as a component of a multi-herbal combination and there were consistent concerns associated with risk of bias in most studies. The goal of this study was to investigate the effects of a curcumin extract (Curcugen™) on gastrointestinal symptoms, mood, and overall quality of life in adults presenting with self-reported digestive complaints. Moreover, to determine the potential therapeutic mechanisms of action associated with curcumin, its effects on intestinal microbiota and small intestinal bowel overgrowth (SIBO) were examined. METHODS: In this 8-week, parallel-group, double-blind, randomised controlled trial, 79 adults with self-reported digestive complaints were recruited and randomised to receive either a placebo or 500 mg of the curcumin extract, Curcugen™. Outcome measures included the Gastrointestinal Symptom Rating Scale (GSRS), intestinal microbial profile (16S rRNA), Depression, Anxiety, and Stress Scale - 21 (DASS-21), Short Form-36 (SF-36), and SIBO breath test. RESULTS: Based on self-report data collected from 77 participants, curcumin was associated with a significantly greater reduction in the GSRS total score compared to the placebo. There was also a greater reduction in the DASS-21 anxiety score. No other significant between-group changes in self-report data were identified. An examination of changes in the intestinal microbial profile and SIBO test revealed curcumin had no significant effect on these parameters. Curcumin was well-tolerated with no significant adverse events. CONCLUSIONS: The curcumin extract, Curcugen™, administered for 8 weeks at a dose of 500 mg once daily was associated with greater improvements in digestive complaints and anxiety levels in adults with self-reported digestive complaints. Compared to the placebo, there were no significant changes in intestinal microbiota or SIBO; however, further research using larger samples and testing methods that allow more detailed microbial analyses will be important. An investigation into other potential mechanisms associated with curcumin's gastrointestinal-relieving effects will also be important such as examining its influence on the intestinal barrier function, inflammation, neurotransmitter activity, and visceral sensitivity. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, Trial ID. ACTRN12619001236189 . Registered 6 September 2019.
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A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression.
A large body of evidence indicates that major affective disorders are accompanied by activated neuro-immune, neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways. Postpartum depression is predicted by end of term prenatal depressive symptoms whilst a lifetime history of mood disorders appears to increase the risk for both prenatal and postpartum depression. This review provides a critical appraisal of available evidence linking IO&NS pathways to prenatal and postpartum depression. The electronic databases Google Scholar, PubMed and Scopus were sources for this narrative review focusing on keywords, including perinatal depression, (auto)immune, inflammation, oxidative, nitric oxide, nitrosative, tryptophan catabolites (TRYCATs), kynurenine, leaky gut and microbiome. Prenatal depressive symptoms are associated with exaggerated pregnancy-specific changes in IO&NS pathways, including increased C-reactive protein, advanced oxidation protein products and nitric oxide metabolites, lowered antioxidant levels, such as zinc, as well as lowered regulatory IgM-mediated autoimmune responses. The latter pathways coupled with lowered levels of endogenous anti-inflammatory compounds, including ω3 polyunsaturated fatty acids, may also underpin the pathophysiology of postpartum depression. Although increased bacterial translocation, lipid peroxidation and TRYCAT pathway activation play a role in mood disorders, similar changes do not appear to be relevant in perinatal depression. Some IO&NS biomarker characteristics of mood disorders are found in prenatal depression indicating that these pathways partly contribute to the association of a lifetime history of mood disorders and perinatal depression. However, available evidence suggests that some IO&NS pathways differ significantly between perinatal depression and mood disorders in general. This review provides a new IO&NS model of prenatal and postpartum depression.
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Graves' disease as a driver of depression: a mechanistic insight.
Graves' disease (GD) is characterized by diffuse enlargement and overactivity of the thyroid gland, which may be accompanied by other physical symptoms. Among them, depression can dramatically damage patients' quality of life, yet its prevalence in GD has not received adequate attention. Some studies have established a strong correlation between GD and increased risk of depression, though the data from current study remains limited. The summary of mechanistic insights regarding GD and depression has underpinned possible pathways by which GD contributes to depression. In this review, we first summarized the clinical evidence that supported the increased prevalence of depression by GD. We then concentrated on the mechanistic findings related to the acceleration of depression in the context of GD, as mounting evidence has indicated that GD promotes the development of depression through various mechanisms, including triggering autoimmune responses, inducing hormonal disorders, and influencing the thyroid-gut-microbiome-brain axis. Finally, we briefly presented potential therapeutic approaches to decreasing the risk of depression among patients with GD.
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Nutritional psychiatry: Towards improving mental health by what you eat.
Does it matter what we eat for our mental health? Accumulating data suggests that this may indeed be the case and that diet and nutrition are not only critical for human physiology and body composition, but also have significant effects on mood and mental wellbeing. While the determining factors of mental health are complex, increasing evidence indicates a strong association between a poor diet and the exacerbation of mood disorders, including anxiety and depression, as well as other neuropsychiatric conditions. There are common beliefs about the health effects of certain foods that are not supported by solid evidence and the scientific evidence demonstrating the unequivocal link between nutrition and mental health is only beginning to emerge. Current epidemiological data on nutrition and mental health do not provide information about causality or underlying mechanisms. Future studies should focus on elucidating mechanism. Randomized controlled trials should be of high quality, adequately powered and geared towards the advancement of knowledge from population-based observations towards personalized nutrition. Here, we provide an overview of the emerging field of nutritional psychiatry, exploring the scientific evidence exemplifying the importance of a well-balanced diet for mental health. We conclude that an experimental medicine approach and a mechanistic understanding is required to provide solid evidence on which future policies on diet and nutrition for mental health can be based.
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A novel stepwise integrative analysis pipeline reveals distinct microbiota-host interactions and link to symptoms in irritable bowel syndrome.
Although incompletely understood, microbiota-host interactions are assumed to be altered in irritable bowel syndrome (IBS). We, therefore, aimed to develop a novel analysis pipeline tailored for the integrative analysis of microbiota-host interactions and association to symptoms and prove its utility in a pilot cohort. A multilayer stepwise integrative analysis pipeline was developed to visualize complex variable associations. Application of the pipeline was demonstrated on a dataset of IBS patients and healthy controls (HC), using the R software package to analyze colonic host mRNA and mucosal microbiota (16S rRNA gene sequencing), as well as gastrointestinal (GI) and psychological symptoms. In total, 42 IBS patients (57% female, mean age 33.6 (range 18-58)) and 20 HC (60% female, mean age 26.8 (range 23-41)) were included. Only in IBS patients, mRNA expression of Toll-like receptor 4 and genes associated with barrier function (PAR2, OCLN, TJP1) intercorrelated closely, suggesting potential functional relationships. This host genes-based "permeability cluster" was associated to mucosa-adjacent Chlamydiae and Lentisphaerae, and furthermore associated to satiety as well as to anxiety, depression and fatigue. In both IBS patients and HC, chromogranins, secretogranins and TLRs clustered together. In IBS patients, this host genes-based "immune-enteroendocrine cluster" was associated to specific members of Firmicutes, and to depression and fatigue, whereas in HC no significant association to microbiota was identified. We have developed a stepwise integrative analysis pipeline that allowed identification of unique host-microbiota intercorrelation patterns and association to symptoms in IBS patients. This analysis pipeline may aid in advancing the understanding of complex variable associations in health and disease.