Gut-brain Pathways Research Articles

New perspectives on microbiome-dependent gut-brain pathways for the treatment of depression with gastrointestinal symptoms: from bench to bedside.

Patients with depression are more likely to have chronic gastrointestinal (GI) symptoms than the general population, but such symptoms are considered only somatic symptoms of depression and lack special attention. There is a chronic lack of appropriate diagnosis and effective treatment for patients with depression accompanied by GI symptoms, and studying the association between depression and GI disorders (GIDs) is extremely important for clinical management. There is growing evidence that depression is closely related to the microbiota present in the GI tract, and the microbiota-gut-brain axis (MGBA) is creating a new perspective on the association between depression and GIDs. Identifying and treating GIDs would provide a key opportunity to prevent episodes of depression and may also improve the outcome of refractory depression. Current studies on depression and the microbially related gut-brain axis (GBA) lack a focus on GI function. In this review, we combine preclinical and clinical evidence to summarize the roles of the microbially regulated GBA in emotions and GI function, and summarize potential therapeutic strategies to provide a reference for the study of the pathomechanism and treatment of depression in combination with GI symptoms.

Vagus Nerve and Gut-Brain Communication.

The vagus nerve, as an important component of the gut-brain axis, plays a crucial role in the communication between the gut and brain. It influences food intake, fat metabolism, and emotion by regulating the gut-brain axis, which is closely associated with the development of gastrointestinal, psychiatric, and metabolism-related disorders. In recent years, significant progress has been made in understanding the vagus-mediated regulatory pathway, highlighting its profound implications in the development of many diseases. Here, we summarize the latest advancements in vagus-mediated gut-brain pathways and the novel interventions targeting the vagus nerve. This will provide valuable insights for future research on treatment of obesity and gastrointestinal and depressive disorders based on vagus nerve stimulation.

The gut microbiome and sociability.

The human gut microbiome plays an important role in the maturation of the neural, immune, and endocrine systems. Research data from animal models shows that gut microbiota communicate with the host's brain in an elaborate network of signaling pathways, including the vagus nerve. Part of the microbiome's influence extends to the behavioral and social development of its host. As a social species, a human's ability to communicate with others is imperative to their survival and quality of life. Current research explores the gut microbiota's developmental influence as well as how these gut-brain pathways can be leveraged to alleviate the social symptoms associated with various neurodevelopmental and psychiatric diseases. One intriguing vein of research in animal models centers on probiotic treatment, which leads to downstream increased circulation of endogenous oxytocin, a neuropeptide hormone relevant to sociability. Further research may lead to therapeutic applications in humans, particularly in the early stages of their lives.

Real-time Analysis of Gut-brain Neural Communication: Cortex wide Calcium Dynamics in Response to Intestinal Glucose Stimulation.

Communication between the gastrointestinal tract and the brain after nutrient absorption plays an essential role in food preference, metabolism, and feeding behaviors. Particularly concerning specific nutrients, many studies have elucidated that the assimilation of glucose within gut epithelial cells instigates the activation of many signaling molecules. Hormones such as glucagon-like peptide-1 are renowned as quintessential signaling mediators. Since hormones predominantly influence the brain through circulatory pathways, they slowly modulate brain activity. However, recent studies have shown two expeditious gut-brain pathways facilitated by the autonomic nervous system. One operates via the spinal afferent neural pathway, while the vagus nerve mediates the other. Consequently, brain responses following glucose assimilation in the gastrointestinal tract are complicated. Moreover, as intestinal stimulation finally induces diverse cortical activities, including sensory, nociceptive, reward, and motor responses, it is necessary to employ methodologies that facilitate the visualization of localized brain circuits and pan-cortical activities to comprehend gut-brain neural transmission fully. Some studies have indicated precipitous alterations in calcium ion (Ca2+) concentrations within the hypothalamus and ventral tegmental area independently through different pathways after intestinal stimulation. However, whether there are changes in cerebral cortex activity has not been known. To observe cerebral cortex activity after intragastric glucose injection, we developed an imaging technique for real-time visualization of cortex wide Ca2+ dynamics through a fully intact skull, using transgenic mice expressing genetically encoded Ca2+ indicators. This study presents a comprehensive protocol for a technique designed to monitor intestinal stimulation-induced transcranial cortex wide Ca2+ imaging following intragastric glucose injection via an implanted catheter. The preliminary data suggest that administering glucose solution into the gut activates the frontal cortex, which remains unresponsive to water administration.

Mechanism and implications of pro-nature physical activity in antagonizing psychological stress: the key role of microbial-gut-brain axis.

Appropriate physical activities and a biodiversity-rich environment are conducive to the relief of psychological stress, and pro-nature physical activities are a combination of the two, which has good application potential in antagonizing psychological stress, but the intervention mechanism is still unclear. The microbiota-gut-brain axis is cyclically associated with psychological stress, and psychological stress can affect the microbiota through the gut-brain pathway, and conversely, the microbiota can also affect the psychological stress-induced symptoms. It is suggested that the microbe-gut-brain axis may provide a new perspective and target for the treatment of psychological stress-related diseases. Pro-nature physical activity can improve the number of Firmicutes, short-chain fatty acids, Akkermansia bacteria, and the gut-brain barrier and further affect the HPA axis, BDNF, and serotonin pathways of gut-brain two-way communication, thereby maintaining the body's homeostasis and reducing antagonistic psychological stress. According to the comprehensive influence of physical activities on the microbiota-gut-brain axis, a "green + exercise prescription hypothesis" in line with the holistic medical concept is revealed, which is expected to be effective in the prevention, alleviation, and treatment of irritable bowel syndrome and neurodegenerative diseases. It provides new means for treating psychological stress-related diseases such as mental disorders and mood disorders. In addition, it enlightens the construction of green infrastructure that is conducive to the diversified contact of microorganisms in outdoor physical activities venues and induces healthy interaction between the human body and the microbial population in the natural ecology. However, the current research is still in its early stages, and the intervention effect and mechanism of pro-nature physical activities need further demonstration in the future.

A gut-brain axis mediates sodium appetite via gastrointestinal peptide regulation on a medulla-hypothalamic circuit.

Salt homeostasis is orchestrated by both neural circuits and peripheral endocrine factors. The colon is one of the primary sites for electrolyte absorption, while its potential role in modulating sodium intake remains unclear. Here, we revealed that a gastrointestinal hormone, secretin, is released from colon endocrine cells under body sodium deficiency and is indispensable for inducing salt appetite. As the neural substrate, circulating secretin activates specific receptors in the nucleus of the solitary tracts, which further activates the downstream paraventricular nucleus of the hypothalamus, resulting in enhanced sodium intake. These results demonstrated a previously unrecognized gut-brain pathway for the timely regulation of sodium homeostasis.

Does bacteria control our appetite?

The gut-brain pathway has been the center of many studies in the past few years, but the mechanisms driving this interaction are still poorly understood. In our work we reveal how parts of a bacterium’s cell wall are able to reach the brain and decrease the activity of certain neurons controlling appetite.

A microbiome-dependent gut-brain pathway regulates motivation for exercise.

Exercise exerts a wide range of beneficial effects for healthy physiology1. However, the mechanisms regulating an individual's motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise-induced neurochemical changes in the brain. Here, we report on the discovery of a gut-brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome-dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut-derived signals to the brain may enhance the motivation for exercise.

Gut-brain pathways for toxin defence.

Gut-brain pathways for toxin defence.

Dietary adaptation for weight loss maintenance at Yale (DAWLY): Protocol and predictions for a randomized controlled trial.

BackgroundCurrent therapies for obesity treatment are effective at producing short-term weight loss, but weight loss maintenance remains a significant challenge. Here we investigate the impact of pre-intervention dietary fat intake on the efficacy of a dietary supplement to support weight loss maintenance. Preclinical work demonstrates that a vagal afferent pathway critical for sensing dietary lipids is blunted by a high-fat diet (HFD), resulting in a reduced preference for a low-fat emulsion and severe blunting of the dopamine (DA) response to the gastric infusion of lipids. Infusion of the gut lipid messenger oleoylethanolamide (OEA), which is also depleted by HFD, immediately reverses this DA blunting and restores preference for the low-fat emulsion. Studies of OEA supplementation for weight loss in humans have had limited success. Given the strong effect of HFD on this pathway, we designed a study to test whether the efficacy of OEA as a weight loss treatment is related to pre-intervention habitual intake of dietary fat.Methods/DesignWe employed a randomized, double-blind, placebo-controlled trial in which 100 adults with overweight/obesity (OW/OB) were randomized to receive either OEA or placebo daily for 16 months. Following a baseline evaluation of diet, metabolic health, adiposity, and brain response to a palatable an energy dense food, participants in both groups underwent a 4-month behavioral weight loss intervention (LEARN®) followed by a 1-year maintenance period. The study aims are to (1) determine if pre-intervention dietary fat intake moderates the ability of OEA to improve weight loss and weight loss maintenance after a gold standard behavioral weight loss treatment; (2) identify biomarkers that predict outcome and optimize a stratification strategy; and (3) test a model underlying OEA’s effectiveness.DiscussionFocusing on interventions that target the gut-brain axis is supported by mounting evidence for the role of gut-brain signaling in food choice and the modulation of this circuit by diet. If successful, this work will provide support for targeting the gut-brain pathway for weight loss maintenance using a precision medicine approach that is easy and inexpensive to implement.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT04614233].

Nutrition and Gut-Brain Pathways Impacting the Onset of Parkinson's Disease.

An emerging body of literature suggests that long-term gut inflammation may be a silent driver of Parkinson’s disease (PD) pathogenesis. Importantly, specific nutritive patterns might improve gut health for PD risk reduction. Here, we review the current literature on the nutritive patterns and inflammatory markers as a predictor for early detection of PD. This knowledge might be used to foster the detection of early nutritive patterns and preclinical biomarkers to potentially alter PD development and progression.

Intracerebroventricular Delivery of Gut-derived Microbial Metabolites in Freely Moving Mice.

The impact of gut microbiota and their metabolites on host physiology and behavior has been extensively investigated in this decade. Numerous studies have revealed that gut microbiota-derived metabolites modulate brain-mediated physiological functions through intricate gut-brain pathways in the host. Short-chain fatty acids (SCFAs) are the major bacteria-derived metabolites produced during dietary fiber fermentation by the gut microbiome. Secreted SCFAs from the gut can act at multiple sites in the periphery, affecting the immune, endocrine, and neural responses due to the vast distribution of SCFAs receptors. Therefore, it is challenging to differentiate the central and peripheral effects of SCFAs through oral and intraperitoneal administration of SCFAs. This paper presents a video-based method to interrogate the functional role of SCFAs in the brain via a guide cannula in freely moving mice. The amount and type of SCFAs in the brain can be adjusted by controlling the infusion volume and rate. This method can provide scientists with a way to appreciate the role of gut-derived metabolites in the brain.

Gut microbes shape microglia and cognitive function during malnutrition.

Fecal‐oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL‐BG). The MAL‐BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non‐neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal‐oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL‐BG mice. Unexpectedly, these changes occurred independently from significant cytokine‐induced inflammation or blood–brain barrier (BBB) disruption, key gut‐brain pathways. Metabolomic profiling of the MAL‐BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant‐associated diet (PAO) mitigated cognitive deficits within the MAL‐BG model. These findings provide valued insight into the malnourished gut microbiota‐brain axis, highlighting PUFA metabolism as a potential therapeutic target.

Compositional and functional alterations in the oral and gut microbiota in patients with psychosis or schizophrenia: A systematic review

Background: Gut and oral microbiota are intrinsically linked to human health. Recent studies suggest a direct link with mental health through bidirectional gut–brain pathways. Emerging evidence suggests that the composition and/or function of intestinal microbiome differs in those with psychosis and schizophrenia as compared with controls. There is relatively little research on the predicted or actual functional alterations associated with the composition of oral and gut microbiota in patients with psychosis. We will perform a systematic review and meta-analysis to identify, evaluate and if possible, combine the published literature on compositional alterations in the oral and gut microbiota in patients with psychosis or schizophrenia compared with healthy controls. We also aim to explore the potential functional impact of any compositional changes. Methods: Original studies involving humans and animals using a case-control, cohort or cross-sectional design will be included. The electronic databases PsycINFO, EMBASE, Web of Science, PubMed/MEDLINE and Cochrane will be systematically searched. Quantitative analyses will be performed using random-effects meta-analyses to calculate mean difference with 95% confidence intervals. Discussion: Changes in microbiota composition in psychosis and schizophrenia have been correlated with alternations in brain structure and function, altered immunity, altered metabolic pathways and symptom severity. Changes have also been identified as potential biomarkers for psychosis that might aid in diagnosis. Understanding how predicted or actual functional alterations in microbial genes or metabolic pathways influence symptomatic expression and downstream clinical outcomes may contribute to the development of microbiome targeted interventions for psychosis. Registration: The study is prospectively registered in PROSPERO, the International Prospective Register of Systematic Reviews (CRD42021260208).

Compositional and functional alterations in the oral and gut microbiota in patients with psychosis or schizophrenia: A systematic review.

Background: Gut and oral microbiota are intrinsically linked to human health. Recent studies suggest a direct link with mental health through bidirectional gut-brain pathways. Emerging evidence suggests that the composition and/or function of intestinal microbiome differs in those with psychosis and schizophrenia as compared with controls. There is relatively little research on the predicted or actual functional alterations associated with the composition of oral and gut microbiota in patients with psychosis. We will perform a systematic review and meta-analysis to identify, evaluate and if possible, combine the published literature on compositional alterations in the oral and gut microbiota in patients with psychosis or schizophrenia compared with healthy controls. We also aim to explore the potential functional impact of any compositional changes. Methods: Original studies involving humans and animals using a case-control, cohort or cross-sectional design will be included. The electronic databases PsycINFO, EMBASE, Web of Science, PubMed/MEDLINE and Cochrane will be systematically searched. Quantitative analyses will be performed using random-effects meta-analyses to calculate mean difference with 95% confidence intervals. Discussion: Changes in microbiota composition in psychosis and schizophrenia have been correlated with alternations in brain structure and function, altered immunity, altered metabolic pathways and symptom severity. Changes have also been identified as potential biomarkers for psychosis that might aid in diagnosis. Understanding how predicted or actual functional alterations in microbial genes or metabolic pathways influence symptomatic expression and downstream clinical outcomes may contribute to the development of microbiome targeted interventions for psychosis. Registration: The study is prospectively registered in PROSPERO, the International Prospective Register of Systematic Reviews (CRD42021260208).

Hypothalamic detection of macronutrients via multiple gut-brain pathways

Food intake is tightly regulated by complex and coordinated gut-brain interactions. Nutrients rapidly modulate activity in key populations of hypothalamic neurons that regulate food intake, including hunger-sensitive agouti-related protein (AgRP)-expressing neurons. Because individual macronutrients engage specific receptors in the gut to communicate with the brain, we reasoned that macronutrients may utilize different pathways to reduce activity in AgRP neurons. Here, we revealed that AgRP neuron activity in hungry mice is inhibited by site-specific intestinal detection of different macronutrients. We showed that vagal gut-brain signaling is required for AgRP neuron inhibition by fat. In contrast, spinal gut-brain signaling relays the presence of intestinal glucose. Further, we identified glucose sensors in the intestine and hepatic portal vein that mediate glucose-dependent AgRP neuron inhibition. Therefore, distinct pathways are activated by individual macronutrients to inhibit AgRP neuron activity.

A Vagal-NTS Neural Pathway that Stimulates Feeding

A fundamental question of physiology is how gut-brain signaling stimulates appetite. While many studies have emphasized the importance of vagal afferents to the brain in inducing satiation, little is known about whether and how the vagal-mediated gut-brain pathway senses orexigenic signals and stimulates feeding. Here, we identified a previously uncharacterized population of fasting-activated catecholaminergic neurons in the nucleus of the solitary tract (NTS). After characterizing the anatomical complexity among NTS catecholaminergic neurons, we surprisingly found that activation of NTS epinephrine (ENTS) neurons co-expressing neuropeptide Y (NPY) stimulated feeding, whereas activation of NTS norepinephrine (NENTS) neurons suppressed feeding. Monosynaptic tracing/activation experiments then showed that these NTS neurons receive direct vagal afferents from nodose neurons. Moreover, activation of the vagal→NPY/ENTS neural circuit stimulated feeding. Our study reveals an orexigenic role of the vagal→NTS pathway in controlling feeding, thereby providing important insights about how gut-brain signaling regulates feeding behavior.

The gut in Parkinson's disease: Bottom-up, top-down, or neither?

The gut-brain axis is a hot topic in Parkinson's disease. In an attempt to decipher its role in the disease pathogenesis, several animal models have been developed. Most of these models tried to reproduce Braak's hypothesis by showing that the pathological process could spread from the gut to the brain (bottom-up scenario). Interestingly, others groups showed that a top-down scenario could also occur and that 6-hydroxydopamine-induced nigrostriatal denervation was sufficient to induce significant changes in the gastrointestinal tract. Aside from this toxic approach, the article by O'Donovan and colleagues in this edition of Neurogastroenterology and Motility showed that bilateral nigral injection of adeno-associated virus (AAV)-alpha-synuclein in rats was accompanied by changes in the enteric nervous system and the gut microbiota, which occurred without any apparent brain-to-gut spread of human injected alpha-synuclein. Some changes observed in the gastrointestinal tract of animals injected with AAV-alpha-synuclein were in line with previous observations in Parkinson's disease patients, including increased expression of glial markers, swollen tyrosine hydroxylase-positive varicosities in the submucosal plexus, and decreases in Faecalibacterium and Lachnospiraceae. These findings suggest that, in addition to gut-brain pathways, the brain-to-gut communication may also be involved in Parkinson's disease pathophysiology. In this mini-review, we describe the strengths and limitations of the existing studies on the gut-brain axis in experimental models of parkinsonism and discuss an alternative hypothesis in which the central and enteric nervous system would evolve separately during disease progression.

Treatment with gut bifidobacteria improves hippocampal plasticity and cognitive behavior in adult healthy rats

At the present time, gut microbiota inspires great interest in the field of neuroscience as a function of its role in normal physiology and involvement in brain function. This aspect suggests a specific gut-brain pathway, mainly modulated by gut microbiota activity. Among the multiple actions controlled by microbiota at the brain level, neuronal plasticity and cognitive function represent two of the most interesting aspects of this cross-talk communication. We address the possible action of two-months implementation of gut Bifidobacteria using a mixture of three different strains (B-MIX) on hippocampal plasticity and related cognitive behavior in adult healthy Sprague Dawley rats. B-MIX treatment increases the hippocampal BDNF with a parallel gain in dendritic spines’ density of hippocampal CA1 pyramidal neurons. Electrophysiological experiments revealed a significant increment of HFS-induced LTP formation on the CA1 hippocampal region in B-MIX treated rats. All these effects are accompanied by a better cognitive performance observed in B-MIX treated animals with no impairments in locomotion activity. Therefore, in adult rats, the treatment with different strains of bifidobacteria is able to markedly enhance neuronal plasticity and the CNS function influencing cognitive behavior, an effect that may suggest a potential therapeutic treatment in brain diseases associated with cognitive functions.

On the roles of the Duodenum and the Vagus nerve in learned nutrient preferences

Background and aimIn most species, including humans, food preference is primarily controlled by nutrient value. However, the gut-brain pathways involved in preference learning remain elusive. The aim of the present study, performed in C57BL6/J mice, was to characterize the roles in nutrient preference of two critical elements of gut-brain pathways, i.e. the duodenum and vagal gut innervation. MethodsAdult wild-type C57BL6/J mice from a normal-weight cohort sustained one of the following three procedures: duodenal-jejunal bypass intestinal rerouting (DJB), total subdiaphragmatic vagotomy (SDV), or sham surgery. Mice were assessed in short-term two-bottle preference tests before and after 24 h s exposures to solutions containing one of glutamate, lipids, sodium, or glucose. ResultsDJB and SDV interfered in preference formation in a nutrient-specific manner: whereas normal preference learning for lipids and glutamate was disrupted by both DJB and SDV, these interventions did not alter the formation of preferences for glucose. Interestingly, sodium preferences were abrogated by DJB but not by SDV. ConclusionsDifferent macronutrients make use of distinct gut-brain pathways to influence food preferences, thereby mirroring nutrient-specific processes of food digestion. Specifically, whereas both vagal innervation and duodenal sensing appear critical for generating responses to fats and protein, glucose preferences recruit post-duodenal, vagal-independent pathways in pair with the control of glucose homeostasis. Overall, our data suggest that the physiological processes involved in digesting and absorbing fats, amino acids, and glucose overlap with those mediating learned preferences for each of these nutrients.