Social anxiety disorder-associated gut microbiota increases social fear.

Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut microbiota has emerged as a key regulator of both brain and behaviour, especially those related to social function. Moreover, increasing data supports a role for immune function and oxytocin signalling in social responses. To investigate whether the gut microbiota plays a causal role in modulating behaviours relevant to SAD, we transplanted the microbiota from SAD patients, which was identified by 16S rRNA sequencing to be of a differential composition compared to healthy controls, to mice. Although the mice that received the SAD microbiota had normal behaviours across a battery of tests designed to assess depression and general anxiety-like behaviours, they had a specific heightened sensitivity to social fear, a model of SAD. This distinct heightened social fear response was coupled with changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis. This work demonstrates an interkingdom basis for social fear responses and posits the microbiome as a potential therapeutic target for SAD.

The Microbiota-Gut-Brain Axis.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI.

BACKGROUND: Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury. METHODS: Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers. RESULTS: The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1ß and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+). CONCLUSIONS: The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population.

The impact of diet on the microbiota composition and the role of diet in supporting optimal mental health have received much attention in the last decade. However, whether whole dietary approaches can exert psychobiotic effects is largely understudied. Thus, we investigated the influence of a psychobiotic diet (high in prebiotic and fermented foods) on the microbial profile and function as well as on mental health outcomes in a healthy human population. Forty-five adults were randomized into either a psychobiotic (n = 24) or control (n = 21) diet for 4 weeks. Fecal microbiota composition and function was characterized using shotgun sequencing. Stress, overall health and diet were assessed using validated questionnaires. Metabolic profiling of plasma, urine and fecal samples was performed. Intervention with a psychobiotic diet resulted in reductions of perceived stress (32% in diet vs. 17% in control group), but not between groups. Similarly, biological marker of stress were not affected. Additionally, higher adherence to the diet resulted in stronger decreases in perceived stress. While the dietary intervention elicited only subtle changes in microbial composition and function, significant changes in the level of 40 specific fecal lipids and urinary tryptophan metabolites were observed. Lastly, microbial volatility was linked to greater changes in perceived stress scores in those on the psychobiotic diet. These results highlight that dietary approaches can be used to reduce perceived stress in a human cohort. Using microbiota-targeted diets to positively modulate gut-brain communication holds possibilities for the reduction of stress and stress-associated disorders, but additional research is warranted to investigate underlying mechanisms, including the role of the microbiota.

The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota-gut-brain axis perspective.

The physiological consequences of stress often manifest in the gastrointestinal tract. Traumatic or chronic stress is associated with widespread maladaptive changes throughout the gut, although comparatively little is known about the effects of acute stress. Furthermore, these stress-induced changes in the gut may increase susceptibility to gastrointestinal disorders and infection, and impact critical features of the neural and behavioural consequences of the stress response by impairing gut-brain axis communication. Understanding the mechanisms behind changes in enteric nervous system circuitry, visceral sensitivity, gut barrier function, permeability, and the gut microbiota following stress is an important research objective with pathophysiological implications in both neurogastroenterology and psychiatry. Moreover, the gut microbiota has emerged as a key aspect of physiology sensitive to the effects of stress. In this review, we focus on different aspects of the gastrointestinal tract including gut barrier function as well as the immune, humoral and neuronal elements involved in gut-brain communication. Furthermore, we discuss the evidence for a role of stress in gastrointestinal disorders. Existing gaps in the current literature are highlighted, and possible avenues for future research with an integrated physiological perspective have been suggested. A more complete understanding of the spatial and temporal dynamics of the integrated host and microbial response to different kinds of stressors in the gastrointestinal tract will enable full exploitation of the diagnostic and therapeutic potential in the fast-evolving field of host-microbiome interactions.

Beta 3-adrenoceptor agonism ameliorates early-life stress-induced visceral hypersensitivity in male rats.

Visceral hypersensitivity, a hallmark of disorders of the gut-brain axis, is associated with exposure to early-life stress (ELS). Activation of neuronal ß3-adrenoceptors (AR) has been shown to alter central and peripheral levels of tryptophan and reduce visceral hypersensitivity. In this study, we aimed to determine the potential of a ß3-AR agonist in reducing ELS-induced visceral hypersensitivity and possible underlying mechanisms. Here, ELS was induced using the maternal separation (MS) model, where Sprague Dawley rat pups were separated from their mother in early life (postnatal day 2-12). Visceral hypersensitivity was confirmed in adult offspring using colorectal distension (CRD). CL-316243, a ß3-AR agonist, was administered to determine anti-nociceptive effects against CRD. Distension-induced enteric neuronal activation as well as colonic secretomotor function were assessed. Tryptophan metabolism was determined both centrally and peripherally. For the first time, we showed that CL-316243 significantly ameliorated MS-induced visceral hypersensitivity. Furthermore, MS altered plasma tryptophan metabolism and colonic adrenergic tone, while CL-316243 reduced both central and peripheral levels of tryptophan and affected secretomotor activity in the presence of tetrodotoxin. This study supports the beneficial role of CL-316243 in reducing ELS-induced visceral hypersensitivity, and suggests that targeting the ß3-AR can significantly influence gut-brain axis activity through modulation of enteric neuronal activation, tryptophan metabolism, and colonic secretomotor activity which may synergistically contribute to offsetting the effects of ELS.

Microbiota-Gut-Brain Axis: New Therapeutic Opportunities.

The traditional fields of pharmacology and toxicology are beginning to consider the substantial impact our gut microbiota has on host physiology. The microbiota-gut-brain axis is emerging as a particular area of interest and a potential new therapeutic target for effective treatment of central nervous system disorders, in addition to being a potential cause of drug side effects. Microbiota-gut-brain axis signaling can occur via several pathways, including via the immune system, recruitment of host neurochemical signaling, direct enteric nervous system routes and the vagus nerve, and the production of bacterial metabolites. Altered gut microbial profiles have been described in several psychiatric and neurological disorders. Psychobiotics, live biotherapeutics or substances whose beneficial effects on the brain are bacterially mediated, are currently being investigated as direct and/or adjunctive therapies for psychiatric and neurodevelopmental disorders and possibly for neurodegenerative disease, and they may emerge as new therapeutic options in the clinical management of brain disorders.

The gut microbiota is important for the maintenance of blood-cerebrospinal fluid barrier integrity.

The gut microbiota communicates with the brain through several pathways including the vagus nerve, immune system, microbial metabolites and through the endocrine system. Pathways along the humoral/immune gut microbiota-brain axis are composed of a series of vascular and epithelial barriers including the intestinal epithelial barrier, gut-vascular barrier, blood-brain barrier and blood-cerebrospinal fluid barrier. Of these barriers, the relationship between the gut microbiota and blood-cerebrospinal fluid barrier is yet to be fully defined. Here, using a germ-free mouse model, we aimed to assess the relationship between the gut microbiota and the integrity of the blood-cerebrospinal fluid barrier, which is localized to the choroid plexus epithelium. Using confocal microscopy, we visualized the tight junction protein zonula occludens-1, an integral aspect of choroid plexus integrity, as well as the choroid plexus fenestrated capillaries. Quantification of tight junction proteins via network analysis led to the observation that there was a decrease in the zonula occludens-1 network organization in germ-free mice; however, we did not observe any differences in capillary structure. Taken together, these data indicate that the blood-cerebrospinal fluid barrier is another barrier along the gut microbiota-brain axis. Future studies are required to elucidate its relative contribution in signalling from microbiota to the brain.

Age-associated deficits in social behaviour are microbiota-dependent.

Aging is associated with remodelling of immune and central nervous system responses resulting in behavioural impairments including social deficits. Growing evidence suggests that the gut microbiome is also impacted by aging, and we propose that strategies to reshape the aged gut microbiome may ameliorate some age-related effects on host physiology. Thus, we assessed the impact of gut microbiota depletion, using an antibiotic cocktail, on aging and its impact on social behavior and the immune system. Indeed, microbiota depletion in aged mice eliminated the age-dependent deficits in social recognition. We further demonstrate that although age and gut microbiota depletion differently shape the peripheral immune response, aging induces an accumulation of T cells in the choroid plexus, that is partially blunted following microbiota depletion. Moreover, an untargeted metabolomic analysis revealed age-dependent alterations of cecal metabolites that are reshaped by gut microbiota depletion. Together, our results suggest that the aged gut microbiota can be specifically targeted to affect social deficits. These studies propel the need for future investigations of other non-antibiotic microbiota targeted interventions on age-related social deficits both in animal models and humans.

Critical windows of early-life microbiota disruption on behaviour, neuroimmune function, and neurodevelopment.

Numerous studies have emphasised the importance of the gut microbiota during early life and its role in modulating neurodevelopment and behaviour. Epidemiological studies have shown that early-life antibiotic exposure can increase an individual's risk of developing immune and metabolic diseases. Moreover, preclinical studies have shown that long-term antibiotic-induced microbial disruption in early life can have enduring effects on physiology, brain function and behaviour. However, these studies have not investigated the impact of targeted antibiotic-induced microbiota depletion during critical developmental windows and how this may be related to neurodevelopmental outcomes. Here, we addressed this gap by administering a broad-spectrum oral antibiotic cocktail (ampicillin, gentamicin, vancomycin, and imipenem) to mice during one of three putative critical windows: the postnatal (PN; P2-9), pre-weaning (PreWean; P12-18), or post-weaning (Wean; P21-27) developmental periods and assessed the effects on physiology and behaviour in later life. Our results demonstrate that targeted microbiota disruption during early life has enduring effects into adolescence on the structure and function of the caecal microbiome, especially for antibiotic exposure during the weaning period. Further, we show that microbial disruption in early life selectively alters circulating immune cells and modifies neurophysiology in adolescence, including altered myelin-related gene expression in the prefrontal cortex and altered microglial morphology in the basolateral amygdala. We also observed sex and time-dependent effects of microbiota depletion on anxiety-related behavioural outcomes in adolescence and adulthood. Antibiotic-induced microbial disruption had limited and subtle effects on social behaviour and did not have any significant effects on depressive-like behaviour, short-term working, or recognition memory. Overall, this study highlights the importance of the gut microbiota during critical windows of development and the subtle but long-term effects that microbiota-targeted perturbations can have on brain physiology and behaviour.

The blood-brain barrier in aging and neurodegeneration.

The blood-brain barrier (BBB) is vital for maintaining brain homeostasis by enabling an exquisite control of exchange of compounds between the blood and the brain parenchyma. Moreover, the BBB prevents unwanted toxins and pathogens from entering the brain. This barrier, however, breaks down with age and further disruption is a hallmark of many age-related disorders. Several drugs have been explored, thus far, to protect or restore BBB function. With the recent connection between the BBB and gut microbiota, microbial-derived metabolites have been explored for their capabilities to protect and restore BBB physiology. This review, will focus on the vital components that make up the BBB, dissect levels of disruption of the barrier, and discuss current drugs and therapeutics that maintain barrier integrity and the recent discoveries of effects microbial-derived metabolites have on BBB physiology.

Biogeography of the large intestinal mucosal and luminal microbiome in cynomolgus macaques with depressive-like behavior.

Most previous studies in the pathophysiology of major depressive disorder (MDD) focused on fecal samples, which limit the identification of the gut mucosal and luminal microbiome in depression. Here, we address this knowledge gap. Male cynomolgus macaques (Macaca fascicularis) were randomly assigned to a chronic unpredictable mild stress (CUMS) group, or to an unstressed control group. Behavioral tests were completed in both groups. At endpoint, microbe composition of paired mucosal and luminal samples from cecum, ascending, transverse, and descending colons were determined by 16S ribosomal RNA gene sequencing. The levels of 34 metabolites involved in carbohydrate or energy metabolism in luminal samples were measured by targeted metabolomics profiling. CUMS macaques demonstrated significantly more depressive-like behaviors than controls. We found differences in mucosal and luminal microbial composition between the two groups, which were characterized by Firmicutes and Bacteriodetes at the phylum level, as well as Prevotellaceae and Lachnospiraceae at the family level. The majority of discriminative microbes correlated with the depressive-like behavioral phenotype. In addition, we found 27 significantly different microbiome community functions between the two groups in mucosa, and one in lumen, which were mainly involved in carbohydrate and energy metabolism. A total of nine metabolites involved in these pathways were depleted in CUMS animals. Together, CUMS macaques with depressive-like behaviors associated with distinct alterations of covarying microbiota, carbohydrate and energy metabolism in mucosa and lumen. Further studies should focus on the mucosal and luminal microbiome to provide a deeper spatiotemporal perspective of microbial alterations in the pathogenesis of MDD.

Metabolomic Workflow for the Accurate and High-Throughput Exploration of the Pathways of Tryptophan, Tyrosine, Phenylalanine, and Branched-Chain Amino Acids in Human Biofluids.

The modulation of host and dietary metabolites by gut microbiota (GM) is important for maintaining correct host physiology and in the onset of various pathologies. An ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for the targeted quantitation in human plasma, serum, and urine of 89 metabolites resulting from human-GM cometabolism of dietary essential amino acids tryptophan, tyrosine, and phenylalanine as well as branched-chain amino acids. Ninety-six-well plate hybrid-SPE enables fast clean-up of plasma and serum. Urine was diluted and filtered. A 15 min cycle enabled the acquisition of 96 samples per day, with most of the metabolites stable in aqueous solution for up to 72 h. Calibration curves were specifically optimized to cover expected concentrations in biological fluids, and limits of detection were at the order of ppb. Matrix effects were in acceptable ranges, and analytical recoveries were in general greater than 80%. Inter and intraday precision and accuracy were satisfactory. We demonstrated its application in plasma and urine samples obtained from the same individual in the frame of an interventional study, allowing the quantitation of 51 metabolites. The method could be considered the reference for deciphering changes in human-gut microbial cometabolism in health and disease. Data are available via Metabolights with the identifier MTBLS4399.

The gut microbiome and adult hippocampal neurogenesis: A new focal point for epilepsy?

Temporal lobe epilepsy (TLE) is a neurological disorder affecting millions of people worldwide and currently represents the most common form of focal epilepsy. Thus, the search for aetiological and pathophysiological parameters of TLE is ongoing. Preclinical work and post-mortem human studies suggest adult hippocampal neurogenesis as a potentially relevant factor in TLE pathogenesis. Although progress has been made in elucidating the molecular links between TLE and hippocampal neurogenesis, recent evidence suggests that additional peripheral mediators may be involved. The microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could comprise a link between neurogenesis and TLE. In this review, we discuss emerging evidence highlighting a potential role for the gut microbiome in connecting TLE pathogenesis and hippocampal neurogenesis. We focus in particular on mechanisms associated with neuronal excitability, neuroinflammation and gut microbial metabolites. As the evidence does not yet support a direct link between gut microbiota-regulated hippocampal neurogenesis and TLE aetiology or pathophysiology, future studies are needed to establish whether current findings comprise circumstantial links or a potentially novel avenue for clinically relevant research.

Diet and the microbiota - gut - brain-axis: a primer for clinical nutrition.

PURPOSE OF REVIEW: Diet is an essential modulator of the microbiota - gut - brain communication in health and disease. Consequently, diet-induced microbiome states can impact brain health and behaviour. The integration of microbiome into clinical nutrition perspectives of brain health is sparse. This review will thus focus on emerging evidence of microbiome-targeted dietary approaches with the potential to improve brain disorders. RECENT FINDINGS: Research in this field is evolving toward randomized controlled trials using dietary interventions with the potential to modulate pathways of the microbiota - gut - brain-axis. Although most studies included small cohorts, the beneficial effects of Mediterranean-like diets on symptoms of depression or fermented foods on the immune function of healthy individuals shed light on how this research line can grow. With a clinical nutrition lens, we highlight several methodological limitations and knowledge gaps, including the quality of dietary intake information, the design of dietary interventions, and missing behavioural outcomes. SUMMARY: Findings in diet - microbiome - brain studies can have groundbreaking implications in clinical nutrition practice and research. Modulating brain processes through diet via the gut microbiota raises numerous possibilities. Novel dietary interventions targeting the microbiota - gut - brain-axis can offer various options to prevent and treat health problems such as mental disorders. Furthermore, knowledge in this field will improve current nutritional guidelines for disease prevention.

Distinct post-sepsis induced neurochemical alterations in two mouse strains.

Sepsis associated encephalopathy, occurs in 70% of severe septic cases, following which survivors exhibit long-term cognitive impairment or global loss of cognitive function. Currently there is no clearly defined neurochemical basis of septic encephalopathy. Moreover, the lingering neurological complications associated with the severe acute respiratory syndrome CoV 2 (SARS-CoV-2) and the significant worsening in outcomes for those individuals with SARS-Cov-2 following sepsis underscore the need to define factors underlying the susceptibility to acute toxic encephalitis. In this study, differential neurochemical sequelae in response to sepsis (lipopolysaccharide (LPS)-induced endotoxemia and caecal ligation and puncture (CLP)), were evaluated in two inbred mouse strains, known to differ in behaviour, immune profile, and neurotransmitter levels, namely BALB/c and C57BL/6J. It was hypothesized that these strains would differ in sepsis severity, cytokine profile, peripheral tryptophan metabolism and central monoamine turnover. BALB/c mice exhibited more pronounced sickness behavioural scores, hypothermia, and significant upregulation of cytokines in the LPS model relative to C57BL/6J mice. Increased plasma kynurenine/tryptophan ratio, hippocampal serotonin and brainstem dopamine turnover were evident in both strains, but the magnitude was greater in BALB/c mice. In addition, CLP significantly enhanced kynurenine levels and hippocampal serotonergic and dopaminergic neurotransmission in C57BL/6J mice. Overall, these studies depict consistent changes in kynurenine, serotonin, and dopamine post sepsis. Further evaluation of these monoamines in the context of septic encephalopathy and cognitive decline is warranted. Moreover, these data suggest the continued evaluation of altered peripheral kynurenine metabolism as a potential blood-based biomarker of sepsis.

The immune-kynurenine pathway in social anxiety disorder.

BACKGROUND: The tryptophan-kynurenine pathway is of major interest in psychiatry and is altered in patients with depression, schizophrenia and panic disorder. Stress and immune alterations can impact this system, through cortisol- and cytokine-induced activation. In addition, there is emerging evidence that the kynurenine pathway is associated with suicidality. There have been no studies to date exploring the immune-kynurenine system in social anxiety disorder (SAD), and indeed very limited human studies on the kynurenine pathway in any clinical anxiety disorder. METHODS: We investigated plasma levels of several kynurenine pathway markers, including kynurenine (KYN), tryptophan (TRYP) and kynurenic acid (KYNA), along with the KYN/TRYP and KYNA/KYN ratios, in a cohort of 32 patients with SAD and 36 healthy controls. We also investigated a broad array of both basal and lipopolysaccharide (LPS)-stimulated blood cytokine levels including IFN-γ, interleukin (IL)-10, IL-1ß, IL-2, IL-4, IL-6, IL-8 and tumor necrosis factor (TNF)-α. RESULTS: SAD patients had elevated plasma KYNA levels and an increased KYNA/KYN ratio compared to healthy controls. No differences in KYN, TRYP or the KYN/TRYP ratio were seen between the two groups. SAD patients with a history of past suicide attempt showed elevated plasma KYN levels and a higher KYN/TRYP ratio compared to patients without a history of suicide attempt. No differences were seen in basal or LPS-stimulated pro-inflammatory cytokine levels between the patients and controls. However, unstimulated IL-10, an anti-inflammatory cytokine, was significantly lower in the SAD group. A significant sex influence was evident with SAD males having lower levels of IL-10 compared to healthy males but no difference seen between SAD females and healthy females. CONCLUSIONS: The peripheral kynurenine pathway is altered in SAD and preferentially directed towards KYNA synthesis. Additionally, kynurenine pathway activation, as evidenced by elevated KYN and KYN/TRYP ratio, is evident in SAD patients with a history of past suicide attempt. While no differences in pro-inflammatory cytokines is apparent in SAD patients, lower anti-inflammatory IL-10 levels are seen in SAD males. Further investigation of the role of the immune-kynurenine pathway in SAD and other clinical anxiety disorders is warranted.

The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies.

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges' g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

Diet and depression: exploring the biological mechanisms of action.

The field of nutritional psychiatry has generated observational and efficacy data supporting a role for healthy dietary patterns in depression onset and symptom management. To guide future clinical trials and targeted dietary therapies, this review provides an overview of what is currently known regarding underlying mechanisms of action by which diet may influence mental and brain health. The mechanisms of action associating diet with health outcomes are complex, multifaceted, interacting, and not restricted to any one biological pathway. Numerous pathways were identified through which diet could plausibly affect mental health. These include modulation of pathways involved in inflammation, oxidative stress, epigenetics, mitochondrial dysfunction, the gut microbiota, tryptophan-kynurenine metabolism, the HPA axis, neurogenesis and BDNF, epigenetics, and obesity. However, the nascent nature of the nutritional psychiatry field to date means that the existing literature identified in this review is largely comprised of preclinical animal studies. To fully identify and elucidate complex mechanisms of action, intervention studies that assess markers related to these pathways within clinically diagnosed human populations are needed.

Gut Reactions: Breaking Down Xenobiotic-Microbiome Interactions.

The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine.