肠道菌群与溃疡性结肠炎的关系研究进展

溃疡性结肠炎(Ulcerative colitis,UC)病因和发病机制目前尚未完全阐明,已有研究认为免疫调节紊乱在多因素致病过程中是关键的发病因素,而肠道菌群可能是导致这种免疫紊乱的重要诱发因素.本文对溃疡性结肠炎与肠道菌群的关系研究做一综述.     

基于肠道菌群探讨益生菌对儿童营养不良的影响

营养不良严重威胁儿童生长发育，是急需解决的公共健康问题。肠道菌群调解人体的多项生理功能，影响机体健康。研究发现提高肠道菌群的稳定性可为治疗相关疾病提供新思路，近年来相关研究也佐证了营养支持和益生菌介入对肠道菌群的有益影响。因此本综述从肠道菌群的生理功能入手，探讨其与儿童营养不良的关系，着重分析益生菌在治疗儿童营养不良方面的影响，从而根据“个性化”的肠道菌群特征制定益生菌“精准治疗”方案，为预防及治疗儿童营养不良提供新思路。     

睡眠剥夺与肠道菌群紊乱的关系及改善睡眠药物研发的探讨

肠道菌群作为人体内一个复杂的微生态系统,在维持宿主生理功能上起非常重要的作用,也与许多代谢性疾病、免疫性疾病有着密切的关系。分析睡眠剥夺与肠道菌群紊乱相关性研究的提出和再提出,综合分析肠道菌群紊乱与睡眠障碍的关系,为以肠道菌群为靶点的改善睡眠药物开发及防治方法与思路提供参考。     

肠道菌群失调介导酒精性肝病发生发展的机制研究进展

酒精性肝病是一种慢性进行性疾病,严重影响患者健康。在一般情况下,肠道菌群处于动态平衡,维持肠道正常生理功能。当机体长期摄入酒精后,酒精及其代谢物通过引起肠道菌群数量改变、肠道通透性增加、细菌位移等方式造成肠道菌群紊乱,从而激活机体免疫应答,诱导肝脏产生促炎症因子,促进酒精性肝病发生发展。而补充益生菌或益生元调节肠道菌群紊乱可以有效的改善酒精性肝病的临床指征,提示调节肠道菌群失调将会成为临床治疗酒精性肝病行之有效的手段。该文就近年来国内外关于酒精摄入、肠道菌群失调、酒精性肝病之间的相互关系及调节菌群紊乱治疗酒精性肝病的进展进行概述,为菌群失调与酒精性肝病的研究和治疗提供理论参考。     

肠道菌群在高血压合并骨质疏松症中的作用

高血压和骨质疏松症(OP)是中老年人群常见疾病,近年来两者共病患者逐渐增多。由于该病起病隐匿,病至后期则易引起骨折及心脑肾的严重并发症,不仅严重损害患者生活质量,而且增加了临床治疗难度,因此,加强对此病的研究尤为必要。肠道菌群紊乱会导致OP的发生,而高血压患者肠道菌群明显失调。本文认为肠道菌群可能是高血压合并OP的关键影响因素,肠道菌群失调会导致短链脂肪酸代谢失衡、免疫炎症反应和交感神经活性增强,从而致使骨稳态失衡并促进OP的发生,由此提出调节肠道菌群可能是干预高血压合并OP的新途径。     

小儿川崎病肠道菌群变化与特异性转录因子RORγt、FOXP3、T淋巴细胞亚群水平的关联性

目的:探究小儿川崎病(KD)肠道菌群变化与特异性转录因子RAR相关孤儿受体γt(RORγt)、叉头蛋白P3(FOXP3)、T淋巴细胞亚群水平的关联性。方法:选取本院2018年1月至2020年6月KD患儿110例,根据是否合并感染分为单纯KD组(68例)与KD合并感染组(42例),另选择同期健康儿童42例作为对照组。比较3组肠道菌群、RORγt、FOXP3、T淋巴细胞亚群变化情况,分析肠道菌群、RORγt、FOXP3、T淋巴细胞亚群与KD合并感染的关系,Pearson相关性分析肠道菌群与RORγt、FOXP3、T淋巴细胞亚群相关性,采用受试者工作特征(ROC)曲线及ROC曲线下面积(AUC)评价肠道菌群、RORγt、FOXP3、T淋巴细胞亚群对KD合并感染的预测价值。结果:KD合并感染组乳酸杆菌属、韦荣球菌属、梭菌属、FOXP3、CD3⁺、CD4⁺/CD8⁺低于单纯KD组、对照组,单纯KD组低于对照组,拟杆菌属、肠球菌属、副杆菌属、RORγt高于单纯KD组、对照组,单纯KD组高于对照组(P<0.05);Logistic回归分析,乳酸杆菌属、韦荣球菌属、梭菌属、RORγt、FOXP3、CD3⁺、CD4⁺/CD8⁺是KD、KD合并感染的重要保护因素,拟杆菌属、肠球菌属、副杆菌属是KD、KD合并感染的重要危险因素(P<0.05);Pearson相关性分析,乳酸杆菌属、韦荣球菌属、梭菌属与RORγt呈负相关,与FOXP3、CD3⁺、CD4⁺/CD8⁺呈正相关,拟杆菌属、肠球菌属、副杆菌属与RORγt呈正相关,与FOXP3、CD3⁺、CD4⁺/CD8⁺呈负相关(P<0.05);ROC曲线显示,肠道菌群、RORγt、FOXP3、T淋巴细胞亚群联合预测KD合并感染AUC为0.888,95%CI为0.822~0.953,P<0.001,预测敏感度为76.19%,特异度为89.71%,优于各指标单一预测。结论:KD患儿肠道菌群变化与RORγt、FOXP3、T淋巴细胞亚群显著相关,且均与KD、KD合并感染联系紧密,联合检测可作为预测感染的重要手段。     

基于肠道菌群发现用于治疗Treg缺失免疫缺陷病的新药

目的肠道菌群紊乱与机体多种免疫失衡疾病的发生密切相关,如自身免疫性疾病、肿瘤和代谢综合征等。正是由于肠道菌群的稳定对人体健康至关重要,因此肠道微生态药物已经成为了现在研究与发展的热门产业。本研究挖掘肠道菌群及其代谢产物,发现可用于治疗Treg缺失免疫缺陷病的益生菌和天然产物。方法利用16S r DNA测序技术对Treg缺失介导的自身免疫性疾病模型小鼠的肠道菌群进行检测;用代谢组学技术检测模型小鼠肠道菌群代谢组谱的变化;用分子生物学、基因敲除小鼠等研究益生菌和代谢物作用的分子机制。结果在Treg缺失介导的免疫缺陷病模型小鼠上,肠道菌群发生了严重的紊乱。根据肠道菌群和代谢组谱的变化,选择罗伊氏乳酸杆菌(L. reuteri)和代谢产物肌苷处理Treg缺失小鼠,L. reuteri和肌苷通过激活腺苷受体A2AR抑制了Treg缺失引起的自身免疫性疾病。结论肠道菌群含有大量的微生物以及产生的许多独特代谢产物,可以作为新型天然药物的重要源泉,用于发现治疗自身免疫性疾病、肿瘤等疾病的新型益生菌和活性天然产物。     

肠道菌群与糖尿病

摘要： 近年来, 肠道菌群与糖尿病的关系成为研究热点。随着对肠道菌群认识的深入, 肠道菌群作为环境因素在调节免疫及代谢性疾病发生中的作用逐渐被大家认识。目前国内外已有大量研究关注肠道菌群影响肥胖和糖尿病的发病机制, 也有研究发现肠道菌群能够从食物难以消化的成分中获取能量, 从而影响人体的能量平衡和代谢。人们通过基因组测序的方法揭示不同类型糖尿病患者肠道菌群的组成、 丰度等, 并在动物体内进行验证, 明确和糖尿病相关的细菌功能。肠道菌群携带的遗传信息可能是未来治疗糖尿病的新突破口。关于2型糖尿病 （T2DM） 及1 型糖尿病 （T1DM） 肠道菌群的研究较多, 但妊娠期糖尿病 （GDM） 肠道菌群的相关研究报道较少。因此, 本文对不同类型糖尿病的肠道菌群特点及肠道菌群参与糖尿病发生的机制作一综述。     

氨苄西林钠和盐酸林可霉素对小鼠肠道菌群的变化规律的影响研究

目的研究氨苄西林钠和盐酸林可霉素对小鼠肠道菌群的影响,为科学研究提供依据。方法以氨苄西林钠和盐酸林可霉素连续灌胃小鼠5 d,分别于停药后第1、3、7、10和第15天检测小鼠直肠球菌、肠杆菌、乳酸菌及双歧杆菌数。结果各给药组小鼠均发生肠道菌群失调,氨苄西林钠组小鼠恢复过程缓慢。结论两种抗生素皆可造成小鼠肠道菌群紊乱。     

微生态制剂与胃肠粘膜屏障

目的探讨微生态制剂对胃肠粘膜屏障的保护及对胃肠道菌群紊乱的治疗作用。方法150例患者分为四组(IBS组、抗生素相关性腹泻组、慢性腹泻组、肠术后组),每组患者再随机分为治疗组与对照组,两组患者各占一半。治疗组主要给予培菲康治疗,而对照组则给予其他相关治疗。所有患者均治疗2周,观察其临床疗效、便常规、便培养及肠道菌群紊乱改善情况。结果培菲康治疗组临床症状改善优于对照组(P<005),便常规的改善与肠道菌群紊乱的纠正亦优于对照组(P<005)。结论微生态制剂——培菲康可以明显改善因肠道菌群失调所致的急、慢性腹泻症状,纠正肠道菌群紊乱、维持肠道微生态平衡,从而保护、强固胃肠粘膜屏障。     

Epidemiology and management of Kawasaki disease

Kawasaki disease (KD) is an acute systemic vasculitis affecting young children and is rising in incidence worldwide. It is most common in children <5 years of age, males and those of Asian ethnicity. It is an important cause of acquired heart disease in children. Standard treatment with high-dose aspirin (acetylsalicylic acid; ASA) and intravenous immune globulin (IVIG) has been shown to decrease the rate of coronary artery aneurysm development. Anti-coagulation has an important place in the management of KD, although guidance based on evidence is lacking. Treatment of refractory KD is an area under intense study and may include IVIG, corticosteroids and/or tumour necrosis factor (TNF)-α inhibitors among immunosuppressive agents. Acute complications of KD include myocarditis/KD shock syndrome and macrophage activation syndrome, which necessitate appropriate awareness in order to initiate proper management.     

学龄儿童川崎病急性期合并心肌梗死一例报告

摘要：川崎病（KD）是儿童常见的系统性血管炎，主要累及冠状动脉。自1967年首次被报道以来，目前病因仍不 明。本文报告我院近期收治的8岁学龄期男童KD急性期伴巨大冠状动脉瘤（CAA）合并心肌梗死（MI）1例。     

Novel compound FLZ alleviates rotenone-induced PD mouse model by suppressing TLR4/MyD88/NF-κB pathway through microbiota–gut–brain axis

Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota–gut–brain axis. However, the explicit mechanisms of microbiota 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 phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo. The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood–brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective 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.     

Genetic polymorphisms in Kawasaki disease

Kawasaki disease (KD) is an acute febrile systemic vasculitis, and the cause of KD is not well understood. It is likely due to multiple interactions between genes and environmental factors. The development of genetic association and genome-wide association studies (GWAS) has opened an avenue to better understanding the molecular mechanisms underlying KD. A novel ITPKC signaling pathway was recently found to be responsible for the susceptibility to KD. Furthermore, the GWAS demonstrated the functionally related susceptibility loci for KD in the Caucasian population. In the last decade, the identification of several genomic regions linked to the pathogenesis of KD has made a major breakthrough in understanding the genetics of KD. This review will focus on genetic polymorphisms associated with KD and describe some of the possible clinical implications and molecular mechanisms that can be used to explain how genetic variants regulate the pathogenesis in KD.     

47例6月龄以下婴儿川崎病临床分析

目的：分析6月龄以下婴儿川崎病的临床发病特点。方法：对2005年5月-2008年5月南京儿童医院收治的47例6月龄以下的川崎病患儿进行回顾性分析。结果：6月龄以下婴儿川崎病男女比例为1.35：1,以典型病例多见,约有15%为不完全型病例,主要症状中口唇充血皲裂、手足硬肿和淋巴结肿大的发生比例明显较低,而指趾端脱屑的发生比例较高（P〈0.05）。不完全型组临床表现早期出现少,炎性指标WBC、CRP、ESR明显增高,与典型组比较差异无统计学意义（P〉0.05）。冠脉病变发生比例两组比较差异无统计学意义（P〉0.05）。冠脉扩张共39例（83%）,有11例形成动脉瘤（23%）。不完全型组的平均确诊时间较典型组长（P〈0.05）。结论：婴儿川崎病临床表现无特异性,对发热持续时间长、抗感染治疗无效婴儿应提高警惕,对疑似病例及早行超声心电图检查,了解冠脉情况,检查ESR、CRP,动态观察PLT变化,有助于早期诊断。     

Case reports: selected dermatoses in children of color

Three conditions, erythema dyschromicum perstans (EDP), granulomatous periorificial dermatitis (GPD), and Kawasaki disease (KD) are seen more frequently in children of color. EDP and GPD are benign and self-limited dermatoses; therapy can shorten the course of the diseases. KD, a systemic vasculitis, can have life threatening cardiac consequences and timely therapy is essential. In all 3 conditions, clinicians should proceed with prompt and appropriate evaluation, diagnosis, and intervention when indicated. A case representing each condition is presented, followed by a discussion,     

Treatments targeting the luminal gut microbiota in patients with irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction affecting 4% of the world's population. Patients with IBS experience chronic or recurrent abdominal pain in combination with altered bowel habits (diarrhea and/or constipation), and have reduced quality of life. Despite the high prevalence and substantial burden of IBS, its pathophysiology is incompletely understood and remains to be elucidated. The importance of the gut microenvironment has been highlighted in IBS, as there are signs that the gut microbiota of patients differs from healthy controls. Recent studies have aimed to alter the gut microbiota and thereby, attempted to alleviate gastrointestinal symptoms in IBS patients. We highlighted recent advances in common treatments that are targeting the luminal gut microbiota in IBS.     

Gut microbiota modulates drug pharmacokinetics

Abstract

Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs.     

Novel compound FLZ alleviates rotenone-induced PD mouse model by suppressing TLR4/MyD88/NF-κB pathway through microbiota–gut–brain axis

Parkinson''s disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota–gut–brain axis. However, the explicit mechanisms of microbiota 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 phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo. The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood–brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective 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.KEY WORDS: FLZ, Microbiota–gut–brain axis, Parkinson''s disease, Rotenone mouse model, TLR4/MyD88/NF-κB pathway, Gastrointestinal dysfunction, Systemic inflammation, Neuroinflammation     

Gut microbiota mediates the absorption of FLZ,a new drug for Parkinson's disease treatment

The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs. FLZ, a novel squamosamide derivative, has been shown to have neuroprotective effects on experimental Parkinson''s disease (PD) models. FLZ is under phase Ⅰ clinical trial now, while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated. Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice, we focused on the gut microbiota to address how FLZ was metabolized and absorbed. In vitro studies revealed that FLZ could be exclusively metabolized to its major metabolite M1 by the lanosterol 14 alpha-demethylase (CYP51) in the gut microbiota, but was almost not metabolized by any other metabolism-related organs, such as liver, kidney, and small intestine. M1 was quickly absorbed into the blood and then remethylated to FLZ by catechol O-methyltransferase (COMT). Notably, dysbacteriosis reduced the therapeutic efficacy of FLZ on the PD mouse model by inhibiting its absorption. The results show that the gut microbiota mediate the absorption of FLZ through a FLZ–M1–FLZ circulation. Our research elucidates the vital role of the gut microbiota in the absorption of FLZ and provides a theoretical basis for clinical pharmacokinetic studies and clinical application of FLZ in the treatment of PD.KEY WORDS: FLZ, Parkinson''s disease, Gut microbiota, CYP51, COMT