Bidirectional regulation of the brain-gut-microbiota axis following traumatic brain injury

Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”

Gut microbiota-astrocyte axis: new insights into age-related cognitive decline

With the rapidly aging human population,age-related cognitive decline and dementia are becoming increasingly prevalent worldwide.Aging is considered the main risk factor for cognitive decline and acts through alterations in the composition of the gut microbiota,microbial metabolites,and the functions of astrocytes.The microbiota–gut–brain axis has been the focus of multiple studies and is closely associated with cognitive function.This article provides a comprehensive review of the specific changes that occur in the composition of the gut microbiota and microbial metabolites in older individuals and discusses how the aging of astrocytes and reactive astrocytosis are closely related to age-related cognitive decline and neurodegenerative diseases.This article also summarizes the gut microbiota components that affect astrocyte function,mainly through the vagus nerve,immune responses,circadian rhythms,and microbial metabolites.Finally,this article summarizes the mechanism by which the gut microbiota–astrocyte axis plays a role in Alzheimer’s and Parkinson’s diseases.Our findings have revealed the critical role of the microbiota–astrocyte axis in age-related cognitive decline,aiding in a deeper understanding of potential gut microbiome-based adjuvant therapy strategies for this condition.

Gut-brain axis as a bridge in obesity and depression:Mechanistic exploration and therapeutic prospects

A recent study by Wang et al,published in the World Journal of Psychiatry,provided preventative and therapeutic strategies for the comorbidity of obesity and depression.The gut-brain axis,which acts as a two-way communication system between the gastrointestinal tract and the central nervous system,plays a pivotal role in the pathogenesis of these conditions.Evidence suggests that metabolic byproducts,such as short-chain fatty acids,lipopolysaccharide and bile acids,which are generated by the gut microbiota,along with neurotransmitters and inflammatory mediators within the gut-brain axis,modulate the host's metabolic processes,neuronal regulation,and immune responses through diverse mechanisms.The interaction between obesity and depression via the gut-brain axis involves disruptions in the gut microbiota balance,inflammatory immune responses,and alterations in the neuroendocrine system.Modulating the gut-brain axis,for example,through a ketogenic diet,the use of probiotics,and the supplementation of antioxidants,offers new remedial approaches for obesity and depression.Future research that explores the mechanisms of the gut-brain axis is needed to provide more evidence for clinical treatment.

Immune regulation of the gut-brain axis and lung-brain axis involved in ischemic stroke

Local ischemia often causes a series of inflammatory reactions when both brain immune cells and the peripheral immune response are activated.In the human body,the gut and lung are regarded as the key reactional targets that are initiated by brain ischemic attacks.Mucosal microorganisms play an important role in immune regulation and metabolism and affect blood-brain barrier permeability.In addition to the relationship between peripheral organs and central areas and the intestine and lung also interact among each other.Here,we review the molecular and cellular immune mechanisms involved in the pathways of inflammation across the gut-brain axis and lung-brain axis.We found that abnormal intestinal flora,the intestinal microenvironment,lung infection,chronic diseases,and mechanical ventilation can worsen the outcome of ischemic stroke.This review also introduces the influence of the brain on the gut and lungs after stroke,highlighting the bidirectional feedback effect among the gut,lungs,and brain.

Importance of the gut microbiota in the gut-liver axis in normal and liver disease

The gut microbiota is of growing interest to clinicians and researchers.This is because there is a growing understanding that the gut microbiota performs many different functions,including involvement in metabolic and immune processes that are systemic in nature.The liver,with its important role in detoxifying and metabolizing products from the gut,is at the forefront of interactions with the gut microbiota.Many details of these interactions are not yet known to clinicians and researchers,but there is growing evidence that normal gut microbiota function is important for liver health.At the same time,factors affecting the gut microbiota,including nutrition or medications,may also have an effect through the gut-liver axis.

Clinical Treatment of Functional Pain Syndromes along the Microbiome-Gut-Brain-Axis: Combined Approach with Neuromodulation-Neurofeedback and Multispecies Probiotic

Functional pain syndromes are very common diseases that negatively impact the quality of life of patients with important socio-economic repercussions. The clinical alterations associated with these pathologies are multiple and have a complex psycho-organic character that moves along the micorobiome-gut-brain-axis. For the present study, 45 patients of both sexes (19 male, 26 female) aged 30 - 59 years were enrolled because of a diagnosis of Functional pain syndromes (FPS) that lasted for more than 6 months. All patients underwent pre-treatment clinical assessments (T0) for anxiety disorder, multidimensional assessment of pain, monitoring of baseline values of Alpha-Theta cerebral rhythm in occipital region and monitoring of salivary cortisol levels. All the patients underwent a clinical treatment combined with central neuromodulation with neurofeedback—Alpha Theta increase protocols (once a week for three months), administration of multispecies probiotic (one dose per day for 3 months) and clinical psychological interviews (once a week for three months). At the end of treatment (T1), patients were re-evaluated. Results show statistically relevant improvements of each feature considered: the Relief from Pain provided by the medication increases on average from 36.6% to 87.3%, the salivary Cortisol level at 11 pm decreases from 6.4 ng/ml to a physiological value of 1.2 ng/ml, and the anxiety rating score is reduced from 28 to 12. Moreover, the 23.9% increase in α-θ relative power shows the positive outcome of the brain autoregulation. This study highlights that the combined approach of Neurofeedback with drugs and multispecies probiotic results in great improvements in the patients’ life.

Influence of Gut and Lung Microbiota and the Gut-Lung Axis on Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia(BPD),also known as neonatal chronic lung disease,is a common respiratory disease in preterm infants.Preterm infants with BPD often exhibit changes in gut and lung microbiota.In recent years,with the development of high-throughput sequencing technology,more and more mechanisms of the gut-lung axis have been confirmed,helping to explore new directions for the treatment of BPD using microecological agents.This paper reviews the roles of gut microbiota,lung microbiota,and the gut-lung axis in the pathogenesis of BPD in preterm infants,providing new research avenues for the prevention and treatment of BPD.

Brain-gut-microbiota axis in Parkinson's disease

Parkinson's disease(PD) is characterized by alphasynucleinopathy that affects all levels of the braingut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological,neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding.Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gutmicrobiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.

Role of gut microbiota via the gut-liver-brain axis in digestive diseases

The gut-brain axis is a bidirectional information interaction system between the central nervous system(CNS) and the gastrointestinal tract, in which gut microbiota plays a key role. The gut microbiota forms a complex network with the enteric nervous system, the autonomic nervous system, and the neuroendocrine and neuroimmunity of the CNS, which is called the microbiota-gut-brain axis. Due to the close anatomical and functional interaction of the gut-liver axis, the microbiota-gut-liver-brain axis has attracted increased attention in recent years. The microbiota-gut-liver-brain axis mediates the occurrence and development of many diseases, and it offers a direction for the research of disease treatment. In this review, we mainly discuss the role of the gut microbiota in the irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis and hepatic encephalopathy via the gut-liver-brain axis, and the focus is to clarify the potential mechanisms and treatment of digestive diseases based on the further understanding of the microbiota-gut-liver-brain axis.

Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis

Minimal hepatic encephalopathy(MHE) is a frequent neurological and psychiatric complication of liver cirrhosis. The precise pathogenesis of MHE is complicated and has yet to be fully elucidated. Studies in cirrhotic patients and experimental animals with MHE have indicated that gut microbiota dysbiosis induces systemic inflammation, hyperammonemia, and endotoxemia, subsequently leading to neuroinflammation in the brain via the gut-liver-brain axis. Related mechanisms initiated by gut microbiota dysbiosis have significant roles in MHE pathogenesis. The currently available therapeutic strategies for MHE in clinical practice, including lactulose, rifaximin, probiotics, synbiotics, and fecal microbiota transplantation, exert their effects mainly by modulating gut microbiota dysbiosis. Microbiome therapies for MHE have shown promised efficacy and safety;however, several controversies and challenges regarding their clinical use deserve to be intensively discussed. We have summarized the latest research findings concerning the roles of gut microbiota dysbiosis in the pathogenesis of MHE via the gut-liver-brain axis as well as the potential mechanisms by which microbiome therapies regulate gut microbiota dysbiosis in MHE patients.

Microbiota-gut-brain axis and its affect inflammatory bowel disease:Pathophysiological concepts and insights for clinicians

Despite the bi-directional interaction between gut microbiota and the brain not being fully understood,there is increasing evidence arising from animal and human studies that show how this intricate relationship may facilitate inflammatory bowel disease(IBD)pathogenesis,with consequent important implications on the possibility to improve the clinical outcomes of the diseases themselves,by acting on the different components of this system,mainly by modifying the microbiota.With the emergence of precision medicine,strategies in which patients with IBD might be categorized other than for standard gut symptom complexes could offer the opportunity to tailor therapies to individual patients.The aim of this narrative review is to elaborate on the concept of the gutbrain-microbiota axis and its clinical significance regarding IBD on the basis of recent scientific literature,and finally to focus on pharmacological therapies that could allow us to favorably modify the function of this complex system.

Early exposure to food contaminants reshapes maturation of the human brain-gut-microbiota axis

Early childhood growth and development is conditioned by the consecutive events belonging to perinatal programming. This critical window of life will be very sensitive to any event altering programming of the main body functions.Programming of gut function, which is starting right after conception, relates to a very well-established series of cellular and molecular events associating all types of cells present in this organ, including neurons, endocrine and immune cells. At birth, this machinery continues to settle with the establishment of extra connection between enteric and other systemic systems and is partially under the control of gut microbiota activity, itself being under the densification and the diversification of microorganisms’ population. As thus, any environmental factor interfering on this pre-established program may have a strong incidence on body functions. For all these reasons, pregnant women, fetuses and infants will be particularly susceptible to environmental factors and especially food contaminants. In this review, we will summarize the actual understanding of the consequences of repeated low-level exposure to major food contaminants on gut homeostasis settlement and on brain/gut axis communication considering the pivotal role played by the gut microbiota during the fetal and postnatal stages and the presumed consequences of these food toxicants on the individuals especially in relation with the risks of developing later in life non-communicable chronic diseases.

Microbiota-gut-brain axis and major depressive disorder:implications for fecal microbiota transplantation therapy

Major depression disorder(MDD),which can affect individuals of any age,is one of the most common diseases,affecting an estimated 350 million people worldwide and placing a significant burden on individuals and society.MDD is heterogeneous.The conventional antidepressants are only partially effective and only 44%of patients are in remission during treatment.Therefore,improving the efficacy of MDD therapy has become a key research focus.An increasing number of studies have shown that the microbiota-gut-brain axis is closely related to the physiological and pathological processes of depression,suggesting that the gut microbiota may have protective or pathogenic effects on the development of MDD.Gut microbiota-oriented treatment is one of the most promising approaches.Fecal microbiota transplantation(FMT)has great potential to improve MDD more directly and effectively,although few research results in this area has been conducted.To assess the gut microbiota's connection with MDD,the efficiency of the nodes and the prospects of FMT therapy for MDD have been reviewed in this paper.

Longitudinal assessment of peripheral organ metabolism and the gut microbiota in an APP/PS1 transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.

Elaidic acid-induced intestinal barrier damage led to gut-liver axis derangement and triggered NLRP3 inflammasome in the liver of SD rats

Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investigated the effects of elaidic acid(EA),a typical TFA,on the gut microbiota to understand the underlying mechanisms of TFA-related chronic diseases.16S rDNA gene sequencing on faecal samples from Sprague-Dawley rats were performed to explore the composition change of the gut microbiota by EA gavage for 4 weeks.The results showed that the intake of EA increased the abundance of well-documented harmful bacteria,such as Proteobacteria,Anaerotruncus,Oscillibacter and Desulfovibrionaceae.Plus,EA induced translocation of lipopolysaccharides(LPS) and the above pathogenic bacteria,disrupted the intestinal barrier,led to gut-liver axis derangement and TLR4 pathway activation in the liver.Overall,EA induced intestinal barrier damage and regulated TLR4-MyD88-NF-κB/MAPK pathways in the liver of SD rats,leading to the activation of NLRP3 inflammasome and inflammatory liver damage.

Functional gastrointestinal disorders and gut-brain axis: What does the future hold?

Despite their high prevalence, lack of understanding of the exact pathophysiology of the functional gastrointestinal disorders has restricted us to symptomatic diagnostic tools and therapies. Complex mechanisms underlying the disturbances in the bidirectional communication between the gastrointestinal tract and the brain have a vital role in the pathogenesis and are key to our understanding of the disease phenomenon. Although we have come a long way in our understanding of these complex disorders with the help of studies on animals especially rodents, there need to be more studies in humans, especially to identify the therapeutic targets. This review study looks at the anatomical features of the gut-brain axis in order to discuss the different factors and underlying molecular mechanisms that may have a role in the pathogenesis of functional gastrointestinal disorders. These molecules and their receptors can be targeted in future for further studies and possible therapeutic interventions. The article also discusses the potential role of artificial intelligence and machine learning and its possible role in our understanding of these scientifically challenging disorders.

Brain-gut axis in the pathogenesis of Helicobacter pylori infection

Helicobacter pylori (H. pylori) infection is the main pathogenic factor for upper digestive tract organic diseases. In addition to direct cytotoxic and proinflammatory effects, H. pylori infection may also induce abnormalities indirectly by affecting the brain-gut axis, similar to other microorganisms present in the alimentary tract. The brain-gut axis integrates the central, peripheral, enteric and autonomic nervous systems, as well as the endocrine and immunological systems, with gastrointestinal functions and environmental stimuli, including gastric and intestinal microbiota. The bidirectional relationship between H. pylori infection and the brain-gut axis influences both the contagion process and the host’s neuroendocrine-immunological reaction to it, resulting in alterations in cognitive functions, food intake and appetite, immunological response, and modification of symptom sensitivity thresholds. Furthermore, disturbances in the upper and lower digestive tract permeability, motility and secretion can occur, mainly as a form of irritable bowel syndrome. Many of these abnormalities disappear following H. pylori eradication. H. pylori may have direct neurotoxic effects that lead to alteration of the brain-gut axis through the activation of neurogenic inflammatory processes, or by microelement deficiency secondary to functional and morphological changes in the digestive tract. In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector, as H. pylori infection is associated with decreased mast cell infiltration in the digestive tract. Nevertheless, unequivocal data concerning the direct and immediate effect of H. pylori infection on the brain-gut axis are still lacking. Therefore, further studies evaluating the clinical importance of these host-bacteria interactions will improve our understanding of H. pylori infection pathophysiology and suggest new therapeutic approaches.

Gut microbiota axis:potential target of phytochemicals from plant-based foods

Food-microbiota-host interactions provide an overarching framework for understanding the function of the gut microbiota axis.Diet is a major modulator of gut microbiota.Plant-based foods are rich in phytochemicals;therefore,it is essential to assess such foods and elucidate the mechanisms underlying their action.In this review,we summarize the role of gut microbiota in the communication between the gut and the brain,liver,lung,kidney,and joints,as well as the role of the gut microbiota axis in diseases involving these organs.In addition,we assess the effects of phytochemicals from plant-based foods on the gut microbiota axis via different pathways.

Focus on the gut-brain axis: multiple sclerosis, the intestinal barrier and the microbiome

The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.

Neuroimaging the brain-gut axis in patients with irritable bowel syndrome

AIM:To summarize and synthesize current literature on neuroimaging the brain-gut axis in patients with irritable bowel syndrome(IBS).METHODS:A database search for relevant literature was conducted using Pub Med,Scopus and Embase in February 2015.Date filters were applied from the year2009 and onward,and studies were limited to those written in the English language and those performed upon human subjects.The initial search yielded 797articles,out of which 38 were pulled for full text review and 27 were included for study analysis.Investigations were reviewed to determine study design,methodology and results,and data points were placed in tabular format to facilitate analysis of study findings across disparate investigations.RESULTS:Analysis of study data resulted in the abstraction of four key themes:Neurohormonal differences,anatomic measurements of brain structure and connectivity,differences in functional responsiveness of the brain during rectal distention,and confounding/correlating patient factors.Studies in this review noted alterations of glutamate in the left hippocampus(HIPP),commonalities across IBS subjects in terms of brain oscillation patterns,cortical thickness/gray matter volume differences,and neuroanatomical regions withincreased activation in patients with IBS:Anterio cingulate cortex,mid cingulate cortex,amygdala anterior insula,posterior insula and prefrontal cortex.A striking finding among interventions was the substantia influence that patient variables(e.g.,sex,psychologica and disease related factors)had upon the identification of neuroanatomical differences in structure and con nectivity.CONCLUSION:The field of neuroimaging can provide insight into underlying physiological differences that distinguish patients with IBS from a healthy population.