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WITHDRAWN: Disturbances of purine and lipid metabolism in the microbiota-gut-brain axis in male adolescent nonhuman primates with depressive-like behaviors.
INTRODUCTION: Major depressive disorder (MDD) in adolescents is a widespread and growing global public health concern with unique characteristics and pathophysiological mechanisms that are distinct from MDD in adults. OBJECTIVE: The purpose of our work was to address this knowledge gap about the unique characteristics and pathophysiological mechanisms of adolescent depression from a microbiota-gut-brain (MGB) axis perspective. METHOD: Ten healthy male cynomolgus macaques (Macaca fascicularis) were paired into five pairs based on age and body weight, and two cynomolgus macaques from each pair were randomly allocated to chronic unpredictable mild stress group, or unstressed control group. At endpoint, microbe composition from cecum, ascending colon, transverse colon, and descending colon were analyzed by metagenome sequencing, and the metabolite profiles of MGB axis including central (prefrontal cortex, hippocampus and amygdala) and peripheral (plasma, gut and feces of cecum, ascending colon, transverse colon and descending colon) samples were analyzed by metabolomic profiling. Then, we compare the gut microbiome and metabolic signatures in MGB axis between adolescent and adult depressed macaques. RESULTS: The microbial composition and gut-brain metabolic signatures were widely divergent between adolescent and adult depressed macaques, though the phylum Firmicutes and lipid metabolism pathways were persistently altered in both populations. Purine and arginine biosynthesis metabolism were a specific hallmark of adolescent depressed macaques, while fatty acyl metabolism was specially altered in adult. These differential metabolic pathways in adolescent and adult depressed macaques were mainly mapped into the prefrontal cortex and hippocampus, respectively. Notably, the genus Clostridium and Haemophilus, characteristically disturbed in adolescent depressed macaques but not in adult, were also significantly associated with the majority of purine metabolites in MGB axis. CONCLUSION: These findings provide a new framework describing divergent pathophysiological mechanisms between adolescent and adult depression, and may open new windows for more effective treatment strategies of adolescent depression.
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Prenatal and Postnatal Maternal Psychological Distress and the Metabolomic Profile of Human Milk.
BACKGROUND: Human milk is the gold standard of infant nutrition, providing nutrients and bioactive metabolites that shape infant immune, cognitive, and metabolic development. Maternal psychological distress, including stress, anxiety, and depression, is prevalent during the perinatal period and may influence milk composition. Emerging evidence suggests that these alter metabolite classes, with potential long-term consequences for infant health. OBJECTIVES: This study aims to identify whether maternal stress, depressive, and anxiety symptoms are associated with differential metabolomic signatures in human milk from 2.5 to 24 mo postpartum. METHODS: Human milk samples were collected longitudinally at multiple postpartum time points from 424 mothers in the FinnBrain Birth Cohort study, yielding 718 samples. Human milk metabolite concentrations were quantified using 1H nuclear magnetic resonance-based metabolomics. Maternal depressive, anxiety, and stress symptoms were assessed using validated self-report scales prenatally and postnatally. Simple linear regression and linear mixed models examined associations between maternal symptom scores and human milk metabolite concentrations across lactation (false discovery rate <0.05). RESULTS: Human milk oligosaccharides such as Lacto-N-tetraose (LNT), lacto-N-fucopentaose I (LNFP I), and lacto-N-difucohexaose I/II (LNDFH I/II) showed negative associations with depressive and stress symptoms, whereas 3'-fucosyllactose (3'FL), 3'-sialyllactose (3'SL), and lacto-N-neotetraose (LNnT) were positively linked, particularly with prenatal symptoms.. Among amino acids, threonine concentrations declined with higher maternal symptom scores, whereas glutamate, glutamine, and taurine exhibited time-dependent associations across lactation. Succinate and hippurate showed positive associations with prenatal maternal symptom scores that shifted to negative associations later in lactation, whereas lactose and caprylate were negatively associated with postnatal symptoms. CONCLUSIONS: Both prenatal and postnatal maternal distress are associated with human milk metabolites. Human milk may buffer infants from some effects of maternal psychological distress because increases in key metabolites suggest potential compensatory roles in immune modulation and healthy gut microbiota. However, reductions in metabolites with established prebiotic and immune regulatory functions reinforce the importance of interventions that support maternal mental health during the perinatal period.
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Electroacupuncture Improves Depression-Like Behavior by Regulating the Abundance of Lactobacillus and Staphylococci in Mice.
BACKGROUND: Growing evidence suggests that gut microbiota can affect depression-like behavior, and electroacupuncture (EA) can regulate the composition and abundance of gut microbiota. At the same time, not a lot of research has been done on how EA affects gut microbiota to depression-like behavior. The objective of this study was to study the associated mechanisms by which EA exerts antidepressant effects by modulating gut microbiota. METHODS: Twenty-four C57BL/6 male mice were randomly divided into three groups, one group (n = 8) was the normal control group (NC). And the other two groups was chronic unpredictable mild stress for modeling + electroacupuncture group (CUMS + EA) (n = 8) and chronic unpredictable mild stress for modeling group (CUMS) (n = 8). Both CUMS and EA groups were subjected to 28 days of CUMS, but only the EA group received an additional 14 days of EA procedure. Behavior tests were used to determine the antidepressant effect of EA. Sequencing of the 16S ribosomal RNA (rRNA) gene was applied to examine alterations in the intestinal microbiome between groups. RESULTS: The findings were compared to those of the NC group, the sucrose preference rate and the total distance of Open Field Test (OFT) in CUMS group decreased, the abundance of Lactobacillus decreased, while the abundance of staphylococci increased. After the intervention of EA, the sucrose preference index and the total distance of OFT increased, the abundance of Lactobacillus increased, while the abundance of staphylococci decreased. CONCLUSIONS: These findings indicated EA may play an antidepressant effect by adjusting the abundance of Lactobacillus and staphylococci.
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Effect of Lactobacillus rhamnosus HN001 in Pregnancy on Postpartum Symptoms of Depression and Anxiety: A Randomised Double-blind Placebo-controlled Trial.
BACKGROUND: Probiotics may help to prevent symptoms of anxiety and depression through several putative mechanisms. OBJECTIVE: The aim of this study was to evaluate the effect of Lactobacillus rhamnosus HN001 (HN001) given in pregnancy and postpartum on symptoms of maternal depression and anxiety in the postpartum period. This was a secondary outcome, the primary outcome being eczema in the offspring at 12months of age. DESIGN, SETTING, PARTICIPANTS: A randomised, double-blind, placebo-controlled trial of the effect of HN001 on postnatal mood was conducted in 423 women in Auckland and Wellington, New Zealand. Women were recruited at 14-16weeks gestation. INTERVENTION: Women were randomised to receive either placebo or HN001 daily from enrolment until 6months postpartum if breastfeeding. OUTCOME MEASURES: Modified versions of the Edinburgh Postnatal Depression Scale and State Trait Anxiety Inventory were used to assess symptoms of depression and anxiety postpartum. TRIAL REGISTRATION: Australia NZ Clinical Trials Registry: ACTRN12612000196842. FINDINGS: 423 women were recruited between December 2012 and November 2014. 212 women were randomised to HN001 and 211 to placebo. 380 women (89.8%) completed the questionnaire on psychological outcomes, 193 (91.0%) in the treatment group and 187 (88.6%) in the placebo group. Mothers in the probiotic treatment group reported significantly lower depression scores (HN001 mean=7·7 (SD=5·4), placebo 9·0 (6·0); effect size -1·2, (95% CI -2·3, -0·1), p=0·037) and anxiety scores (HN001 12·0 (4·0), placebo 13·0 (4·0); effect size -1·0 (-1·9, -0·2), p=0·014) than those in the placebo group. Rates of clinically relevant anxiety on screening (score>15) were significantly lower in the HN001 treated mothers (OR=0·44 (0·26, 0·73), p=0·002). INTERPRETATION: Women who received HN001 had significantly lower depression and anxiety scores in the postpartum period. This probiotic may be useful for the prevention or treatment of symptoms of depression and anxiety postpartum. FUNDING SOURCE: Health Research Council of New Zealand (11/318) and Fonterra Co-operative Group Ltd.
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"I Am I and My Bacterial Circumstances": Linking Gut Microbiome, Neurodevelopment, and Depression.
Recently, there has been renewed interest in the role played by microbiome in both human health and human disease. A correct equilibrium between the human host and their microorganisms is important for an appropriate physiological function. Extensive research has shown that microbes that inhabit the gastrointestinal tract-or gut microbiota-are involved not only in both nutritive and digestive activities but also in immunological processes. Moreover, the gut microbiome influences both central nervous system and energy homeostasis. An altered gut microbiome has been associated with the pathophysiology of different diseases, including neuropsychiatric disorders. Apparently, both environmental-diet, exposition to antibiotics, and infections-and host-genetic factors have a strong influence on gut microbiome, modulating the risk for neuropsychiatric illness. Also, early life disruption of the microbiome-gut-brain (MGB) axis has been associated with an increased risk of developing depression later in life, suggesting a link between gut microbiome, neurodevelopment, and depression. This review aims to contribute to this growing area of research by exploring the role played by the gut microbiome in neurodevelopment and in the etiology of the depressive syndrome, including nutritional, immunological, and energy homeostasis approaches.
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Psychedelic medicine: The biology underlying the persisting psychedelic effects.
Psychedelic substances have regained interest as therapeutic agents in the treatment of stress-related disorders. The effects seem to be of persisting nature even after a single dose. Also in lower than 'regular' recreational doses, so-called micro-doses, without the typical effects on consciousness, users report beneficial effects on cognitive processes and well-being. The exact neurobiological mechanism underlying these persisting effects is not clear. While previous research has mainly focused on the central nervous system including the immune system and the neuroendocrine system, I propose a central role for sleep and the microbiome in the effects of regular and low doses of psychedelics respectively. It will be explained why this is hypothesized and studies to test this idea proposed. It is concluded that while these studies are needed to understand the biology underlying psychedelic medicine, it is also important to approach it in a holistic way, including all the above mentioned biological processes psychedelics are known to affect, and explore the role of other substance-related factors like route of administration and form, and factors like diet and lifestyle which are part of the psychedelic experience.
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Characterization of "microbiome-metabolome-immunity" in depressed rats with divergent responses to Paroxetine.
OBJECTIVES: Selective serotonin reuptake inhibitors (SSRIs) are the first-line anti-depressants. Unfortunately, about 30 % depressed patients do not effectively respond to SSRIs. It is still unclear that the gastrointestinal characteristics of responders and non-responders, and the differences. METHODS: Herein, we characterized gut microbiome and metabolome of depressed rats with differential responses to Paroxetine (PX) by 16S rRNA sequencing and 1H NMR-based metabolomics, respectively. On top of this, we constructed both inter- and inner-layer networks, intuitively showing the correlations among behavioral indicators, immune factors, intestinal bacteria, and differential metabolites. RESULTS: Consequently, we found that depressed rats differently responded to PX, which could be divided into PX responsive (PX-R) and non-responsive (PX-N) groups. Firstly, the depressive behaviors of PX-R rats and PX-N rats significantly differed. Meanwhile, inflammatory balance was also characterized for depressed rats with different responses to PX. Overall, PX-R rats and PX-N rats exhibited differential gut microbiome and metabolome, including intestinal structures, intestinal functions, metabolic profiles, metabolites, and metabolic pathways. LIMITATIONS: Metabolites that identified by metabolomics based on 1H NMR are not comprehensive enough. CONCLUSIONS: Taken together, our study demonstrated that gut microbiome and metabolome, as well as related functions, are of significance in differential responses of depressed rats to PX, which might be novel insights in uncovering the mechanisms of differences in efficacies of antidepressants.
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A role of gut-brain axis on prophylactic actions of arketamine in male mice exposed to chronic restrain stress.
The gut-brain axis, which includes gut microbiota and microbiome-derived metabolites, might be implicated in depression. We reported the sustained prophylactic effects of a new antidepressant arketamine in chronic restrain stress (CRS) model of depression. In this study, we investigated the role of gut-brain axis on the prophylactic effects of arketamine in the CRS (7 days) model. Pretreatment with arketamine (10 mg/kg, 1 day prior to the CRS onset) significantly prevented CRS-induced body weight loss, increased immobility time of forced swimming test, decreased sucrose preference of sucrose preference test, and reduced expressions of synaptic proteins (GluA1 and PSD-95) in the prefrontal cortex (PFC) in the male mice. Gut microbiota analysis showed that pretreatment with arketamine might restore altered abundance of gut microbiota in CRS-exposed mice. An untargeted metabolomics analysis revealed four metabolites (e.g., L-leucine, N-acetyl-l-glutamine, 2-(2,4-dichlorophenyl)-3-[4-(dimethylamino)phenyl]acrylonitrile, L-threonine amide) that were altered between control and CRS group; however, there were found to be altered between the saline + CRS group and the arketamine + CRS group. Network analysis demonstrated correlations among synaptic proteins in the PFC and certain microbiota, and blood metabolites. These findings suggest that gut-brain axis, including its metabolites, might partially contribute to the persistent prophylactic effects of arketamine in the CRS model.
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Identifying causative mechanisms linking early-life stress to psycho-cardio-metabolic multi-morbidity: The EarlyCause project.
INTRODUCTION: Depression, cardiovascular diseases and diabetes are among the major non-communicable diseases, leading to significant disability and mortality worldwide. These diseases may share environmental and genetic determinants associated with multimorbid patterns. Stressful early-life events are among the primary factors associated with the development of mental and physical diseases. However, possible causative mechanisms linking early life stress (ELS) with psycho-cardio-metabolic (PCM) multi-morbidity are not well understood. This prevents a full understanding of causal pathways towards the shared risk of these diseases and the development of coordinated preventive and therapeutic interventions. METHODS AND ANALYSIS: This paper describes the study protocol for EarlyCause, a large-scale and inter-disciplinary research project funded by the European Union's Horizon 2020 research and innovation programme. The project takes advantage of human longitudinal birth cohort data, animal studies and cellular models to test the hypothesis of shared mechanisms and molecular pathways by which ELS shapes an individual's physical and mental health in adulthood. The study will research in detail how ELS converts into biological signals embedded simultaneously or sequentially in the brain, the cardiovascular and metabolic systems. The research will mainly focus on four biological processes including possible alterations of the epigenome, neuroendocrine system, inflammatome, and the gut microbiome. Life-course models will integrate the role of modifying factors as sex, socioeconomics, and lifestyle with the goal to better identify groups at risk as well as inform promising strategies to reverse the possible mechanisms and/or reduce the impact of ELS on multi-morbidity development in high-risk individuals. These strategies will help better manage the impact of multi-morbidity on human health and the associated risk.
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Administration Time and Dietary Patterns Modified the Effect of Inulin on CUMS-Induced Anxiety and Depression.
SCOPE: Prebiotics exert anxiolytic and antidepressant effects through the microbiota-gut-brain axis in animal models. However, the influence of prebiotic administration time and dietary pattern on stress-induced anxiety and depression is unclear. In this study, whether administration time can modify the effect of inulin on mental disorders within normal and high-fat diets are investigated. METHODS AND RESULTS: Mice subjected to chronic unpredicted mild stress (CUMS) are administered with inulin in the morning (7:30-8:00 am) or evening (7:30-8:00 pm) for 12 weeks. Behavior, intestinal microbiome, cecal short-chain fatty acids, neuroinflammatory responses, and neurotransmitters are measured. A high-fat diet aggravated neuroinflammation and is more likely to induce anxiety and depression-like behavior (p < 0.05). Morning inulin treatment improves the exploratory behavior and sucrose preference better (p < 0.05). Both inulin treatments decrease the neuroinflammatory response (p < 0.05), with a more evident trend for the evening administration. Furthermore, morning administration tends to affect the brain-derived neurotrophic factor and neurotransmitters. CONCLUSION: Administration time and dietary patterns seem to modify the effect of inulin on anxiety and depression. These results provide a basis for assessing the interaction of administration time and dietary patterns, providing guidance for the precise regulation of dietary prebiotics in neuropsychiatric disorders.