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.

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.

Update on the gut microbiome in health and diseases

The Human Microbiome Project,Earth Microbiome Project,and next-generation sequencing have advanced novel genome association,host genetic linkages,and pathogen identification.The microbiome is the sum of the microbes,their genetic information,and their ecological niche.This study will describe how millions of bacteria in the gut affect the human body in health and disease.The gut microbiome changes in relation with age,with an increase in Bacteroidetes and Firmicutes.Host and environmental factors affecting the gut microbiome are diet,drugs,age,smoking,exercise,and host genetics.In addition,changes in the gut microbiome may affect the local gut immune system and systemic immune system.In this study,we discuss how the microbiome may affect the metabolism of healthy subjects or may affect the pathogenesis of metabolism-generating metabolic diseases.Due to the high number of publications on the argument,from a methodologically point of view,we decided to select the best papers published in referred journals in the last 3 years.Then we selected the previously published papers.The major goals of our study were to elucidate which microbiome and by which pathways are related to healthy and disease conditions.

Characterization of oral and gut microbiome and plasma metabolomics in COVID-19 patients after 1-year follow-up

Background:Due to the outbreak and rapid spread of coronavirus disease 2019(COVID-19),more than 160 million patients have become convalescents worldwide to date.Significant alterations have occurred in the gut and oral microbiome and metabonomics of patients with COVID-19.However,it is unknown whether their characteristics return to normal after the 1-year recovery.Methods:We recruited 35 confirmed patients to provide specimens at discharge and 1 year later,as well as 160healthy controls.A total of 497 samples were prospectively collected,including 219 tongue-coating,129 stool and 149 plasma samples.Tongue-coating and stool samples were subjected to 16S rRNA sequencing,and plasma samples were subjected to untargeted metabolomics testing.Results:The oral and gut microbiome and metabolomics characteristics of the 1-year convalescents were restored to a large extent but did not completely return to normal.In the recovery process,the microbial diversity gradually increased.Butyric acid-producing microbes and Bifidobacterium gradually increased,whereas lipopolysaccharideproducing microbes gradually decreased.In addition,sphingosine-1-phosphate,which is closely related to the inflammatory factor storm of COVID-19,increased significantly during the recovery process.Moreover,the predictive models established based on the microbiome and metabolites of patients at the time of discharge reached high efficacy in predicting their neutralizing antibody levels one year later.Conclusions:This study is the first to characterize the oral and gut microbiome and metabonomics in 1-year convalescents of COVID-19.The key microbiome and metabolites in the process of recovery were identified,and provided new treatment ideas for accelerating recovery.And the predictive models based on the microbiome and metabolomics afford new insights for predicting the recovery situation which benefited affected individuals and healthcare.

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.

Gut microbiome therapeutic modulation to alleviate drug-induced hepatic damage in COVID-19 patients

Coronavirus disease 2019(COVID-19)infection caused by the severe acute respiratory syndrome coronavirus 2 virus,its symptoms,treatment,and post-COVID-19 effects have been a major focus of research since 2020.In addition to respiratory symptoms,different clinical variants of the virus have been associated with dynamic symptoms and multiorgan diseases,including liver abnormalities.The release of cytokines by the activation of innate immune cells during viral infection and the high doses of drugs used for COVID-19 treatment are considered major drivers of liver injury in COVID-19 patients.The degree of hepatic inflammation in patients suffering from chronic liver disease and having COVID-19 could be severe and can be estimated through different liver chemistry abnormality markers.Gut microbiota influences liver chemistry through its metabolites.Gut dysbiosis during COVID-19 treatment can promote liver inflammation.Here,we highlighted the bidirectional association of liver physiology and gut microbiota(gut-liver axis)and its potential to manipulate drug-induced chemical abnormalities in the livers of COVID-19 patients.

Clinical impact of microbiome in patients with decompensated cirrhosis

Cirrhosis is an increasing cause of morbidity and mortality. Recent studies are trying to clarify the role of microbiome in clinical exacerbation of patients with decompensated cirrhosis. Nowadays, it is accepted that patients with cirrhosis have altered salivary and enteric microbiome, characterized by the presence of dysbiosis. This altered microbiome along with small bowel bacterial overgrowth, through translocation across the gut, is associated with the development of decompensating complications. Studies have analyzed the correlation of certain bacterial families with the development of hepatic encephalopathy in cirrhotics. In general, stool and saliva dysbiosis with reduction of autochthonous bacteria in patients with cirrhosis incites changes in bacterial defenses and higher risk for bacterial infections, such as spontaneous bacterial peritonitis, and sepsis. Gut microbiome has even been associated with oncogenic pathways and under circumstances might promote the development of hepatocarcinogenesis. Lately, the existence of the oral-gutliver axis has been related with the development of decompensating events. This link between the liver and the oral cavity could be via the gut through impaired intestinal permeability that allows direct translocation of bacteria from the oral cavity to the systemic circulation. Overall, the contribution of the microbiome to pathogenesis becomes more pronounced with progressive disease and therefore may represent an important therapeutic target in the management of cirrhosis.

Global research trends in the microbiome related to irritable bowel syndrome: A bibliometric and visualized study

BACKGROUND Irritable bowel syndrome(IBS) is a common functional gastrointestinal disorder. Dysregulation of the gut–brain axis plays a central role in the pathophysiology of IBS. It is increasingly clear that the microbiome plays a key role in the development and normal functioning of the gut–brain axis.AIM To facilitate the identification of specific areas of focus that may be of relevance to future research. This study represents a bibliometric analysis of the literature pertaining to the microbiome in IBS to understand the development of this field.METHODS The data used in our bibliometric analysis were retrieved from the Scopus database. The terms related to IBS and microbiome were searched in titles or abstracts within the period of 2000–2019. VOSviewer software was used for data visualization.RESULTS A total of 13055 documents related to IBS were retrieved at the global level. There were 1872 scientific publications focused on the microbiome in IBS. There was a strong positive correlation between publication productivity related to IBS in all fields and productivity related to the microbiome in IBS(r = 0.951, P < 0.001). The United States was the most prolific country with 449(24%) publications, followed by the United Kingdom(n = 176, 9.4%), China(n = 154, 8.2%), and Italy(n = 151, 8.1%). The h-index for all retrieved publications related to the microbiome in IBS was 138. The hot topics were stratified into four clusters:(1) The gut–brain axis related to IBS;(2) Clinical trials related to IBS and the microbiome;(3) Drugmediated manipulation of the gut microbiome;and(4) The role of the altered composition of intestinal microbiota in IBS prevention.CONCLUSION This is the first study to evaluate and quantify global research productivity pertaining to the microbiome in IBS. The number of publications regarding the gut microbiota in IBS has continuously grown since 2013. This finding suggests that the future outlook for interventions targeting the gut microbiota in IBS remains promising.

Human microbiome is a diagnostic biomarker in hepatocellular carcinoma

Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords"microbiota"or"microbiome"or"microbe"and"liver cancer"or"hepato-cellular carcinoma",and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.

Microbiome and colorectal carcinogenesis:Linked mechanisms and racial differences

Various studies have shown the interplay between the intestinal microbiome,environmental factors,and genetic changes in colorectal cancer(CRC)development.In this review,we highlight the various gut and oral microbiota associated with CRC and colorectal adenomas,and their proposed molecular mechanisms in relation to the processes of“the hallmarks of cancer”,and differences in microbial diversity and abundance between race/ethnicity.Patients with CRC showed increased levels of Bacteroides,Prevotella,Escherichia coli,enterotoxigenic Bacteroides fragilis,Streptococcus gallolyticus,Enterococcus faecalis,Fusobacterium nucleatum(F.nucleatum)and Clostridium difficile.Higher levels of Bacteroides have been found in African American(AA)compared to Caucasian American(CA)patients.Pro-inflammatory bacteria such as F.nucleatum and Enterobacter species were significantly higher in AAs.Also,AA patients have been shown to have decreased microbial diversity compared to CA patients.Some studies have shown that using microbiome profiles in conjunction with certain risk factors such as age,race and body mass index may help predict healthy colon vs one with adenomas or carcinomas.Periodontitis is one of the most common bacterial infections in humans and is more prevalent in Non-Hispanic-Blacks as compared to Non-Hispanic Whites.This condition causes increased systemic inflammation,immune dysregulation,gut microbiota dysbiosis and thereby possibly influencing colorectal carcinogenesis.Periodontal-associated bacteria such as Fusobacterium,Prevotella,Bacteroides and Porphyromonas have been found in CRC tissues and in feces of CRC patients.Therefore,a deeper understanding of the association between oral and gastrointestinal bacterial profile,in addition to identifying prevalent bacteria in patients with CRC and the differences observed in ethnicity/race,may play a pivotal role in predicting incidence,prognosis,and lead to the development of new treatments.

Gut microbial regulation of innate and adaptive immunity after traumatic brain injury

Acute care management of traumatic brain injury is focused on the prevention and reduction of secondary insults such as hypotension,hypoxia,intracranial hypertension,and detrimental inflammation.However,the imperative to balance multiple clinical concerns simultaneously often results in therapeutic strategies targeted to address one clinical concern causing unintended effects in other remote organ systems.Recently the bidirectional communication between the gastrointestinal tract and the brain has been shown to influence both the central nervous system and gastrointestinal tract homeostasis in health and disease.A critical component of this axis is the microorganisms of the gut known as the gut microbiome.Changes in gut microbial populations in the setting of central nervous system disease,including traumatic brain injury,have been reported in both humans and experimental animal models and can be further disrupted by off-target effects of patient care.In this review article,we will explore the important role gut microbial populations play in regulating brain-resident and peripheral immune cell responses after traumatic brain injury.We will discuss the role of bacterial metabolites in gut microbial regulation of neuroinflammation and their potential as an avenue for therapeutic intervention in the setting of traumatic brain injury.

Lung microbiome in healthy and diseased individuals

The data on quantitative and qualitative microbial composition of the respiratory tract of healthy individuals revealed significant differences when compared with the microbiota of patients suffering from respiratory diseases. Possible etiological role of microbiota in pulmonary diseases as well as drug resistance development is of profound interest nowadays. Numerous studies have provided evidence confirming the relationship between gut microbiome and those of lungs. This relationship could explain how changes in the microbial communities in one organ may lead to pathological changes in the other. Till date, some progress has been made in the study of the biological properties of probiotic bacteria, considering their modulating effect on inflammatory immune response. The use of probiotics which exhibits an immunomodulatory potential looks promising.

Interplay of gut microbiota,glucagon-like peptide receptor agonists,and nutrition:New frontiers in metabolic dysfunction-associated steatotic liver disease therapy

The gut-liver axis plays a crucial role in the development and progression of metabolic dysfunction-associated steatotic liver disease(MASLD).Key metabolites,including lipopolysaccharides,short-chain fatty acids(SCFAs),bile acids,and beneficial gut bacteria such as Bifidobacterium and Lactobacillus,are pivotal in this process.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)show promise in managing MASLD by promoting weight loss,enhancing insulin secretion,and improving liver health.They restore gut-liver axis functionality,and their effects are amplified through dietary modifications and gut microbiometargeted therapies.Emerging research highlights the interplay between GLP-1 RAs and gut microbiota,indicating that the gut microbiome significantly influences therapeutic outcomes.Metabolites produced by gut bacteria,can stimulate glucagon-like peptide-1(GLP-1)secretion,further improving metabolic health.Integrating dietary interventions with GLP-1 RA treatment may enhance liver health by modulating the gut microbiota-SCFAs-GLP-1 pathway.Future research is needed to understand personalized effects,with prebiotics and probiotics offering treatment avenues for MASLD.

Gut dysbiosis is associated with poorer long-term prognosis in cirrhosis

BACKGROUND Gut dysbiosis is common in cirrhosis.AIM To study the influence of gut dysbiosis on prognosis in cirrhosis.METHODS The case-control study included 48 in-patients with cirrhosis and 21 healthy controls.Stool microbiome was assessed using 16S ribosomal ribonucleic acid gene sequencing.We used modified dysbiosis ratio(MDR):[Bacilli(%)+Proteobacteria(%)]/[Clostridia(%)+Bacteroidetes(%)].Patients with MDR more the median made up the group with severe dysbiosis,others did the group with nonsevere dysbiosis.The follow-up period was 4 years.RESULTS The mortality rate of patients with severe dysbiosis was significantly higher than that of patients with non-severe dysbiosis(54.2%vs 12.5%;P=0.001).The presence of severe dysbiosis was independent risk factors for death[hazard ratio=8.6×(1.9-38.0);P=0.005].The abundance of Enterobacteriaceae(P=0.002),Proteobacteria(P=0.002),and Lactobacillaceae(P=0.025)was increased and the abundance of Firmicutes(P=0.025)and Clostridia(P=0.045)was decreased in the deceased patients compared with the survivors.The deceased patients had a higher MDR value than the survivors[0.131×(0.069-0.234)vs 0.034×(0.009-0.096);P=0.004].If we applied an MDR value of 0.14 as the cutoff point,then it predicted patient death within the next year with a sensitivity of 71.4%and a specificity of 82.9%[area under the curve=0.767×(0.559-0.974)].MDR was higher in patients with cirrhosis than in health controls[0.064×(0.017-0.131)vs 0.005×(0.002-0.007);P<0.001],and in patients with decompensated cirrhosis than in patients with compensated cirrhosis[0.106×(0.023-0.211)vs 0.033×(0.012-0.074);P=0.031].MDR correlated negatively with prothrombin(r=-0.295;P=0.042),cholinesterase(r=-0.466;P=0.014)and serum albumin(r=-0.449;P=0.001)level and positively with Child–Turcotte–Pugh scale value(r=0.360;P=0.012).CONCLUSION Gut dysbiosis is associated with a poorer long-term prognosis in cirrhosis.

微生物-肠-肝轴与酒精性肝病及其营养干预研究进展

酒精性肝病(alcoholic liver disease,ALD)是全球最普遍的慢性肝病类型,早期表现为脂肪肝,进而演变成脂肪性肝炎,随着饮酒时间延长会发展成肝纤维化和肝硬化。肠-肝轴是指肠道及其微生物群与肝脏之间的双向作用,由门静脉和胆道建立。酒精会破坏这一双向作用,导致肠道微生物群紊乱和病原体易位到肝脏,造成肝损伤。本文以肠道屏障、肠道微生物组成、肠道微生物成分和肠道微生物代谢产物为主,综述了肠-肝轴介导ALD发生发展的作用机制以及ALD的营养干预措施,尤其是靶向噬菌体干预肠道微生物群以及三甲胺、溶细胞素、念珠菌溶素在ALD中的作用,以期为以肠-肝轴为靶点抗ALD功能物质的发现、营养干预和功能性食品的开发提供基础。

基于肠道菌群探讨阿尔茨海默病发病机制及中医药治疗研究进展

阿尔茨海默病(AD)是一种神经退行性疾病。肠道菌群(GM)在AD的发病机制中起着至关重要的作用。GM失调不仅影响β-淀粉蛋白和磷酸化tau蛋白的病理累积,还通过增加肠道和血脑屏障的通透性、激活中枢神经系统的炎症反应、增强氧化应激、调节神经递质水平,推动AD的进展。鉴于西药治疗的局限性,中医药疗法以其多靶点、多机制的优势,在调控GM平衡及其代谢物水平方面显示出独特的潜力。本研究探讨中药及其有效成分、中药复方、针刺在调节GM及其代谢物水平,改善AD症状方面的潜在作用,为未来防治AD提供参考。

肠-视网膜轴机制及其与眼科疾病的相互作用

肠道菌群是维持机体稳态的重要组成部分,近年来,随着16S rRNA和宏基因组等测序技术的快速发展,人们对微生物有了更加深入而全面的认识,在动物和人类中的研究证实肠道菌群不仅参与免疫性、代谢性和神经系统等全身性疾病的病变过程,还与眼病的发生密切相关。宿主高血糖、免疫异常、衰老和高眼压等因素可引起肠道菌群失调,肠-血屏障通透性增加。肠道菌群相关的脂多糖和肽聚糖等病原相关分子模式穿过受损的肠道屏障进入体循环,最终沉积到视网膜和葡萄膜组织中,参与免疫及炎症反应过程,而肠道来源的宿主免疫细胞或损伤相关的分子模式又可加重眼部炎症的级联反应。同时,包括饮食和环境诱导在内的肠道菌群代谢产物,如胆红素、胆汁酸和短链脂肪酸等,通过调节免疫T细胞平衡、miRNA表达和视网膜细胞炎性活化等参与视网膜疾病的进展。本文拟对近年来国内外关于肠道菌群与糖尿病视网膜病变、葡萄膜炎、年龄相关性黄斑变性和青光眼的相关研究进行综述,探讨肠道菌群通过肠-视网膜轴参与眼科疾病的可能机制,为眼部疾病的机理研究和防治提供一些新的思路。

肠道菌群及代谢物在神经认知恢复延迟中作用的研究进展

随着手术和全身麻醉患者数的增加,神经认知恢复延迟的发生率也相应增加,这对患者的生活质量产生了严重影响。微生物-脑-肠轴作为中枢神经系统与肠神经系统的双向通道,越来越引起人们的关注。肠道微生物及其代谢产物不仅在维持肠道内环境稳定方面起着至关重要的作用,而且与神经认知恢复延迟密切相关。目前,对神经认知恢复延迟的治疗尚没有确切的方法,明确肠道菌群及其代谢产物与神经认知恢复延迟的关系可为该疾病的治疗和诊断提供思路和参考。因此,该文针对肠道微生物及其代谢物,分析研究神经认知恢复延迟可能发生和发展的过程。通过深入了解肠道微生物与神经认知恢复延迟的关联,探索其潜在的机制,并为寻找预防和治疗神经认知恢复延迟的方法提供参考。

基于CiteSpace的龋病微生态微生物领域的趋势与热点研究

目的探究龋病微生态微生物领域相关研究的趋势与热点,为龋病研究提供参考。方法本研究从Web of Science核心合集(Web of Science Core Collection,WOSCC)数据库中提取了2014至2023年发表的龋病微生态微生物领域相关文献,通过CiteSpace文献计量学可视化评估方法对该研究领域的发文量、期刊、国家、作者、机构、共被引文献、关键词等方面开展可视化分析。结果共纳入3192篇文献,其中研究型论文2664篇、综述528篇,年发文量总体呈上升趋势。美国和中国的发文量位居前列,但在国际合作方面美国处于优势。发文量占比前10的期刊主要是牙科学期刊,其次是微生物学期刊。发文量位居前列的作者网络有以四川大学周学东为主的作者网络以及以马里兰大学巴尔的摩分校Xu Hockin H.K和Weir Michael D为主的作者网络。龋病微生态微生物研究的活跃点集中在微生物致龋毒力及相互作用、口腔微生物群系、龋病与系统性疾病的关系等。共被引频次较高的文章主要涉及龋病、口腔生物膜、口腔微生物群系、变异链球菌等主题。关键词研究显示了在过去十年中龋病、变异链球菌、细菌、牙菌斑和抗菌活性一直是研究重点;健康、口腔健康等关键词的数量呈上升趋势。最新出现的“gut microbiome/microbiota”提示口腔⁃肠道微生物组轴是该领域的研究前沿,研究人员的视野逐渐转向龋病与全身疾病间的联系。结论近10年关于龋病微生态微生物领域相关文献的发文量逐年上升,研究趋势将朝口腔微生物多组学方向发展,新的研究方法和技术将会促进龋病学研究领域的发展.

肠道微生物-肠-脑轴与卒中后认知障碍的相关性研究进展

卒中后认知障碍(PSCI)是卒中后常见的功能障碍,严重影响患者的生活质量和正常功能。研究显示肠道微生物群失调与中枢神经系统疾病关系密切,肠道菌群通过调节肠-脑轴可维持神经、代谢和免疫系统的稳定性,对人类生理健康产生多方面的影响。众多研究发现,肠道微生物-肠-脑轴在卒中及相关PSCI的发生和发展中发挥重要作用,调节肠道微生物-肠-脑轴有望成为PSCI治疗的潜在靶标。本文对肠道微生物-肠-脑轴与PSCI的相关性研究进展进行综述,以期为相关的机制探索和临床防治提供参考。