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.

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.

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 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.

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.

Healthy axis: Towards an integrated view of the gut-brain health

Despite the lack of precise mechanisms of action, a growing number of studies suggests that gut microbiota is involved in a great number of physiological functions of the human organism. In fact, the composition and the relations of intestinal microbial populations play a role, either directly or indirectly, to both the onset and development of various pathologies. In particular, the gastrointestinal tract and nervous system are closely connected by the so-called gut–brain axis, a complex bidirectional system in which the central and enteric nervous system interact with each other, also engaging endocrine, immune and neuronal circuits. This allows us to put forward new working hypotheses on the origin of some multifactorial diseases: from eating to neuropsychiatric disorders (such as autism spectrum disorders and depression) up to diabetes and tumors (such as colorectal cancer). This scenario reinforces the idea that the microbiota and its composition represent a factor, which is no longer negligible, not only in preserving what we call “health” but also in defining and thus determining it. Therefore, we propose to consider the gut-brain axis as the focus of new scientific and clinical investigation as long as the locus of possible systemic therapeutic interventions.

Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide

Long-acting glucagon-like peptide-1(GLP-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2 D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors(GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions(e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2 D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation(thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2 D, stroke and Alzheimer disease(AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone's regulation of some autonomic functions and liraglutide's neuroprotective potential.

Psycho-gastroenterological profile of an Italian population of children with disorders of gut-brain interaction:A case-control study

BACKGROUND Disorders of gut-brain interaction(DGBI)are common,but knowledge about their physiopathology is still poor,nor valid tools have been used to evaluate them in childhood.AIM To develop a psycho-gastroenterological questionnaire(PGQ)to assess the psycho-gastroenterological profile and social characteristics of a pediatric population with and without DGBI.METHODS One hundred and nineteen Italian children(age 11-18)were included:28 outpatient patients with DGBI(Rome IV criteria)and 91 healthy controls.They filled the PGQ,faces pain scale revised(FPS-R),Bristol stool chart,ga-strointestinal symptoms rating scale,state-trait anxiety inventory,Toronto alexithymia scale 20,perceived self-efficacy in the management of negative emotions and expression of positive emotions(APEN-G,APEP-G),irritable bowel syndrome-quality of life questionnaire,school performances,tobacco use,early life events,degree of digital-ization.RESULTS Compared to controls,patients had more medical examinations(35%of them went to the doctor more than five times),a higher school performance(23%vs 13%,P<0.05),didn’t use tobacco(never vs 16%,P<0.05),had early life events(28%vs 1%P<0.05)and a higher percentage of pain classified as 4 in the FPS-R during the examination(14%vs 7%,P<0.05).CONCLUSION Pediatric outpatients with DGBI had a higher prevalence of early life events,a lower quality of life,more medical examinations rising health care costs,lower anxiety levels.

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.

基于“微生物-肠-脑轴”探讨补肾通腑方对APP/PS1小鼠肠道菌群及LPS/TLR4/NF-κB通路的影响

目的探讨补肾通腑方调控肠道菌群,改善阿尔茨海默病(Alzheimer’s disease,AD)模型小鼠学习记忆能力的作用机制。方法以APP/PS1小鼠为研究对象,给予补肾通腑方治疗8周,采用Morris水迷宫法观察小鼠空间学习记忆能力变化;16S rDNA检测小鼠肠道菌群丰度、多样性变化;HE染色观察海马病理形态学变化;免疫荧光检测海马区小胶质细胞活化情况;Western blot检测TLR4、NF-κB、IL-6等炎症因子表达。结果与模型组相比,补肾通腑方可以缩短AD模型小鼠逃避潜伏期、游泳路径,增加跨越平台次数(P<0.05),提升肠道菌群多样性,调节肠道菌群丰度,促进海马神经元细胞损伤修复,降低iNOS/Iba1共表达,提高Arg1/Iba1共表达(P<0.01),促进小胶质细胞从M1型向M2型转化,下调TLR4、NF-κB、IL-6等促炎因子的表达。结论补肾通腑方改善AD模型小鼠学习记忆能力的作用机制可能与调节肠道菌群介导的LPS/TLR4/NF-κB通路,从而抑制促炎型小胶质细胞活化、减轻中枢神经系统炎症、改善海马区神经元细胞损伤有关。

Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice

ProBiotic-4 is a probiotic preparation composed of Bifidobacterium lactis,Lactobacillus casei,Bifidobacterium bifidum,and Lactobacillus acidophilus.This study aims to investigate the effects of ProBiotic-4 on the microbiota-gut-brain axis and cognitive deficits,and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8(SAMP8)mice.ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks.We observed that ProBiotic-4 significantly improved the memory deficits,cerebral neuronal and synaptic injuries,glial activation,and microbiota composition in the feces and brains of aged SAMP8 mice.ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood-brain barrier,decreased interleukin-6 and tumor necrosis factor-αat both mRNA and protein levels,reduced plasma and cerebral lipopolysaccharide(LPS)concentration,toll-like receptor 4(TLR4)expression,and nuclear factor-κB(NF-κB)nuclear translocation in the brain.In addition,not only did ProBiotic-4 significantly decreased the levels ofγ-H2 AX,8-hydroxydesoxyguanosine,and retinoic-acid-inducible gene-I(RIG-I),it also abrogated RIG-I multimerization in the brain.These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota-gut-brain axis and cognitive function in aging,and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-κB signaling pathway and inflammatory responses.

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.

Gut hormones in microbiota-gut-brain cross-talk

The homeostasis of the gut-brain axis has been shown to exert several effects on physiological and psychological health.The gut hormones released by enteroendocrine cells scattered throughout the gastrointestinal tract are important signaling molecules within the gut-brain axis.The interaction between gut microbiota and gut hormones has been greatly appreciated in gut-brain cross-talk.The microbiota plays an essential role in modulating many gut-brain axis-related diseases,ranging from gastrointestinal disorders to psychiatric diseases.Similarly,gut hormones also play pleiotropic and important roles in maintaining health,and are key signals involved in gut-brain axis.More importantly,gut microbiota can affect the release and functions of gut hormones.This review highlights the role of gut microbiota in the gut-brain axis and focuses on how microbiota-related gut hormones modulate various physiological functions.Future studies could target the microbiota-hormones-gut brain axis to develop novel therapeutics for different psychiatric and gastrointestinal disorders,such as obesity,anxiety,and depression.

Amino acid sensing in the gut and its mediation in gut-brain signal transduction

Animal gastrointestinal tract is not only a digestive organ, but also a nutrient sensing organ which detects luminal nutrient and thus can regulate food intake. There are many amino acid sensing receptors and transporters in the gut. Amino acids sensing by these receptors and transporters can stimulate the intestinal endocrine cells to release a variety of gut hormones. These hormones trigger a series of physiological effects via the nerve system. This review summarized the recent advance on the amino acid sensing receptors and transporters in the gastrointestinal tract, the gut hormones released from the intestinal endocrine cells and the hormones-induced signal transduction between the gut and brain. A better understanding of these processes may help to gain further insight into the specific role of amino acids in digestion and provide guidelines in developing strategy for the better use of amino acids in the diet.

“Sentinel or accomplice”:gut microbiota and microglia crosstalk in disorders of gut-brain interaction

Abnormal brain-gut interaction is considered the core pathological mechanism behind the disorders of gut-brain interaction(DGBI),in which the intestinal microbiota plays an important role.Microglia are the“sentinels”of the central nervous system(CNS),which participate in tissue damage caused by traumatic brain injury,resist central infection and participate in neurogenesis,and are involved in the occurrence of various neurological diseases.With in-depth research on DGBI,we could find an interaction between the intestinal microbiota and microglia and that they are jointly involved in the occurrence of DGBI,especially in individuals with comorbidities of mental disorders,such as irritable bowel syndrome(IBS).This bidirectional regulation of microbiota and microglia provides a new direction for the treatment of DGBI.In this review,we focus on the role and underlying mechanism of the interaction between gut microbiota and microglia in DGBI,especially IBS,and the corresponding clinical application prospects and highlight its potential to treat DGBI in individuals with psychiatric comorbidities.

基于脑肠轴理论探讨捏脊对儿童生长发育的影响

脑肠轴理论是现代医学提出的关于大脑与肠道之间相互作用的概念。而祖国传统医学中的捏脊手法是通过刺激“入络脑”的“阳脉之海”——督脉,以及其两旁的肌肉激发人体各脏腑、系统功能,从而对人体尤其是生长发育期儿童的脏腑调节、生长发育、脑发育等起到正向作用。本文基于脑肠轴理论,探讨肠道如何通过神经内分泌、免疫、代谢物通路影响大脑功能的机制,联系捏脊手法作用于背部特定经络区域,从而激活神经内分泌系统、调控肠菌群、调节免疫系统等的现代医学作用机制,以及通过刺激督脉维系脏腑之元阳、汇一身之阳入督荣脑以达到脑肠同调的中医作用机制,探讨捏脊疗法在儿童生长发育中对其调节脏腑,促进大脑发育的影响。

高原缺氧脱习服小鼠学习记忆能力与肠道菌群变化的肠脑轴研究

目的研究小鼠模拟高原低压缺氧后回到平原脱习服阶段学习记忆能力变化,并通过高原缺氧环境对肠道菌群变化探索其发生改变的肠脑轴机制,为高原脱习服采取针对性的保障措施提供依据。方法26只昆明小鼠随机分为对照组和实验组,对照组不给予任何处理,实验组在动物实验低压舱内给予低压缺氧。动物离开低压舱后立即采集粪便标本,进行肠道菌群16S rDNA扩增子测序,筛选差异菌群,并对差异菌群的功能进行分析;通过Morris水迷宫实验检测两组小鼠的学习记忆能力;尼氏染色观察小鼠脑组织海马病理学变化。采用SPSS 17.0和GraphPad Prism v9.5.1.733软件进行数据分析。结果Morris水迷宫实验表明高原低氧脱习服可致小鼠定向航行能力降低(P<0.05)。尼氏染色显示实验组较对照组小鼠的海马区神经元变性坏死严重。肠道菌群分析研究发现,对照组与实验组的分组具有统计学差异(P<0.05);两组微生物结构主成分分析发现,实验组微生物结构与对照组具有差异(P<0.05);线性判别分析及影响因子分析线性判别分析值分布柱状图显示组间细菌物种具有统计学差异(LDA Score>2)。结论高原低氧环境可造成肠道菌群紊乱,且差异菌主要集中在衰老、感染和变性,这些通路与学习记忆功能关系密切,而高原缺氧脱习服阶段小鼠出现海马神经元变性坏死、学习记忆能力下降,提示高原低压缺氧可能影响肠道菌群,通过肠脑轴影响脑组织衰老和发生退行性改变,从而影响其回到平原脱习服阶段的学习记忆能力。

The gut-brain axis in the pathogenesis of Parkinson’s disease

Parkinson’s disease(PD)is the second most common neurodegenerative disease.Its pathological markers include Lewy bodies and Lewy neuritis,which primarily affect the substantia nigra.However,in recent years,mounting evidence suggests that PD is a multifocal neurodegenerative process that influences several neuronal structures aside from the substantia nigra,one of which is the enteric nervous system.Many clinical studies have reported that patients with PD experience gastrointestinal dysfunction for many years before the onset of motor symptoms.Emerging evidence indicates thatα-synuclein deposition may start in the enteric nervous system and then propagate to the central nervous system.The gut-brain axis plays an important role in PD pathogenesis.Recent evidence suggests that these interactions may be primarily affected by the intestinal microbiota.In this review,the authors discuss recent research,and illustrate how changes in the composition of the gut microbiota may trigger inflammation,thus contributing to neurodegeneration in PD.