Disruption of the microbiota-gut-brain axis results in a wide range of pathologies that are affected, from the brain to the intestine. Gut hormones released by enteroendocrine cells to the gastrointestinal (GI) tract are important signaling molecules within this axis. In the search for the language that allows microbiota to communicate with the gut and the brain, serotonin seems to be the most important mediator. In recent years, serotonin has emerged as a key neurotransmitter in the gut-brain axis because it largely contributes to both GI and brain physiology. In addition, intestinal microbiota are crucial in serotonin signaling, which gives more relevance to the role of the serotonin as an important mediator in microbiota-host interactions. Despite the numerous investigations focused on the gut-brain axis and the pathologies associated, little is known regarding how serotonin can mediate in the microbiota-gut-brain axis. In this review, we will mainly discuss serotonergic system modulation by microbiota as a pathway of communication between intestinal microbes and the body on the microbiota-gut-brain axis, and we explore novel therapeutic approaches for GI diseases and mental disorders.

A balanced intake of macronutrients-protein, carbohydrate and fat-is essential for the well-being of organisms. An adequate calorific intake but with insufficient protein consumption can lead to several ailments, including kwashiorkor. Taste receptors (T1R1-T1R3) can detect amino acids in the environment, and cellular sensors (Gcn2 and Tor) monitor the levels of amino acids in the cell. When deprived of dietary protein, animals select a food source that contains a greater proportion of protein or essential amino acids (EAAs). This suggests that food selection is geared towards achieving the target amount of a particular macronutrient with assistance of the EAA-specific hunger-driven response, which is poorly understood. Here we show in Drosophila that a microbiome-gut-brain axis detects a deficit of EAAs and stimulates a compensatory appetite for EAAs. We found that the neuropeptide CNMamide (CNMa) was highly induced in enterocytes of the anterior midgut during protein deprivation. Silencing of the CNMa-CNMa receptor axis blocked the EAA-specific hunger-driven response in deprived flies. Furthermore, gnotobiotic flies bearing an EAA-producing symbiotic microbiome exhibited a reduced appetite for EAAs. By contrast, gnotobiotic flies with a mutant microbiome that did not produce leucine or other EAAs showed higher expression of CNMa and a greater compensatory appetite for EAAs. We propose that gut enterocytes sense the levels of diet- and microbiome-derived EAAs and communicate the EAA-deprived condition to the brain through CNMa.

Hypertension is a critical risk factor of cardiovascular diseases. A new concept of microbiota-gut-brain axis has been established recently, mediating the bidirectional communication between the gut and its microbiome and the brain. Alterations in bidirectional interactions are believed to be involved in the blood pressure regulation. Neuroinflammation and increased sympathetic outflow act as the descending innervation signals from the brain. Increased sympathetic activation plays a recognized role in the genesis of hypertension. The present evidence demonstrates that gut dysbiosis is associated with central nervous system neuroinflammation. However, how the gut influences the brain remains unclear. We reviewed the roles of neuroinflammation and gut microbiota and their interactions in the pathogenesis of hypertension and described the ascending signaling mechanisms behind the microbiota-gut-brain axis in detail. Additionally, the innovative prohypertensive mechanisms of dietary salt through the microbiota-gut-brain axis are summarized. The bidirectional communication mechanisms were proposed for the first time that the descending signals from the brain and the ascending connections from the gut form a vicious circle of hypertension progression, acting as a premise for hypertension therapy.

The gut microbiota is the set of microorganisms present in the gut, and it is connected to the central nervous system via the gut-brain axis. Despite there is not a definitive description of the eubiotic microbiota architecture, numerous studies have demonstrated its involvement in human behaviour and its relationship with several pathologies. This is a systematic review about the association between dysbiosis on the gut microbiota and the presence of neurological or neuropsychiatric diseases such as cognitive impairment, Alzheimer's disease, Parkinson's disease, ADHD, and depression. Furthermore, this study analyzes the potential benefits of psychobiotics supplementation for these pathologies. Searches were conducted in the electronic databases PubMed and PsycINFO. 17 articles were included in this review, the majority were published after 2019. The results showed that gut dysbiosis predicts the development of these pathologies and influences their pathogenesis. In addition, it was found that different psychobiotics, mainly dietary fibers and probiotics of the Lactobacillus family, improved different cognitive functions such as cognitive performance and induce a reduced cortisol response. Improvement in different cognitive functions is possible when understanding gut microbiota-brain axis, enteric nervous system, neural-immune system, neuroendocrine system, and central nervous system's relationship.

The 'apple-shaped' anatomical pattern that accompanies visceral adiposity increases risk for multiple chronic diseases, including conditions that impact the brain, such as diabetes and hypertension. However, distinguishing between the consequences of visceral obesity, as opposed to visceral adiposity-associated metabolic and cardiovascular pathologies, presents certain challenges. This review summarizes current literature on relationships between adipose tissue distribution and cognition in preclinical models and highlights unanswered questions surrounding the potential role of tissue- and cell type-specific insulin resistance in these effects. While gaps in knowledge persist related to insulin insensitivity and cognitive impairment in obesity, several recent studies suggest that cells of the neurovascular unit contribute to hippocampal synaptic dysfunction, and this review interprets those findings in the context of progressive metabolic dysfunction in the CNS. Signalling between cerebrovascular endothelial cells, astrocytes, microglia, and neurons has been linked with memory deficits in visceral obesity, and this article describes the cellular changes in each of these populations with respect to their role in amplification or diminution of peripheral signals. The picture emerging from these studies, while incomplete, implicates pro-inflammatory cytokines, insulin resistance, and hyperglycemia in various stages of obesity-induced hippocampal dysfunction. As in the parable of the five blind wanderers holding different parts of an elephant, considerable work remains in order to assemble a model for the underlying mechanisms linking visceral adiposity with age-related cognitive decline.

ABSTRACT:Excess pain after visceral provocation has been suggested as a marker for chronic pelvic pain risk in women. However, few noninvasive tests have been validated that could be performed readily on youth in early risk windows. Therefore, we evaluated the validity and reliability of a noninvasive bladder pain test in 124 healthy premenarchal females (median age 11, [interquartile range 11-12]), as previously studied in adult women. We explored whether psychosocial, sensory factors, and quantitative sensory test results were associated with provoked bladder pain and assessed the relation of bladder pain with abdominal pain history. Compared with findings in young adult females (age 21 [20-28]), results were similar except that adolescents had more pain at first sensation to void (P = 0.005) and lower maximum tolerance volume (P < 0.001). Anxiety, depression, somatic symptoms, and pain catastrophizing predicted provoked bladder pain (P's < 0.05). Bladder pain inversely correlated with pressure pain thresholds (r = -0.25, P < 0.05), but not with cold pressor pain or conditioned pain modulation effectiveness. Bladder pain was also associated with frequency of abdominal pain symptoms (r = 0.25, P = 0.039). We found strong retest reliability for bladder pain at standard levels of sensory urgency in 21 adolescents who attended repeat visits at 6 to 12 months (intraclass correlations = 0.88-0.90). Noninvasive bladder pain testing seems reproducible in adolescent females and may predict abdominal pain symptomatology. Confirmation of our findings and further investigation of the bladder test across menarche will help establish how visceral sensitivity contributes to the early trajectory of pelvic pain risk.

Disturbances of the gut-brain axis are characterized by complex dysfunctions on peripheral and central nervous system levels, which can contribute to visceral hypervigilance and hyperalgesia and imprint visceral pain. Numerous cognitive, emotional and psychoneurobiological factors are involved in visceral pain modulation, which in the psychosocial treatment concept can have a positive as well as a negative impact on the experience of visceral pain. Nocebo effects induced by negative expectations are of high clinical relevance in acute and especially in chronic visceral pain but the underlying mechanisms remain insufficiently understood. Verbal instructions, previous experiences and learning processes as well as emotional factors, such as fear and stress contribute to the development and maintenance of negative expectation effects. Targeted communication strategies, a sensitive use of information in the clarification and positive environmental context conditions can contribute to establishing an adequate expectation management and minimize negative expectation effects in the clinical practice. At the same time, translational research approaches are required to gain further insights into the mediators and moderators of negative expectation effects and to transfer these into clinical practice. In this way the treatment of patients with disorders of the gut-brain communication can be improved.

Accumulating evidence show that the gut microbiota is deeply involved not only in host nutrient metabolism but also in immune function, endocrine regulation, and chronic disease. In neurodegenerative conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis, the gut-brain axis, the bidirectional interaction between the brain and the gut, provides new route of pathological spread and potential therapeutic targets. Although studies of gut microbiota have been conducted mainly in mice, mammalian gut microbiota is highly diverse, complex, and sensitive to environmental changes. Drosophila melanogaster, a fruit fly, has many advantages as a laboratory animal: short life cycle, numerous and genetically homogenous offspring, less ethical concerns, availability of many genetic models, and low maintenance costs. Drosophila has a simpler gut microbiota than mammals and can be made to remain sterile or to have standardized gut microbiota by simple established methods. Research on the microbiota of Drosophila has revealed new molecules that regulate the brain-gut axis, and it has been shown that dysbiosis of the fly microbiota worsens lifespan, motor function, and neurodegeneration in AD and PD models. The results shown in fly studies represents a fundamental part of the immune and proteomic process involving gut-microbiota interactions that are highly conserved. Even though the fly's gut microbiota are not simple mimics of humans, flies are a valuable system to learn the molecular mechanisms of how the gut microbiota affect host health and behavior.

Since decades, there is a change in concept of the gut-brain axis. There is differential increase in evidences focusing on the bidirectional communication between the gut microbiome and the brain. It supports existence of far-reaching model of "gut-brain axis." This axis is attaining more adherence to fields investigating biological and physiological footing of psychiatric, neuro-developmental, age-related, and neurodegenerative disorders. Many factors can change microbiota composition in early life as well as with the increasing age. Stress can affect the microbiota-gut-brain axis at every stages of life. Recent advances have involved the gut microbiota in many conditions including severe mental illness, autism, anxiety, obesity, Parkinson's disease, and Alzheimer's disease. The current studies target on elaborating the underlying mechanisms of microbiota-gut-brain axis and attempt to exemplify intervention and therapeutic strategies for neuropsychiatric disorders.

Dreams may be recalled after awakening from sleep following a defined electroencephalographic pattern that involves local decreases in low-frequency activity in the posterior cortical regions. Although a dreaming experience implies bodily changes at many organ, system, and timescale levels, the entity and causal role of such peripheral changes in a conscious dream experience are unknown. We performed a comprehensive, causal, multivariate analysis of physiological signals acquired during rapid eye movement (REM) sleep at night, including high-density electroencephalography and peripheral dynamics including electrocardiography and blood pressure. In this preliminary study, we investigated multiple recalls and nonrecalls of dream experiences using data from nine healthy volunteers. The aim was not only to investigate the changes in central and autonomic dynamics associated with dream recalls and nonrecalls, but also to characterize the central-peripheral dynamical and (causal) directional interactions, and the temporal relations of the related arousals upon awakening. We uncovered a brain-body network that drives a conscious dreaming experience that acts with specific interaction and time delays. Such a network is sustained by the blood pressure dynamics and the increasing functional information transfer from the neural heartbeat regulation to the brain. We conclude that bodily changes play a crucial and causative role in a conscious dream experience during REM sleep.

Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson's disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease.

The accumulating evidence linking bacteria in the gut and neurons in the brain (the microbiota-gut-brain axis) has led to a paradigm shift in the neurosciences. Understanding the neurobiological mechanisms supporting the relevance of actions mediated by the gut microbiota for brain physiology and neuronal functioning is a key research area. In this review, we discuss the literature showing how the microbiota is emerging as a key regulator of the brain's function and behavior, as increasing amounts of evidence on the importance of the bidirectional communication between the intestinal bacteria and the brain have accumulated. Based on recent discoveries, we suggest that the interaction between diet and the gut microbiota, which might ultimately affect the brain, represents an unprecedented stimulus for conducting new research that links food and mood. We also review the limited work in the clinical arena to date, and we propose novel approaches for deciphering the gut microbiota-brain axis and, eventually, for manipulating this relationship to boost mental wellness.

Inflammatory bowel disease (IBD) is a multisystemic disease with a wide range of extraintestinal manifestations in both ulcerative colitis and Crohn's disease, while increasing evidence supports the interaction between gut and central nervous system, described as "gut-brain axis". According to epidemiological studies, it seems that patients with IBD present more frequently with impaired mental status compared to the general population, leading to diagnostic and management problems in this group of patients. The association between IBD and mental disorders, such as dementia and autism spectrum disorders, has not been fully clarified; genetic factors and the gut-brain axis seem to be involved. The purpose of this review is to present and analyze the epidemiological data about this issue, describe the possible pathogenetic mechanisms and discuss some considerations about the management of patients with IBD and impaired mental status.

The human body is home to a complex community of dynamic equilibrium microbiota, including bacteria, fungi, parasites, and viruses. It is known that the gut microbiome plays a crucial role in regulating innate and adaptive immune responses, intestinal peristalsis, intestinal barrier homeostasis, nutrient uptake, and fat distribution. The complex relationship between the host and microbiome suggests that when this relationship is out of balance, the microbiome may contribute to disease development. The brain-gut-microbial axis is composed of many signal molecules, gastrointestinal mucosal cells, the vagus nerve, and blood-brain barrier, which plays an essential role in developing many diseases. The microbiome can influence the central nervous system function through the brain-gut axis; the central nervous system can also affect the composition and partial functions of the gut microbiome in the same way. Different dietary patterns, specific dietary components, and functional dietary factors can significantly affect intestinal flora's structure, composition, and function, thereby affecting human health. Based on the above, this paper reviewed the relationship between diet, intestinal flora, and human health, and the strategies to prevent mental illness through the dietary modification of intestinal microorganisms.

Osteoporosis (OP) is a chronic metabolic bone disease characterized by the decrease of bone tissue per unit volume under the combined action of genetic and environmental factors, which leads to the decrease of bone strength, makes the bone brittle, and raises the possibility of bone fracture. However, the exact mechanism that determines the progression of OP remains to be underlined. There are hundreds of trillions of symbiotic bacteria living in the human gut, which have a mutually beneficial symbiotic relationship with the human body that helps to maintain human health. With the development of modern high-throughput sequencing (HTS) platforms, there has been growing evidence that the gut microbiome may play an important role in the programming of bone metabolism. In the present review, we discuss the potential mechanisms of the gut microbiome in the development of OP, such as alterations of bone metabolism, bone mineral absorption, and immune regulation. The potential of gut microbiome-targeted strategies in the prevention and treatment of OP was also evaluated. Cite this article: 2020;9(8):524-530.

Osteoporosis (OP) is a kind of systemic metabolic disease characterized by decreased bone mass and destruction of the bone microstructure. In recent years, it has become an expected research trend to explore the cross-linking relationship in the pathogenesis process of OP so as to develop reasonable and effective intervention strategies. With the further development of intestinal microbiology and the profound exploration of the gut microbiota (GM), it has been further revealed that the "brain-gut" axis may be a potential target for the bone, thereby affecting the occurrence and progression of OP. Hence, based on the concept of "brain-gut-bone" axis, we look forward to deeply discussing and summarizing the cross-linking relationship of OP in the next three parts, including the "brain-bone" connection, "gut-bone" connection, and "brain-gut" connection, so as to provide an emerging thought for the prevention strategies and mechanism researches of OP.

The gut-brain axis refers to the bidirectional communication between the gut and brain, and regulates intestinal homeostasis and the central nervous system neural networks and neuroendocrine, immune, and inflammatory pathways. The development of sequencing technology has evidenced the key regulatory role of the gut microbiota in several neurological disorders, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Epilepsy is a complex disease with multiple risk factors that affect more than 50 million people worldwide; nearly 30% of patients with epilepsy cannot be controlled with drugs. Interestingly, patients with inflammatory bowel disease are more susceptible to epilepsy, and a ketogenic diet is an effective treatment for patients with intractable epilepsy. Based on these clinical facts, the role of the microbiome and the gut-brain axis in epilepsy cannot be ignored. In this review, we discuss the relationship between the gut microbiota and epilepsy, summarize the possible pathogenic mechanisms of epilepsy from the perspective of the microbiota gut-brain axis, and discuss novel therapies targeting the gut microbiota. A better understanding of the role of the microbiota in the gut-brain axis, especially the intestinal one, would help investigate the mechanism, diagnosis, prognosis evaluation, and treatment of intractable epilepsy.

BACKGROUND:Interactions between the gut microbiota, microglia, and aging may modulate Alzheimer's disease (AD) pathogenesis but the precise nature of such interactions is not known. METHODS:We developed an integrated multi-dimensional, knowledge-driven, systems approach to identify interactions among microbial metabolites, microglia, and AD. Publicly available datasets were repurposed to create a multi-dimensional knowledge-driven pipeline consisting of an integrated network of microbial metabolite-gene-pathway-phenotype (MGPPN) consisting of 34,509 nodes (216 microbial metabolites, 22,982 genes, 1329 pathways, 9982 mouse phenotypes) and 1,032,942 edges. RESULTS:We evaluated the network-based ranking algorithm by showing that abnormal microglia function and physiology are significantly associated with AD pathology at both genetic and phenotypic levels: AD risk genes were ranked at the top 6.4% among 22,982 genes, P < 0.001. AD phenotypes were ranked at the top 11.5% among 9982 phenotypes, P < 0.001. A total of 8094 microglia-microbial metabolite-gene-pathway-phenotype-AD interactions were identified for top-ranked AD-associated microbial metabolites. Short-chain fatty acids (SCFAs) were ranked at the top among prioritized AD-associated microbial metabolites. Through data-driven analyses, we provided evidence that SCFAs are involved in microglia-mediated gut-microbiota-brain interactions in AD at both genetic, functional, and phenotypic levels. CONCLUSION:Our analysis produces a novel framework to offer insights into the mechanistic links between gut microbial metabolites, microglia, and AD, with the overall goal to facilitate disease mechanism understanding, therapeutic target identification, and designing confirmatory experimental studies.

Normal eating behaviour is coordinated by the tightly regulated balance between intestinal and extra-intestinal homeostatic and hedonic mechanisms. By contrast, food addiction is a complex, maladaptive eating behaviour that reflects alterations in brain-gut-microbiome (BGM) interactions and a shift of this balance towards hedonic mechanisms. Each component of the BGM axis has been implicated in the development of food addiction, with both brain to gut and gut to brain signalling playing a role. Early-life influences can prime the infant gut microbiome and brain for food addiction, which might be further reinforced by increased antibiotic usage and dietary patterns throughout adulthood. The ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food can further shift this balance towards hedonic eating through both central (disruptions in dopaminergic signalling) and intestinal (vagal afferent function, metabolic endotoxaemia, systemic immune activation, changes to gut microbiome and metabolome) mechanisms. In this Review, we propose a systems biology model of BGM interactions, which incorporates published reports on food addiction, and provides novel insights into treatment targets aimed at each level of the BGM axis.

BACKGROUND:The most common endocrine and metabolic disorders in premenopausal women is polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, chronic anovulation, and/or ultrasound evidence of small ovarian cysts. Obesity and insulin resistance are also the main factors influencing the clinical manifestations of this syndrome. Alzheimer's disease (AD) is the most typical progressive neurodegenerative disorder of the brain, and recent studies suggest a relationship between endocrinal dysregulation and neuronal loss during AD pathology. AIM:This study aimed to evaluate the common risk factors for Alzheimer's and PCOS based on previous studies. Knowing the common risk factors and eliminating them may prevent neurodegenerative Alzheimer's disease in the future. METHOD:In this narrative review, international databases, including Google Scholar, Scopus, PubMed, and the Web of Science, were searched to retrieve the relevant studies. The relevant studies' summaries were categorized to discuss the possible pathways that may explain the association between Alzheimer's and PCOS signs/symptoms and complications. RESULTS:According to our research, the factors involved in Alzheimer's and PCOS disorders may share some common risk factors. In patients with PCOS, increased LH to FSH ratio, decreased vitamin D, insulin resistance, and obesity are some of the most important factors that may increase the risk of Alzheimer's disease.

Brain physiological functions or pathological dysfunctions do surely depend on the activity of both neuronal and non-neuronal populations. Nevertheless, over the last decades, compelling and fast accumulating evidence showed that the brain is not alone. Indeed, the so-called "gut brain," composed of the microbial populations living in the gut, forms a symbiotic superorganism weighing as the human brain and strongly communicating with the latter the gut-brain axis. The gut brain does exert a control on brain (dys)functions and it will eventually become a promising valuable therapeutic target for a number of brain pathologies. In the present review, we will first describe the role of gut microbiota in normal brain physiology from neurodevelopment till adulthood, and thereafter we will discuss evidence from the literature showing how gut microbiota alterations are a signature in a number of brain pathologies ranging from neurodevelopmental to neurodegenerative disorders, and how pre/probiotic supplement interventions aimed to correct the altered dysbiosis in pathological conditions may represent a valuable future therapeutic strategy.

The gut microbiome has attracted increasing attention from researchers in recent years. The microbiota can have a specific and complex cross-talk with the host, particularly with the central nervous system (CNS), creating the so-called "gut-brain axis". Communication between the gut, intestinal microbiota, and the brain involves the secretion of various metabolites such as short-chain fatty acids (SCFAs), structural components of bacteria, and signaling molecules. Moreover, an imbalance in the gut microbiota composition modulates the immune system and function of tissue barriers such as the blood-brain barrier (BBB). Therefore, the aim of this literature review is to describe how the gut-brain interplay may contribute to the development of various neurological disorders, combining the fields of gastroenterology and neuroscience. We present recent findings concerning the effect of the altered microbiota on neurodegeneration and neuroinflammation, including Alzheimer's and Parkinson's diseases, as well as multiple sclerosis. Moreover, the impact of the pathological shift in the microbiome on selected neuropsychological disorders, i.e., major depressive disorders (MDD) and autism spectrum disorder (ASD), is also discussed. Future research on the effect of balanced gut microbiota composition on the gut-brain axis would help to identify new potential opportunities for therapeutic interventions in the presented diseases.

Schizophrenia is a severe neuropsychiatric disorder, and its etiology remains largely unknown. Environmental factors have been reported to play roles in the pathogenesis of schizophrenia, and one of the major environmental factors identified for this disorder is psychosocial stress. Several studies have suggested that stressful life events, as well as the chronic social stress associated with city life, may lead to the development of schizophrenia. The other factor is the gut-brain axis. The composition of the gut microbiome and alterations thereof may affect the brain and may lead to schizophrenia. The main interest of this review article is in overviewing the major recent findings on the effects of stress and the gut-brain axis, as well as their possible bidirectional effects, in the pathogenesis of schizophrenia.

The gut and brain are linked via various bidirectional pathways, and they communicate withand affect each other. The interaction between the gut-brain axis and the gut microbiota has attracted much attention in the development of hypertension. In this review, we have discussed the gut-brain-microbiota axis and its association with gut dysbiosis in terms of regulation of blood pressure using the autonomic nervous system, immune system, metabolites, hormones, and neurotransmitters. In addition, the treatments using microbiota that have been tried, to date, are briefly summarized. By understanding the mechanism by which gut-brainmicrobiota regulates blood pressure, the novel targets for hypertension treatment or a new therapeutic approach using the gut-brain-microbiota could be investigated.

Some food additives have demonstrated to induce dysbiosis leading to the development gut and gastrointestinal diseases. In order to clarify how this dysbiosis affects the microbiota gut-brain axis, a systematic interpretative literature review is carried out in this work. This review was made in seven academic search engines using the keywords shown below. The main finding of this work is a clear link between the changes in the gut microbiota promoted by food additives and the causes that lead to many reported diseases related to chronic food additives consumption. Despite the findings, studies on the effects of food additives on microbiota are still insufficient. Therefore, this work should serve as a motivation for future research on this subject.

Growing evidence from animal and human studies show that opioids have a major impact on the composition and function of gut microbiota. This leads to disruption in gut permeability and altered microbial metabolites, driving both systemic and neuroinflammation, which in turn impacts central nervous system (CNS) homeostasis. Tolerance and dependence are the major comorbidities associated with prolonged opioid use. Inflammatory mediators and signaling pathways have been implicated in both opioid tolerance and dependence. We provide evidence that targeting the gut microbiome during opioid use through prebiotics, probiotics, antibiotics, and fecal microbial transplantation holds the greatest promise for novel treatments for opioid abuse. Basic research and clinical trials are required to examine what is more efficacious to yield new insights into the role of the gut-brain axis in opioid abuse.

The developmental programs that build and sustain animal forms also encode the capacity to sense and adapt to the microbial world within which they evolved. This is abundantly apparent in the development of the digestive tract, which typically harbors the densest microbial communities of the body. Here, we review studies in human, mouse, zebrafish and Drosophila that are revealing how the microbiota impacts the development of the gut and its communication with the nervous system, highlighting important implications for human and animal health.

Many studies provided compelling evidence that extracellular vesicles (EVs) are involved in the regulation of the immune response, acting as both enhancers and dampeners of the immune system, depending on the source and type of vesicle. Research, including ours, has shown anti-inflammatory effects of milk-derived EVs, using human breast milk as well as bovine colostrum and store-bought pasteurized cow milk, in systems as well as therapeutically in animal models. Although it is not completely elucidated which proteins and miRNAs within the milk-derived EVs contribute to these immunosuppressive capacities, one proposed mechanism of action of the EVs is the modulation of the crosstalk between the (intestinal) microbiome and their host health. There is increasing awareness that the gut plays an important role in many inflammatory diseases. Enhanced intestinal leakiness, dysbiosis of the gut microbiome, and bowel inflammation are not only associated with intestinal diseases like colitis and Crohn's disease, but also characteristic for systemic inflammatory diseases such as lupus, multiple sclerosis, and rheumatoid arthritis (RA). Strategies to target the gut, and especially its microbiome, are under investigation and hold a promise as a therapeutic intervention for these diseases. The use of milk-derived EVs, either as stand-alone drug or as a drug carrier, is often suggested in recent years. Several research groups have studied the tolerance and safety of using milk-derived EVs in animal models. Due to its composition, milk-derived EVs are highly biocompatible and have limited immunogenicity even cross species. Furthermore, it has been demonstrated that milk-derived EVs, when taken up in the gastro-intestinal tract, stay intact after absorption, indicating excellent stability. These characteristics make milk-derived EVs very suitable as drug carriers, but also by themselves, these EVs already have a substantial immunoregulatory function, and even without loading, these vesicles can act as therapeutics. In this review, we will address the immunomodulating capacity of milk-derived EVs and discuss their potential as therapy for RA patients. Review criteria:The search terms "extracellular vesicles", "exosomes", "microvesicles", "rheumatoid arthritis", "gut-joint axis", "milk", and "experimental arthritis" were used. English-language full text papers (published between 1980 and 2021) were identified from PubMed and Google Scholar databases. The reference list for each paper was further searched to identify additional relevant articles.

Bone is the main supporting structure of the body and the main organ involved in body movement and calcium and phosphorus metabolism. Recent studies have shown that bone is also a potential new endocrine organ that participates in the physiological and pathophysiological processes of the cardiovascular, digestive, and endocrine systems through various bioactive cytokines secreted by bone cells and bone marrow. Bone-derived active cytokines can also directly act on the central nervous system and regulate brain function and individual behavior. The bidirectional regulation of the bone-brain axis has gradually attracted attention in the field of neuroscience. This paper reviews the regulatory effects of bone-derived active cytokines and bone-derived cells on individual brain function and brain diseases, as well as the occurrence and development of related neuropsychiatric diseases. The central regulatory mechanism function is briefly introduced, which will broaden the scope for mechanistic research and help establish prevention and treatment strategies for neuropsychiatric diseases based on the bone-brain axis.

Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain "connectome" has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain "connectome" and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms.

IMPORTANCE:Literature exploring the relationship between the intestinal microbiome and its effects on general health and well-being has grown significantly in recent years, and our knowledge of this subject continues to grow. Mounting evidence indicates that the intestinal microbiome is a potential target for therapeutic intervention in psychiatric illness and in neurodegenerative disorders such as Alzheimer disease. It is reasonable to consider modulating not just a patient's neurochemistry, behavior, or cognitive habits, but also their intestinal microbiome in an effort to improve psychiatric symptoms. OBSERVATIONS:In this review paper, we show that intestinal microbiota possess the ability to directly influence both physical and mental well-being; therefore, should be included in future discussions regarding psychiatric treatment. CONCLUSIONS:Clinicians are encouraged to consider patients' gut health when evaluating and treating psychiatric conditions, such as anxiety and depression. Optimization and diversification of gut flora through the use of psychobiotics-probiotics that confer mental health benefits-may soon become standard practice in conjunction with traditional psychiatric treatment modalities such as pharmacotherapy and psychotherapy.

Maternal obesity has been reported to be related to neurodevelopmental disorders in the offspring. However, the underlying mechanisms and effective interventions remain unclear. This cross-sectional study with 778 children aged 7-14 years in China indicated that maternal obesity is strongly associated with children's lower cognition and sociality. Moreover, it has been demonstrated that maternal obesity in mice disrupted the behavior and gut microbiome in offspring, both of which were restored by a high-fiber diet in either dams or offspring via alleviating synaptic impairments and microglial maturation defects. Co-housing and feces microbiota transplantation experiments revealed a causal relationship between microbiota and behavioral changes. Moreover, treatment with the microbiota-derived short-chain fatty acids also alleviated the behavioral deficits in the offspring of obese dams. Together, our study indicated that the microbiota-metabolites-brain axis may underlie maternal obesity-induced cognitive and social dysfunctions and that high dietary fiber intake could be a promising intervention.

PURPOSE OF REVIEW:In recent years, landmark clinical trials investigating the role of early oral exposure to food antigens for food allergy (FA) prevention have highlighted the importance of immunoregulatory pathways in the 'gut-skin axis'. This review highlights recent literature on the mechanisms of the immune system and microbiome involved in the gut-skin axis, contributing to the development of atopic dermatitis (AD), FA, allergic rhinitis (AR) and asthma. Therapeutic interventions harnessing the gut-skin axis are also discussed. RECENT FINDINGS:Epicutaneous sensitization in the presence of AD is capable of inducing Th2 allergic inflammation in the intestinal tract and lower respiratory airways, predisposing one to the development of AR and asthma. Probiotics have demonstrated positive effects in preventing and treating AD, though there is no evident relationship of its beneficial effects on other allergic diseases. Prophylactic skin emollients use has not shown consistent protection against AD, whereas there is some evidence for the role of dietary changes in alleviating AD and airway inflammation. More randomized controlled trials are needed to clarify the potential of epicutaneous immunotherapy as a therapeutic strategy for patients with FA. SUMMARY:The growing understanding of the gut-skin interactions on allergic disease pathogenesis presents novel avenues for therapeutic interventions which target modulation of the gut and/or skin.

PURPOSE OF REVIEW:Growing evidence show the importance of gut/kidney axis in renal diseases. Advances in gut microbiome sequencing, associated metabolites, detection of gut permeability and inflammation provide new therapeutic strategies targeting gut for kidney diseases and particularly for Immunoglobulin A (IgA) nephropathy (IgAN). RECENT FINDINGS:The diversity and composition of gut flora have been recently deeply explored in kidney diseases. Modulation and depletion of microbiota in animal models allowed the understanding of molecular mechanisms involved in the crosstalk between gut, immune system and kidney. New clinical trials in order to positively modulate microbiota result in improvement of gastrointestinal disorders and inflammation in patients suffering with kidney diseases. SUMMARY:The investigation of gut alterations in kidney diseases open new therapeutic strategies. In IgAN, targeted treatments for intestinal inflammation and modifications of gut microbiota seem promising.

The microbes that colonize the small and large intestines, known as the gut microbiome, play an integral role in optimal brain development and function. The gut microbiome is a vital component of the bidirectional communication pathway between the brain, immune system, and gut, also known as the brain-gut-immune axis. To date, there has been minimal investigation into the implications of improper development of the gut microbiome and the brain-gut-immune axis on the sleep-wake cycle, particularly during sensitive periods of physical and neurological development, such as childhood, adolescence, and senescence. Therefore, this review will explore the current literature surrounding the overlapping developmental periods of the gut microbiome, brain, and immune system from birth through to senescence, while highlighting how the brain-gut-immune axis affects the maturation and organization of the sleep-wake cycle. We also examine how a dysfunction to either the microbiome or the sleep-wake cycle negatively affects the bidirectional relationship between the brain and gut, and subsequently the overall health and functionality of this complex system. Additionally, this review integrates therapeutic studies to demonstrate when dietary manipulations, such as supplementation with probiotics and prebiotics, can modulate the gut microbiome to enhance the health of the brain-gut-immune axis and optimize our sleep-wake cycle.

The gut-brain axis plays an important role in maintaining homeostasis. Many intrinsic and extrinsic factors influence signaling along this axis, modulating the function of both the enteric and central nervous systems. More recently the role of the microbiome as an important factor in modulating gut-brain signaling has emerged and the concept of a microbiota-gut-brain axis has been established. In this review, we highlight the role of this axis in modulating enteric and central nervous system function and how this may impact disorders such as irritable bowel syndrome and disorders of mood and affect. We examine the overlapping biological constructs that underpin these disorders with a special emphasis on the neurotransmitter serotonin, which plays a key role in both the gastrointestinal tract and in the brain. Overall, it is clear that although animal studies have shown much promise, more progress is necessary before these findings can be translated for diagnostic and therapeutic benefit in patient populations.

PURPOSE OF REVIEW:There is a growing body of evidence implicating the role of the gut-brain axis in a multitude of inflammatory and non-inflammatory gastrointestinal disorders. The interaction between the gut and the brain is bidirectional and its therapeutic manipulation is gaining traction as the new frontier in the management of gastrointestinal disorders. This review summarizes the recent literature on this subject and serves as a reference for future research directions. RECENT FINDINGS:Recent studies have shown that the gut-brain axis, through its main communicator - the vagal nerve - plays a multimodal role in manipulating gastrointestinal physiology. This is evident systemically via the cholinergic anti-inflammatory pathway, through its effect on intestinal barrier function and also locally on intestinal epithelial and immune cells. Vagal nerve stimulation and faecal microbiota transplantation are two ways by which therapeutic manipulation has been attempted with success. SUMMARY:There has been exceptional progress in our understanding of the gut-brain axis in recent literature. Its role in the modulation of a multitude of gastrointestinal disorders is becoming clear. Preclinical findings are sufficient for this research to proceed to clinical trials in order to harness its clinical therapeutic potential for the care of patients.

The microbiota-gut-brain axis has emerged as a focal point of biomedical research. Alterations of gut microbiota are involved in not only various immune/inflammatory disorders but also neurological disorders including Alzheimer's disease (AD). The initial stage of the involvement of gut microbiota in the pathogenesis of AD may be the dysfunction of the blood-brain barrier (BBB). Gut microbiota-derived products in the circulation can worsen the BBB integrity, easily cross the disrupted BBB and enter the brain to promote pathological changes in AD. In this review, we first summarize the current evidence of the associations among gut microbiota, AD, and BBB integrity. We then discuss the mechanism of gut microbiota on BBB dysfunction with a focus on bacteria-derived lipopolysaccharide and exosomal high-mobility group box 1. Novel insights into the modification of the BBB as an intervention approach for AD are highlighted as well.

In recent decades, several neuroprotective agents have been provided in combating neuronal dysfunctions; however, no effective treatment has been found towards the complete eradication of neurodegenerative diseases. From the pathophysiological point of view, growing studies are indicating a bidirectional relationship between gut and brain termed gut-brain axis in the context of health/disease. Revealing the gut-brain axis has survived new hopes in the prevention, management, and treatment of neurodegenerative diseases. Accordingly, introducing novel alternative therapies in regulating the gut-brain axis seems to be an emerging concept to pave the road in fighting neurodegenerative diseases. Growing studies have developed marine-derived natural products as hopeful candidates in a simultaneous targeting of gut-brain dysregulated mediators towards neuroprotection. Of marine natural products, carotenoids (e.g., fucoxanthin, and astaxanthin), phytosterols (e.g., fucosterol), polysaccharides (e.g., fucoidan, chitosan, alginate, and laminarin), macrolactins (e.g., macrolactin A), diterpenes (e.g., lobocrasol, excavatolide B, and crassumol E) and sesquiterpenes (e.g., zonarol) have shown to be promising candidates in modulating gut-brain axis. The aforementioned marine natural products are potential regulators of inflammatory, apoptotic, and oxidative stress mediators towards a bidirectional regulation of the gut-brain axis. The present study aims at describing the gut-brain axis, the importance of gut microbiota in neurological diseases, as well as the modulatory role of marine natural products towards neuroprotection.