The gut-brain axis in individuals with alcohol use disorder: An exploratory study of associations among clinical symptoms, brain morphometry, and the gut microbiome.

BACKGROUND: Alcohol use disorder (AUD) is commonly associated with distressing psychological symptoms. Pathologic changes associated with AUD have been described in both the gut microbiome and brain, but the mechanisms underlying gut-brain signaling in individuals with AUD are unknown. This study examined associations among the gut microbiome, brain morphometry, and clinical symptoms in treatment-seeking individuals with AUD. METHODS: We performed a secondary analysis of data collected during inpatient treatment for AUD in subjects who provided gut microbiome samples and had structural brain magnetic resonance imaging (MRI; n = 16). Shotgun metagenomics sequencing was performed, and the morphometry of brain regions of interest was calculated. Clinical symptom severity was quantified using validated instruments. Gut-brain modules (GBMs) used to infer neuroactive signaling potential from the gut microbiome were generated in addition to microbiome features (e.g., alpha diversity and bacterial taxa abundance). Bivariate correlations were performed between MRI and clinical features, microbiome and clinical features, and MRI and microbiome features. RESULTS: Amygdala volume was significantly associated with alpha diversity and the abundance of several bacteria including taxa classified to Blautia, Ruminococcus, Bacteroides, and Phocaeicola. There were moderate associations between amygdala volume and GBMs, including butyrate synthesis I, glutamate synthesis I, and GABA synthesis I & II, but these relationships were not significant after false discovery rate (FDR) correction. Other bacterial taxa with shared associations to MRI features and clinical symptoms included Escherichia coli and Prevotella copri. CONCLUSIONS: We identified gut microbiome features associated with MRI morphometry and AUD-associated symptom severity. Given the small sample size and bivariate associations performed, these results require confirmation in larger samples and controls to provide meaningful clinical inferences. Nevertheless, these results will inform targeted future research on the role of the gut microbiome in gut-brain communication and how signaling may be altered in patients with AUD.

Prenatal stress impacts foetal neurodevelopment: Temporal windows of gestational vulnerability.

Prenatal maternal stressors ranging in severity from everyday occurrences/hassles to the experience of traumatic events negatively impact neurodevelopment, increasing the risk for the onset of psychopathology in the offspring. Notably, the timing of prenatal stress exposure plays a critical role in determining the nature and severity of subsequent neurodevelopmental outcomes. In this review, we evaluate the empirical evidence regarding temporal windows of heightened vulnerability to prenatal stress with respect to motor, cognitive, language, and behavioural development in both human and animal studies. We also explore potential temporal windows whereby several mechanisms may mediate prenatal stress-induced neurodevelopmental effects, namely, excessive hypothalamic-pituitary-adrenal axis activity, altered serotonin signalling and sympathetic-adrenal-medullary system, changes in placental function, immune system dysregulation, and alterations of the gut microbiota. While broadly defined developmental windows are apparent for specific psychopathological outcomes, inconsistencies arise when more complex cognitive and behavioural outcomes are considered. Novel approaches to track molecular markers reflective of the underlying aetiologies throughout gestation to identify tractable biomolecular signatures corresponding to critical vulnerability periods are urgently required.

Maternal high-fat diet-induced microbiota changes are associated with alterations in embryonic brain metabolites and adolescent behaviour.

The developing central nervous system is highly sensitive to nutrient changes during the perinatal period, emphasising the potential impact of alterations of maternal diet on offspring brain development and behaviour. A growing body of research implicates the gut microbiota in neurodevelopment and behaviour. Maternal overweight and obesity during the perinatal period has been linked to changes in neurodevelopment, plasticity and affective disorders in the offspring, with implications for microbial signals from the maternal gut. Here we investigate the impact of maternal high-fat diet (mHFD)-induced changes in microbial signals on offspring brain development, and neuroimmune signals, and the enduring effects on behaviour into adolescence. We first demonstrate that maternal caecal microbiota composition at term pregnancy (embryonic day 18: E18) differs significantly in response to maternal diet. Moreover, mHFD resulted in the upregulation of microbial genes in the maternal intestinal tissue linked to alterations in quinolinic acid synthesis and elevated kynurenine levels in the maternal plasma, both neuronal plasticity mediators related to glutamate metabolism. Metabolomics of mHFD embryonic brains at E18 also detected molecules linked to glutamate-glutamine cycle, including glutamic acid, glutathione disulphide and kynurenine. During adolescence, the mHFD offspring exhibited increased locomotor activity and anxiety-like behaviour in a sex-dependent manner, along with upregulation of glutamate-related genes compared to controls. Overall, our results demonstrate that maternal exposure to high-fat diet results in microbiota changes, behavioural imprinting, altered brain metabolism and glutamate signalling during critical developmental windows during the perinatal period.

Opening the doors of precision medicine: novel tools to assess intestinal barrier in inflammatory bowel disease and colitis-associated neoplasia.

Mounting evidence underscores the pivotal role of the intestinal barrier and its convoluted network with diet and intestinal microbiome in the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC). Moreover, the bidirectional association of the intestinal barrier with the liver and brain, known as the gut-brain axis, plays a crucial role in developing complications, including extraintestinal manifestations of IBD and CRC metastasis. Consequently, barrier healing represents a crucial therapeutic target in these inflammatory-dependent disorders, with barrier assessment predicting disease outcomes, response to therapy and extraintestinal manifestations.New advanced technologies are revolutionising our understanding of the barrier paradigm, enabling the accurate assessment of the intestinal barrier and aiding in unravelling the complexity of the gut-brain axis. Cutting-edge endoscopic imaging techniques, such as ultra-high magnification endocytoscopy and probe-based confocal laser endomicroscopy, are new technologies allowing real-time exploration of the 'cellular' intestinal barrier. Additionally, novel advanced spatial imaging technology platforms, including multispectral imaging, upconversion nanoparticles, digital spatial profiling, optical spectroscopy and mass cytometry, enable a deep and comprehensive assessment of the 'molecular' and 'ultrastructural' barrier. In this promising landscape, artificial intelligence plays a pivotal role in standardising and integrating these novel tools, thereby contributing to barrier assessment and prediction of outcomes.Looking ahead, this integrated and comprehensive approach holds the promise of uncovering new therapeutic targets, breaking the therapeutic ceiling in IBD. Novel molecules, dietary interventions and microbiome modulation strategies aim to restore, reinforce, or modulate the gut-brain axis. These advancements have the potential for transformative and personalised approaches to managing IBD.

Social fear extinction susceptibility is associated with Microbiota-Gut-Brain axis alterations.

Social anxiety disorder is a common psychiatric condition that severely affects quality of life of individuals and is a significant societal burden. Although many risk factors for social anxiety exist, it is currently unknown how social fear sensitivity manifests biologically. Furthermore, since some individuals are resilient and others are susceptible to social fear, it is important to interrogate the mechanisms underpinning individual response to social fear situations. The microbiota-gut-brain axis has been associated with social behaviour, has recently been linked with social anxiety disorder, and may serve as a therapeutic target for modulation. Here, we assess the potential of this axis to be linked with social fear extinction processes in a murine model of social anxiety disorder. To this end, we correlated differential social fear responses with microbiota composition, central gene expression, and immune responses. Our data provide evidence that microbiota variability is strongly correlated with alterations in social fear behaviour. Moreover, we identified altered gene candidates by amygdalar transcriptomics that are linked with social fear sensitivity. These include genes associated with social behaviour (Armcx1, Fam69b, Kcnj9, Maoa, Serinc5, Slc6a17, Spata2, and Syngr1), inflammation and immunity (Cars, Ckmt1, Klf5, Maoa, Map3k12, Pex5, Serinc5, Sidt1, Spata2), and microbe-host interaction (Klf5, Map3k12, Serinc5, Sidt1). Together, these data provide further evidence for a role of the microbiota-gut-brain axis in social fear responses.

A novel animal model for understanding secondary traumatic stress and visceral pain in male rats.

Empathetic relationships and the social transference of behaviours have been shown to occur in humans, and more recently through the development of rodent models, where both fear and pain phenotypes develop in observer animals. Clinically, observing traumatic events can induce 'trauma and stressor-related disorders' as defined in the DSM 5. These disorders are often comorbid with pain and gastrointestinal disturbances; however, our understanding of how gastrointestinal - or visceral - pain can be vicariously transmitted is lacking. Visceral pain originates from the internal organs, and despite its widespread prevalence, remains poorly understood. We established an observation paradigm to assess the impact of witnessing visceral pain. We utilised colorectal distension (CRD) to induce visceral pain behaviours in a stimulus rodent while the observer rodent observed. Twenty four hours post-observation, the observer rodent's visceral sensitivity was assessed using CRD. The observer rodents were found to have significant hyperalgesia as determined by lower visceral pain threshold and higher number of total pain behaviours compared with controls. The behaviours of the observer animals during the observation were found to be correlated with the behaviours of the stimulus animal employed. We found that observer animals had hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis, highlighted by reduced corticosterone at 90 minutes post-CRD. Using c-Fos immunohistochemistry we showed that observer animals also had increased activation of the anterior cingulate cortex, and decreased activation of the paraventricular nucleus, compared with controls. These results suggest that witnessing another animal in pain produces a behavioural phenotype and impacts the brain-gut axis.

A gut (microbiome) feeling about addiction: Interactions with stress and social systems.

In recent years, an increasing attention has given to the intricate and diverse connection of microorganisms residing in our gut and their impact on brain health and central nervous system disease. There has been a shift in mindset to understand that drug addiction is not merely a condition that affects the brain, it is now being recognized as a disorder that also involves external factors such as the intestinal microbiota, which could influence vulnerability and the development of addictive behaviors. Furthermore, stress and social interactions, which are closely linked to the intestinal microbiota, are powerful modulators of addiction. This review delves into the mechanisms through which the microbiota-stress-immune axis may shape drug addiction and social behaviors. This work integrates preclinical and clinical evidence that demonstrate the bidirectional communication between stress, social behaviors, substance use disorders and the gut microbiota, suggesting that gut microbes might modulate social stress having a significance in drug addiction.

The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut.

Chronic stress disrupts microbiota-gut-brain axis function and is associated with altered tryptophan metabolism, impaired gut barrier function, and disrupted diurnal rhythms. However, little is known about the effects of acute stress on the gut and how it is influenced by diurnal physiology. Here, we used germ-free and antibiotic-depleted mice to understand how microbiota-dependent oscillations in tryptophan metabolism would alter gut barrier function at baseline and in response to an acute stressor. Cecal metabolomics identified tryptophan metabolism as most responsive to a 15-min acute stressor, while shotgun metagenomics revealed that most bacterial species exhibiting rhythmicity metabolize tryptophan. Our findings highlight that the gastrointestinal response to acute stress is dependent on the time of day and the microbiome, with a signature of stress-induced functional alterations in the ileum and altered tryptophan metabolism in the colon.

Exercise mitigates a gut microbiota-mediated reduction in adult hippocampal neurogenesis and associated behaviours in rats.

Lifestyle factors, especially exercise, impact the manifestation and progression of psychiatric and neurodegenerative disorders such as depression and Alzheimer's disease, mediated by changes in hippocampal neuroplasticity. The beneficial effects of exercise may be due to its promotion of adult hippocampal neurogenesis (AHN). Gut microbiota has also been showed to be altered in a variety of brain disorders, and disturbances of the microbiota have resulted in alterations in brain and behaviour. However, whether exercise can counteract the negative effects of altered gut microbiota on brain function remains under explored. To this end, chronic disruption of the gut microbiota was achieved using an antibiotic cocktail in rats that were sedentary or allowed voluntary access to running wheels. Sedentary rats with disrupted microbiota displayed impaired performance in hippocampal neurogenesis-dependent tasks: the modified spontaneous location recognition task and the novelty suppressed feeding test. Performance in the elevated plus maze was also impaired due to antibiotics treatment. These behaviours, and an antibiotics-induced reduction in AHN were attenuated by voluntary exercise. The effects were independent of changes in the hippocampal metabolome but were paralleled by caecal metabolomic changes. Taken together these data highlight the importance of the gut microbiota in AHN-dependent behaviours and demonstrate the power of lifestyle factors such as voluntary exercise to attenuate these changes.

Do microbes play a role in Alzheimer's disease?

Alzheimer's disease is a complex and progressive condition that affects essential neurological functions such as memory and reasoning. In the brain, neuronal loss, synaptic dysfunction, proteinopathy, neurofibrillary tangles, and neuroinflammation are the hallmarks of Alzheimer's disease pathophysiology. In addition, recent evidence has highlighted that microbes, whether commensal or pathogenic, also have the ability to interact with their host and to regulate its immune system, therefore participating in the exchanges that lead to peripheral inflammation and neuropathology. Because of this intimate relationship, bacteria, viruses, fungi, and protozoa have been implicated in the development of Alzheimer's disease. Here, we bring together current and most recent evidence of the role of microbes in Alzheimer's disease, raising burning questions that need to be addressed to guide therapeutic approaches and potential prophylactic strategies.

The gut virome is associated with stress-induced changes in behaviour and immune responses in mice.

The microbiota-gut-brain axis has been shown to play an important role in the stress response, but previous work has focused primarily on the role of the bacteriome. The gut virome constitutes a major portion of the microbiome, with bacteriophages having the potential to remodel bacteriome structure and activity. Here we use a mouse model of chronic social stress, and employ 16S rRNA and whole metagenomic sequencing on faecal pellets to determine how the virome is modulated by and contributes to the effects of stress. We found that chronic stress led to behavioural, immune and bacteriome alterations in mice that were associated with changes in the bacteriophage class Caudoviricetes and unassigned viral taxa. To determine whether these changes were causally related to stress-associated behavioural or physiological outcomes, we conducted a faecal virome transplant from mice before stress and autochthonously transferred it to mice undergoing chronic social stress. The transfer of the faecal virome protected against stress-associated behaviour sequelae and restored stress-induced changes in select circulating immune cell populations, cytokine release, bacteriome alterations and gene expression in the amygdala. These data provide evidence that the virome plays a role in the modulation of the microbiota-gut-brain axis during stress, indicating that these viral populations should be considered when designing future microbiome-directed therapies.

Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota-gut-brain axis.

Crosstalk between gut and brain has long been appreciated in health and disease, and the gut microbiota is a key player in communication between these two distant organs. Yet, the mechanisms through which the microbiota influences development and function of the gut-brain axis remain largely unknown. Barriers present in the gut and brain are specialized cellular interfaces that maintain strict homeostasis of different compartments across this axis. These barriers include the gut epithelial barrier, the blood-brain barrier and the blood-cerebrospinal fluid barrier. Barriers are ideally positioned to receive and communicate gut microbial signals constituting a gateway for gut-microbiota-brain communication. In this Review, we focus on how modulation of these barriers by the gut microbiota can constitute an important channel of communication across the gut-brain axis. Moreover, barrier malfunction upon alterations in gut microbial composition could form the basis of various conditions, including often comorbid neurological and gastrointestinal disorders. Thus, we should focus on unravelling the molecular and cellular basis of this communication and move from simplistic framing as 'leaky gut'. A mechanistic understanding of gut microbiota modulation of barriers, especially during critical windows of development, could be key to understanding the aetiology of gastrointestinal and neurological disorders.

Fermented foods: Harnessing their potential to modulate the microbiota-gut-brain axis for mental health.

Over the past two decades, whole food supplementation strategies have been leveraged to target mental health. In addition, there has been increasing attention on the ability of gut microbes, so called psychobiotics, to positively impact behaviour though the microbiota-gut-brain axis. Fermented foods offer themselves as a combined whole food microbiota modulating intervention. Indeed, they contain potentially beneficial microbes, microbial metabolites and other bioactives, which are being harnessed to target the microbiota-gut-brain axis for positive benefits. This review highlights the diverse nature of fermented foods in terms of the raw materials used and type of fermentation employed, and summarises their potential to shape composition of the gut microbiota, the gut to brain communication pathways including the immune system and, ultimately, modulate the microbiota-gut-brain axis. Throughout, we identify knowledge gaps and challenges faced in designing human studies for investigating the mental health-promoting potential of individual fermented foods or components thereof. Importantly, we also suggest solutions that can advance understanding of the therapeutic merit of fermented foods to modulate the microbiota-gut-brain axis.

Existing and Future Strategies to Manipulate the Gut Microbiota With Diet as a Potential Adjuvant Treatment for Psychiatric Disorders.

Nutrition and diet quality play key roles in preventing and slowing cognitive decline and have been linked to multiple brain disorders. This review compiles available evidence from preclinical studies and clinical trials on the impact of nutrition and interventions regarding major psychiatric conditions and some neurological disorders. We emphasize the potential role of diet-related microbiome alterations in these effects and highlight commonalities between various brain disorders related to the microbiome. Despite numerous studies shedding light on these findings, there are still gaps in our understanding due to the limited availability of definitive human trial data firmly establishing a causal link between a specific diet and microbially mediated brain functions and symptoms. The positive impact of certain diets on the microbiome and cognitive function is frequently ascribed with the anti-inflammatory effects of certain microbial metabolites or a reduction of proinflammatory microbial products. We also critically review recent research on pro- and prebiotics and nondietary interventions, particularly fecal microbiota transplantation. The recent focus on diet in relation to brain disorders could lead to improved treatment outcomes with combined dietary, pharmacological, and behavioral interventions.

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.

Microbiota-Gut-Brain Axis and Antidepressant Treatment.

In the treatment of depressive disorders, conventional antidepressant therapy has been the mainstay of clinical management, along with well-established nonpharmacological interventions such as various kinds of psychotherapy. Over the last 2 decades, there has been considerable interest in the role of the gastrointestinal system and its microbiota on brain function, behavior, and mental health. Components of what is referred to as the microbiota-gut-brain axis have been uncovered, and further research has elicited functional capabilities such as "gut-brain modules." Some studies have found associations with compositional alterations of gut microbiota in patients with depressive disorders and individuals experiencing symptoms of depression. Regarding the pathogenesis and neurobiology of depression itself, there appears to be a multifactorial contribution, in addition to the theories involving deficits in catecholaminergic and monoamine neurotransmission. Interestingly, there is evidence to suggest that antidepressants may play a role in modulating the gut microbiota, thereby possibly having an impact on the microbiota-gut-brain axis in this manner. The development of prebiotics, probiotics, and synbiotics has led to studies investigating not only their impact on the microbiota but also their therapeutic value in mental health. These psychobiotics have the potential to be used as therapeutic adjuncts in the treatment of depression. Regarding future directions, and in an attempt to further understand the role of the microbiota-gut-brain axis in depression, more studies such as those involving fecal microbiota transplantation will be required. In addition to recent findings, it is also suggested that more research will have to be undertaken to elicit whether specific strains of gut organisms are linked to depression. In terms of further investigation of the therapeutic potential of prebiotics, probiotics, and synbiotics as adjuncts to antidepressant treatment, we also expect there to be more research targeting specific microorganisms, as well as a strong focus on the effects of specific prebiotic fibers from an individualized (personalized) point of view.

John F. Cryan.

John Cryan focuses his research on the intersection of the brain, gut, and microbiome. He discusses with Neuron the growing acceptance among neuroscientists for the role of the microbiome in brain function. A passionate scientific communicator, Cryan gives insight into the importance of public advocacy and seeking a broad network.

Fiber intake and fiber intervention in depression and anxiety: a systematic review and meta-analysis of observational studies and randomized controlled trials.

CONTEXT: Dietary fibers hold potential to influence depressive and anxiety outcomes by modulating the microbiota-gut-brain axis, which is increasingly recognized as an underlying factor in mental health maintenance. OBJECTIVE: Evidence for the effects of fibers on depressive and anxiety outcomes remains unclear. To this end, a systematic literature review and a meta-analysis were conducted that included observational studies and randomized controlled trials (RCTs). DATA SOURCES: The PubMed, Embase, CENTRAL, CINAHL, and PsychINFO databases were searched for eligible studies. DATA EXTRACTION: Study screening and risk-of-bias assessment were conducted by 2 independent reviewers. DATA ANALYSIS: Meta-analyses via random effects models were performed to examine the (1) association between fiber intake and depressive and anxiety outcomes in observational studies, and (2) effect of fiber intervention on depressive and anxiety outcomes compared with placebo in RCTs. A total of 181 405 participants were included in 23 observational studies. In cross-sectional studies, an inverse association was observed between fiber intake and depressive (Cohen's d effect size [d]: -0.11; 95% confidence interval [CI]: -0.16, -0.05) and anxiety (d = -0.25; 95%CI, -0.38, -0.12) outcomes. In longitudinal studies, there was an inverse association between fiber intake and depressive outcomes (d = -0.07; 95%CI, -0.11, -0.04). In total, 740 participants were included in 10 RCTs, all of whom used fiber supplements. Of note, only 1 RCT included individuals with a clinical diagnosis of depression. No difference was found between fiber supplementation and placebo for depressive (d = -0.47; 95%CI, -1.26, 0.31) or anxiety (d = -0.30; 95%CI, -0.67, 0.07) outcomes. CONCLUSION: Although observational data suggest a potential benefit for higher fiber intake for depressive and anxiety outcomes, evidence from current RCTs does not support fiber supplementation for improving depressive or anxiety outcomes. More research, including RCTs in clinical populations and using a broad range of fibers, is needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021274898.