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.

Unraveling the gut-brain axis:the impact of steroid hormones and nutrition on Parkinson's disease

This comprehensive review explores the intricate relationship between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the context of the gut-brain axis.The gut-brain axis plays a pivotal role in neurodegenerative diseases like Parkinson's disease,encompassing diverse components such as the gut microbiota,immune system,metabolism,and neural pathways.The gut microbiome,profoundly influenced by dietary factors,emerges as a key player.Nutrition during the first 1000 days of life shapes the gut microbiota composition,influencing immune responses and impacting both child development and adult health.High-fat,high-sugar diets can disrupt this delicate balance,contributing to inflammation and immune dysfunction.Exploring nutritional strategies,the Mediterranean diet's anti-inflammatory and antioxidant properties show promise in reducing Parkinson's disease risk.Microbiome-targeted dietary approaches and the ketogenic diet hold the potential in improving brain disorders.Beyond nutrition,emerging research uncovers potential interactions between steroid hormones,nutrition,and Parkinson's disease.Progesterone,with its anti-inflammatory properties and presence in the nervous system,offers a novel option for Parkinson's disease therapy.Its ability to enhance neuroprotection within the enteric nervous system presents exciting prospects.The review addresses the hypothesis thatα-synuclein aggregates originate from the gut and may enter the brain via the vagus nerve.Gastrointestinal symptoms preceding motor symptoms support this hypothesis.Dysfunctional gut-brain signaling during gut dysbiosis contributes to inflammation and neurotransmitter imbalances,emphasizing the potential of microbiota-based interventions.In summary,this review uncovers the complex web of interactions between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the gut-brain axis framework.Understanding these connections not only offers novel therapeutic insights but also illuminates the origins of neurodegenerative diseases such as Parkinson's disease.

Cellular interplay to 3D in vitro microphysiological disease model:cell patterning microbiota-gut-brain axis

The microbiota-gut-brain axis(MGBA)has emerged as a key prospect in the bidirectional communication between two major organ systems:the brain and the gut.Homeostasis between the two organ systems allows the body to function without disease,whereas dysbiosis has long-standing evidence of etiopathological conditions.The most common communication paths are the microbial release of metabolites,soluble neurotransmitters,and immune cells.However,each pathway is intertwined with a complex one.With the emergence of in vitro models and the popularity of three-dimensional(3D)cultures and Transwells,engineering has become easier for the scientific understanding of neurodegenerative diseases.This paper briefly retraces the possible communication pathways between the gut microbiome and the brain.It further elaborates on three major diseases:autism spectrum disorder,Parkinson’s disease,and Alzheimer’s disease,which are prevalent in children and the elderly.These diseases also decrease patients’quality of life.Hence,understanding them more deeply with respect to current advances in in vitro modeling is crucial for understanding the diseases.Remodeling of MGBA in the laboratory uses many molecular technologies and biomaterial advances.Spheroids and organoids provide a more realistic picture of the cell and tissue structure than monolayers.Combining them with the Transwell system offers the advantage of compartmentalizing the two systems(apical and basal)while allowing physical and chemical cues between them.Cutting-edge technologies,such as bioprinting and microfluidic chips,might be the future of in vitro modeling,as they provide dynamicity.

Magnesium-L-threonate treats Alzheimer's disease by modulating the microbiota-gut-brain axis

Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1(APP/PS1). Here, we performed 16S r RNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-Lthreonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesiumL-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins(zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.

Traditional Chinese medicine treatment of insomnia based on microbial-gut-brain axis theory

In recent years,insomnia has gradually become a common disease in society,which seriously affects people's quality of life.At present,with the deepening of research on intestinal microbiota-gut-brain axis in Western medicine,many studies suggest that regulating the gastrointestinal tract can treat brain-related diseases.It is found that brain-gut-bacteria axis plays an important role in the prevention and treatment of primary insomnia.At present,although the clinical treatment of insomnia with Western medicine can improve the insomnia symptoms of patients to a certain extent,there are still obvious adverse reactions,such as anxiety and depression,drug addiction,etc.,so long-term oral drug therapy cannot be carried out.Traditional Chinese medicine(TCM)and acu-puncture techniques have certain therapeutic effects on insomnia.TCM believes that the brain and gastrointestinal system are connected through the meridian,and the pathophysiology is closely related.This paper will discuss the theory and feasibility of TCM for the treatment of insomnia from the pathological relation-ship between brain-gut axis,intestinal flora and insomnia.

Discussion on Traditional Chinese Medicine Treatment of Liver-Depression-Spleen-Deficiency Type Insomnia Based on the State-Target Theory and the Regulation of Microbiome-Gut-Brain Axis

Insomnia has become an urgent clinical problem in modern society.Current research has found that the gut flora-gut-brain axis plays an important role in regulating insomnia.The state-target theory is a product of the combination of traditional Chinese medicine and modern molecular biology technology.This paper clarifies the correlation between the state-target theory,the intestinal flora-gut-brain axis,and liver-depression-spleen-deficiency insomnia.The use of traditional Chinese medicine to regulate the structure and abundance of intestinal flora was also explored,aiming to integrate traditional Chinese medicine with Western medicine for the prevention and treatment of liver-depression-spleen-deficiency insomnia.

Research progress on insomnia treated by traditional Chinese medicine and acupuncture based on microbial-gut-brain axis theory

Insomnia,as one of the emotional diseases,has been increasing in recent years,which has a great impact on people's life and work.Therefore,researchers are eager to find a more perfect treatment.The microbiome-gut-brain axis is a new theory that has gradually become popular abroad in recent years and has a profound impact in the field of insomnia.In recent years,traditional Chinese medicine(TCM)has played an increasingly important role in the treatment of insomnia,especially acupuncture and Chinese herbal medicine.It is the main method of TCM in the treatment of insomnia.This paper mainly reviews the combination degree of"microorganism-gut-brain axis"theory with TCM and acupuncture under the system of TCM.To explore the mechanism of TCM and acupuncture in the treatment of insomnia under the guidance of"microorganismgut-brain axis"theory,in order to provide a new idea for the diagnosis and treatment of insomnia.

Gut-brain axis:Focus on gut metabolites short-chain fatty acids

Emerging evidence supports that the gut microbiome,reconsidered as a new organ in the human body,can not only affect the local gut,but also communicate with the brain via multiple pathways related to neuroendocrine,immune,and neural pathways,thereby proposing the new concept of the microbiome-gut-brain(MGB)axis.Recently,the role of short-chain fatty acids(SCFAs),which are the main anaerobic fermented metabolites of the gut microbiota in the MGB axis,has garnered significant attention.SCFAs are involved in a broad range of central neurological diseases,including neurodegenerative diseases,cerebral vascular diseases,epilepsy,neuroimmune inflammatory diseases,and mood disorders.However,the underlying mechanism of SCFA-related distant organ crosstalk is yet to be elucidated.Herein,we summarize current knowledge regarding interactions between SCFAs and the MGB axis,as well as their protective effects against central neurological diseases.

Gut bless you:The microbiota-gut-brain axis in irritable bowel syndrome

Irritable bowel syndrome(IBS)is a common clinical label for medically unexplained gastrointestinal symptoms,recently described as a disturbance of the microbiota-gut-brain axis.Despite decades of research,the pathophysiology of this highly heterogeneous disorder remains elusive.However,a dramatic change in the understanding of the underlying pathophysiological mechanisms surfaced when the importance of gut microbiota protruded the scientific picture.Are we getting any closer to understanding IBS’etiology,or are we drowning in unspecific,conflicting data because we possess limited tools to unravel the cluster of secrets our gut microbiota is concealing?In this comprehensive review we are discussing some of the major important features of IBS and their interaction with gut microbiota,clinical microbiota-altering treatment such as the low FODMAP diet and fecal microbiota transplantation,neuroimaging and methods in microbiota analyses,and current and future challenges with big data analysis in IBS.

Novel compound FLZ alleviates rotenone-induced Parkinson disease model by sup⁃pressing TLR4/MyD88/NF-κB pathway through microbiota-gut-brain axis

OBJECTIVES Parkinson disease(PD)is the second most common neurodegener⁃ative disease,but none of the current treatments for PD could halt the progress of the disease due to the limited understanding of the pathogenesis.Increasing evidence proves that the close com⁃munication between the brain and the gastroin⁃testinal system is influenced by gut microbiota in PD pathogenesis,known as microbiota-gut-brain axis.However,the explicit mechanisms of micro⁃biota dysbiosis in PD development have not been well elucidated yet.FLZ,a novel squamosamide derivative,has been proved to be effective in many PD models and is undergoing the phaseⅠclinical trial to treat PD in China.The aims of our study are to assess the neuroprotective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool.METHODS Chronic administration of rotenone(30 mg·kg-1 per day)was utilized to induce a mouse model to mimic the pathological process of PD.Behavioral tests and gastrointestinal function tests were conduct⁃ed to evaluate the PD symptoms.Gut microbiota alterations were analyzed by 16s rRNA sequenc⁃ing.The intestinal permeability and blood-brain barrier structures were assessed by various methods.The pro-inflammatory cytokines and LPS levels in the colon,serum,and brain were detected by ELISA.Furthermore,the levels of in⁃flammation and TLR4/MyD88/NF-κB pathway in the substantia nigra(SN)and colon were mea⁃sured.RESULTS Behavioral tests and gastroin⁃testinal function tests found that rotenone-in⁃duced mice showed gastrointestinal dysfunctions(week 3)prior to the motor deficits(week 4).However,FLZ treatment significantly alleviated these PD symptoms.16S rRNA sequencing illus⁃trated that PD-related microbiota alterations in⁃duced by rotenone were reversed by FLZ treatment at various taxa levels.Especially,we identified an increased genus Akkermansia in the Rotenone group(P=0.0006),which could be reversed by FLZ administration(P=0.0070).By reducing microbiota dysbiosis,qPCR results showed that FLZ treatment suppressed intestinal inflammation of rotenone-challenged mice.After⁃wards,transmission electron microscopy(TEM),in vivo FITC permeability assay,bacterial translocation assay,and Western blotting togeth⁃er suggested that FLZ treatment attenuated the intestinal barrier destruction induced by rote⁃none.Subsequently,ELISA results showed that FLZ administration inhibited the leakage of pro-inflammatory cytokines(TNF-α,IL-1β,and IL-6)and LPS into the serum,suggesting the atten⁃uation of systemic inflammation.Then,several experiments including TEM analysis found that FLZ treatment restored blood-brain barrier struc⁃ture.Consequently,the immunofluorescence staining demonstrated that neuroinflammation(increased Iba-1+and GFAP+cells)and dopami⁃nergic neuronal death(reduced TH+cells)in the SN caused by rotenone were remarkably attenu⁃ated.Further mechanistic research proved that the anti-inflammatory effects of FLZ administra⁃tion were mediated through the TLR4/MyD88/NF-κB pathway both in the SN and colon.CONCLU⁃SION FLZ treatment ameliorates microbiota dys⁃biosis to protect the PD model via inhibiting TLR4 pathway,which contributes to one of the underlying mechanisms beneath its neuroprotec⁃tive effects.Our research also supports the importance of microbiota-gut-brain axis in PD pathogenesis,suggesting its potential role as a novel therapeutic target for PD treatment.

Clinical Report on the Treatment of Post-stroke Cognitive Impairment Based on Microbe-Gut-Brain Axis Theory

Based on the close relationship between MGBA and PSCI,one PSCI related case is reported,and it is emphasized to improve clinicians'understanding of MGBA theory in the treatment of PSCI,thereby providing new ideas for exploring pathogenesis and treatment of PSCI.

Intestinal flora and depressive disorders:exploration and prospect of microbial-gut-brain axis

This paper examines the correlation between depressive disorders and intestinal flora.Depression is a common affective disorder characterized by low mood,loss of interest,anhedonia,high incidence,high recurrence rate,high disability rate,and high medical costs.The incidence and harmfulness of depressive disorder are gradually increasing,and its etiology is complex and diverse,among which the abnormal intestinal flora is considered to be one of the causes of depressive disorder.This article reviews the results of several studies that found intestinal flora imbalance in depressed patients,including changes in the type and quantity of flora and changes in metabolic pathways.In addition,antibiotic and probiotic treatments have also been shown to be effective in alleviating depressive symptoms,further indicating the importance of intestinal flora disturbances in the pathogenesis of depression.We also explored the relationship between intestinal flora and the pathogenesis of depressive disorders.Through neuro-immuno-endo-crine-metabolic pathways,intestinal flora can affect the function of the central nervous system,cause changes in the host’s mental behavior,and lead to or aggravate depressive symptoms.Overall,this study not only found differences in the intestinal flora of patients with depressive disorders but also revealed the potential role of intestinal flora in the pathogenesis.Importantly,this provides a new theoretical basis for further clarifying the pathogenesis of depressive disorders and formulating diagnosis and treatment strategies.

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.

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.

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.

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.

The gut-eye axis:from brain neurodegenerative diseases to age-related macular degeneration

Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision.Unfortunately,the specific pathogenesis remains unclear,and effective early treatment options are consequently lacking.The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host.The intestinal microbiome undergoes dynamic changes owing to age,diet,genetics,and other factors.Such dysregulation of the intestinal flora can disrupt the microecological balance,resulting in immunological and metabolic dysfunction in the host,and affecting the development of many diseases.In recent decades,significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract,including the brain.Indeed,several studies have demonstrated the critical role of the gut-brain axis in the development of brain neurodegenerative diseases,including Alzheimer’s disease and Parkinson’s disease.Similarly,the role of the“gut-eye axis”has been confirmed to play a role in the pathogenesis of many ocular disorders.Moreover,age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies.As such,the intestinal flora may play an important role in age-related macular degeneration.Given the above context,the present review aims to clarify the gut-brain and gut-eye connections,assess the effect of intestinal flora and metabolites on age-related macular degeneration,and identify potential diagnostic markers and therapeutic strategies.Currently,direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited,while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration.Organ-on-a-chip technology has shown promise in clarifying the gut-eye interactions,while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms.

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.

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.”

The role of gut microbiota in the gut-brain axis:current challenges and perspectives

Brain and the gastrointestinal(GI)tract are intimately con-nected to form a bidirectional neurohumoral communica-tion system.The communication between gut and brain,knows as the gut-brain axis,is so well established that the functional status of gut is always related to the condi-tion of brain.The researches on the gut-brain axis were traditionally focused on the psychological status affecting the function of the GI tract.However,recent evidences showed that gut microbiota communicates with the brain via the gut-brain axis to modulate brain development and behavioral phenotypes.These recent fi ndings on the new role of gut microbiota in the gut-brain axis implicate that gut microbiota could associate with brain functions as well as neurological diseases via the gut-brain axis.To elucidate the role of gut microbiota in the gut-brain axis,precise identification of the composition of microbes constituting gut microbiota is an essential step.However,identifi cation of microbes constituting gut microbiota has been the main technological challenge currently due to massive amount of intestinal microbes and the diffi culties in culture of gut microbes.Current methods for identifi ca-tion of microbes constituting gut microbiota are depend-ent on omics analysis methods by using advanced high tech equipment.Here,we review the association of gut microbiota with the gut-brain axis,including the pros and cons of the current high throughput methods for identi-fi cation of microbes constituting gut microbiota to eluci-date the role of gut microbiota in the gut-brain axis.