粪菌移植治疗难治性肠道疾病的临床应用

人体肠道内菌群结构失衡与肠道疾病的发生发展密切相关。粪菌移植可以纠正肠道菌群结构失调,早在东晋时期,已有相关的临床应用记载。近年来,粪菌移植已成功应用于部分肠道菌群失调相关的难治性肠道疾病的治疗,如复发性难辨梭状芽孢杆菌感染、炎症性肠病、肠易激综合征、慢性功能性便秘等,均取得了较好的疗效。文章对粪菌移植治疗难治性肠道疾病的相关临床研究进行了文献回顾,重点分析了粪菌移植治疗难治性肠道疾病的难点和对策,并探讨了粪菌移植的应用前景。     

《儿童粪菌移植技术规范的共识》解读

粪便微生物群移植,即粪菌移植(fecal microbiota transplantation,FMT)是通过各种方式将健康捐赠者的粪便菌群移植入患者的消化道内,改善其肠道微生态,以达到治疗疾病的目的。中华预防医学会微生态学分会儿科微生态学组于2016年组织制定了《儿童粪菌移植技术规范的共识》。本文就该共识涉及的儿童粪菌移植适应证、必备条件、方法学(包括捐赠者筛查、排除及剔除的标准、粪菌液制备、粪菌移植途径和剂量的选择、粪菌移植后的观察及处理以及粪菌移植后的随访)等方面的关键问题进行解读。     

过敏性鼻炎患儿肠道菌群变化 及双歧杆菌三联活菌散对其辅助治疗效果

摘要：目的 观察过敏性鼻炎患儿肠道菌群变化及双歧杆菌三联活菌散对其辅助治疗的效果。方法 选取我院就诊的过敏性鼻炎患儿60例,从中随机抽取10例为疾病组,并以10例体检的健康儿童为健康对照组,采集两组对象粪便标本,用高通量测序法对比过敏性鼻炎患儿与健康对照组肠道菌结构的差异。另一方面,将入选的60例过敏性鼻炎患儿分为对照组（30例,采用常规治疗）和治疗组（30例,常规治疗联合双歧杆菌三联活菌治疗）。两组患儿连续治疗8周后,观察其治疗前后临床症状评分及血清IL-4、IL-12、IgE水平变化。结果 过敏性鼻炎患儿肠道菌群多样性低于健康对照组。患儿肠道菌群以拟杆菌门为主,健康对照组以厚壁菌门为主（P＜0.05)。患儿肠道双歧杆菌属数量低于健康对照组,而毛螺菌属,瘤胃菌属,红蝽菌属和普雷沃菌属有所增多（均P＜0.05)。治疗8周后,治疗组患儿临床症状评分明显降低,治疗的总有效率高于对照组（P<0.05）。治疗组患儿血清IL-4、IgE水平明显降低,IL-12水平明显升高,且治疗组患儿以上指标的改善程度均优于对照组（均P<0.05）。结论 过敏性鼻炎患儿与健康儿童相比肠道菌群存在差异,肠道菌群失衡可能是促进过敏性鼻炎发生发展的一个因素。双歧杆菌三联活菌散对过敏性鼻炎有辅助治疗的作用,能显著改善患儿临床症状,调节机体的免疫能力,具有一定临床应用价值。     

儿童功能性便秘肠道传输功能与肠道微生态的关系

目的采用不透光X线标志物测定结肠传输指数(TI)对功能性排便障碍进行分型,探讨各型功能性便秘患儿之间及其与健康儿童之间肠道菌群差异。方法选取功能性便秘儿童40例,进行结肠传输试验并进行分型,其中33例出口梗阻型(出口梗阻组),7例慢传输型(慢传输组)。留取便秘儿童新鲜粪便样本,同时收集20例正常儿童(对照组)粪便标本,存放于-80℃冰箱。采用16S rRNA测序技术鉴定菌群。结果菌群多样性分析:出口梗阻组、慢传输组与对照组粪便标本在丰富度上差异存在统计学意义(P0.01),出口梗阻组、慢传输组的肠道菌群丰度明显增高,3组在多样性上差异无统计学意义。门水平分析:出口梗阻型与慢传输型相比、出口梗阻型儿童与健康儿童相比,差异均无统计学意义;拟杆菌门丰度慢传输型儿童较健康儿童高,差异存在统计学意义(P0.05)。属水平分析:出口梗阻型与慢传输型相比,Subdoligranulum、Ruminococcus_2、Lachnospira、Collinsella数量在慢传输型儿童中均明显减少,差异存在统计学意义(均P0.05);毛螺菌属、Lachnoclostridium、Anaerostipes、Dorea、志贺菌属丰度慢传输型儿童较健康儿童低(均P0.05);Blautia、Anaerostipes、Lachnoclostridium丰度出口梗阻型儿童较健康儿童低(均P0.05);Alistipes、Parasutterella、Ruminococcus_2、Ruminococcaceae_UCG-005、Ruminococcaceae_UCG-002丰度出口梗阻型儿童较健康儿童高(均P0.05)。结论出口梗阻型与慢传输型相比,有部分菌种在慢传输型便秘儿童中明显减少,这需要进一步研究论证;便秘儿童肠道菌群与健康人群存在较大差异,改变肠道菌群可能成为治疗慢性功能性便秘的新策略。慢传输型便秘病例数较少,需增加样本量后进一步分析。     

粪菌移植治疗儿童肠道外疾病的研究进展和临床应用前景

肠道微生物群影响着人体的生理状况和营养吸收代谢。粪菌移植(fecal microbiota transplantation,FMT)是将健康人粪便中的功能菌群移植到患者体内,重塑肠内菌群结构进而调节人类肠道微生物群,成为新兴的治疗手段。本文回顾了近年来粪菌移植对儿童代谢性疾病、过敏性疾病与孤独症谱系障碍等肠道外疾病的运用与进展,表明粪菌移植治疗安全有效改变了肠道病理生理,有望成为治疗多种儿科疾病的技术。现就FMT在儿童肠道外疾病的应用现状及前景进行探讨。     

肠道微生态在儿童难治性癫痫发病及治疗中的研究进展CSCD

儿童难治性癫痫是一种常见的儿科神经系统疾病。许多临床前及临床证据表明儿童难治性癫痫患者体内优势菌群与健康人相比存在显著差异;抗癫痫干预后难治性癫痫儿童体内肠道菌群分布发生改变;动物粪菌移植实验进一步证实肠道菌群的改变与癫痫发病及抗癫痫疗效存在因果关系。临床上益生菌的添加可能增强抗癫痫疗效,抗生素的使用往往也影响临床的抗癫痫疗效。肠道微生态可能通过内源性机制(如改变神经递质含量等)及外源性机制(如感染和损伤等)改变儿童难治性癫痫患者的代谢、遗传、免疫和感染等。本综述通过总结近年来国内外肠道微生态与儿童癫痫发病和抗癫痫效果的相关研究,阐述肠道微生态在儿童癫痫发病及治疗中的作用并对其可能的作用机制进行探讨。     

粪菌移植对慢性肠炎患者预后的影响

目的初步分析粪菌移植对慢性肠炎患者预后的影响。方法以我院2017年1月至2019年6月收治的100例慢性肠炎患者为研究对象,采用简单随机抽样法分为观察组与对照组各50例。移植粪菌均来自于健康志愿者。移植方法为以50 mL/h注入粪汁50 mL,间隔2 h,再次以50 mL/h注入粪汁50 mL。对照组患者共移植粪便50 g,观察组患者共移植粪便100 g。对比两组患者腹泻频率、观察指标及血清炎症因子以及肠道菌群改善情况。结果治疗第1个月两组患者腹泻频率差异无统计学意义(P0.05),但随着治疗时间的延长患者腹泻频率逐渐降低,且观察组低于对照组(均P0.05)。治疗前两组患者家属疾病认知程度、主观幸福度及家属焦虑抑郁评分差异无统计学意义(均P0.05)。治疗6个月后,两组患者主观幸福度评分、患者家属疾病认知程度均提升,家属焦虑抑郁量表评分均下降,且观察组优于对照组(均P0.05)。治疗前,两组患者TNF-α与IL-6水平差异无统计学意义(均P0.05)。治疗后,试验组患者TNF-α与IL-6水平均低于对照组(均P0.05)。治疗后两组患者肠镜检查结果以及肠道菌群检查结果均得到改善。结论粪菌移植能有效改善慢性肠炎患者的临床症状,值得临床推广。     

以肠道菌群为靶向的粪菌移植法及其在畜牧业的应用潜能

肠道微生物与宿主机体健康息息相关。粪便微生物移植(又称为粪菌移植,fecal microbiota transplantation,FMT)通过将健康供体粪便中的完整肠道菌群移入肠道微生态失衡的患者胃肠道内,经肠道菌群重构、恢复至正常状态。用FMT治疗某些肠道疾病如复发性艰难梭菌感染、溃疡性结肠炎、肠易激综合症、克罗恩病效果显著,且可能对因肠道菌群紊乱引起的肠道外疾病的治疗有潜在价值。本文主要对FMT技术的发展进程、在疾病上的研究以及在畜牧业上的应用潜能进行综述,并分析其应用的制约因素。     

罗伊氏乳杆菌(息敏乐)辅助治疗儿童功能性便秘的多中心研究

目的探讨罗伊氏乳杆菌(息敏乐)辅助治疗儿童功能性便秘的临床疗效及安全性,为后续研究提供参考。方法选择2016年6月至2018年6月期间5个研究中心收治的237例功能性便秘患儿为研究对象,按照随机数表法分为对照组(n=76)、观察A组(n=78)、观察B组(n=83)。对照组患儿采用饮食调节及排便习惯锻炼等常规治疗,观察组患儿在此基础上加用息敏乐治疗,其中观察A组剂量为1次/d,观察B组剂量为2次/d,3组患儿均持续治疗4周并随访2个月。对比3组患儿治疗后总有效率、大便性状评分、排便困难评分、每周排便次数、排便时间、排便间隔、粪便pH值、肠道菌群变化、复发率及不良反应情况。结果治疗后观察B组患儿的总有效率(93.98%)明显高于对照组(80.26%)及A组(85.90%),每周排便次数及肠道乳杆菌数量多于对照组及A组,排便时间短于对照组,排便间隔短于对照组及A组,粪便性状评分、排便困难评分、粪便pH值、肠道产气夹膜梭菌、肠球菌、肠杆菌数量及复发率明显低于对照组及A组(均P0.05)。3组患儿不良反应发生率差异无统计学意义(P0.05)。结论罗伊氏乳杆菌辅助治疗可调节功能性便秘患儿肠道菌群平衡,疗效显著,患儿不易复发,安全性较高。     

肠道菌群与孤独症谱系障碍儿童功能性便秘的关系

目的 探讨孤独症谱系障碍（autism spectrum disorder,ASD）儿童肠道菌群组成与功能性便秘之间的关系,为该类患者的治疗提供参考。方法 选择101例2～7岁ASD儿童和82例年龄、性别相匹配健康儿童为研究对象,采用罗马Ⅳ标准评估便秘,将所有儿童分为ASD便秘组（ASD constipated,AD-C）、ASD非便秘组（ASD non-constipated,AD-NC）、正常便秘组（neurotypical constipated,NT-C）、正常非便秘组（neurotypical non-constipated,NT-NC）。对所有粪便样本中细菌16S rRNA基因V3-V4高变区进行测序,检测肠道菌群。结果 与NT组相比,AD组儿童肠道菌群α多样性指数（Chao1）显著升高（t=2.258,P=0.006）,组间β多样性差异有统计学意义（R=0.210,P<0.001）。AD组儿童肠道优势菌群为双歧杆菌属、柯林斯菌属、脱硫弧菌属等。与NT-NC组相比,AD-NC组患儿肠道菌群Chao1指数显著升高（t=2.170,P=0.021）,组间β多样性差异有统计...     

Microbial treatment in chronic constipation

Chronic functional constipation is a kind of common intestinal disease that occurs in children, adults and elderly people. This disease not only causes great influence to physiological function, but also results in varying degrees of psychological barriers. At present, constipation treatments continue to rely on traditional methods such as purgative therapy and surgery. However, these approaches can disrupt intestinal function. Recent research between intestinal diseases and gut microbiota has gradually revealed a connection between constipation and intestinal flora disturbance, providing a theoretical basis for microbial treatment in chronic constipation. Microbial treatment mainly includes probiotic preparations such as probiotics, prebiotics, synbiotics and fecal microbiota transplantation (FMT). Due to its safety, convenience and curative effect, probiotic preparations have been widely accepted, especially gradually developed FMT with higher curative effects. Microbial treatment improves clinical symptoms, promotes the recovery of intestinal flora, and has no complications during the treatment process. Compared with traditional treatments, microbial treatment in chronic constipation has advantages, and is worthy of further promotion from clinical research to clinical application.     

Long-term follow-up of the effects of fecal microbiota transplantation in combination with soluble dietary fiber as a therapeutic regimen in slow transit constipation

As some studies have reported that strategies targeting the gut microbiota such as fecal microbiota transplantation (FMT) with or without other microecological therapy might have efficacy in treating slow transit constipation (STC), we conducted a single-center, open-label trial to study the long-term effect of FMT combined with soluble dietary fiber (pectin) on STC. Thirty-one adult patients with STC were enrolled into the trial. Patients received 6-day FMT procedures repeatedly for the first 3 months and soluble dietary fiber (pectin) daily during the follow-up. The rate of clinical remission and improvement, stool consistency, the Wexner constipation scale, and assessment of constipation-related symptoms were evaluated at week 4 and 1 year later. The clinical remission and improvement rates at week 4 were 69.0% (20/29) and 75.9% (22/29), respectively. At the end of the study, 48.3% (14/29) of patients continued to have at least three complete spontaneous bowel movements per week and 58.6% (17/29) of patients showed clinical improvements. Stool consistency, the Wexner constipation scale, and constipation symptoms improved both at short-term and long-term follow-up. The results indicated that FMT in combination with soluble dietary fiber (pectin) had both short-term and long-term efficacy in treating STC.     

三联疗法抗幽门螺杆菌感染对儿童肠道菌群状态的影响

目的　探讨抗幽门螺杆菌治疗对儿童肠道菌群状态的影响。方法　分别称取18例幽门螺杆菌感染儿童治疗前后新鲜粪便1.0 g,对肠道菌群中最有代表性的3种需氧菌(肠杆菌、肠球菌和酵母菌)和4种厌氧菌(双歧杆菌、乳杆菌、类杆菌和产气荚膜梭菌) ,分别进行需氧和厌氧培养,菌落计数,同时计算B/ E值来代表定植抗力。结果　抗Hp治疗后,双歧杆菌、乳杆菌和类杆菌较治疗前明显降低( P<0 .0 5 ) ,B/ E值明显下降( P<0 .0 1) ,肠杆菌数量明显增加( P<0 .0 5 ) ,酵母菌的检出率明显增加( P<0 .0 5 )。结论　三联疗法抗Hp治疗对儿童肠道菌群产生明显的影响,因此在治疗Hp感染时须考虑到大量抗生素治疗后可能对患儿产生的副作用及潜在的危险     

Microbiota Dynamics in Patients Treated with Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection

Clostridium difficile causes antibiotic-associated diarrhea and pseudomembraneous colitis and is responsible for a large and increasing fraction of hospital-acquired infections. Fecal microbiota transplantation (FMT) is an alternate treatment option for recurrent C. difficile infection (RCDI) refractory to antibiotic therapy. It has recently been discussed favorably in the clinical and scientific communities and is receiving increasing public attention. However, short- and long-term health consequences of FMT remain a concern, as the effects of the transplanted microbiota on the patient remain unknown. To shed light on microbial events associated with RCDI and treatment by FMT, we performed fecal microbiota analysis by 16S rRNA gene amplicon pyrosequencing of 14 pairs of healthy donors and RCDI patients treated successfully by FMT. Post-FMT patient and healthy donor samples collected up to one year after FMT were studied longitudinally, including one post-FMT patient with antibiotic-associated relapse three months after FMT. This analysis allowed us not only to confirm prior reports that RCDI is associated with reduced diversity and compositional changes in the fecal microbiota, but also to characterize previously undocumented post-FMT microbiota dynamics. Members of the Streptococcaceae, Enterococcaceae, or Enterobacteriaceae were significantly increased and putative butyrate producers, such as Lachnospiraceae and Ruminococcaceae were significantly reduced in samples from RCDI patients before FMT as compared to post-FMT patient and healthy donor samples. RCDI patient samples showed more case-specific variations than post-FMT patient and healthy donor samples. However, none of the bacterial groups were invariably associated with RCDI or successful treatment by FMT. Overall microbiota compositions in post-FMT patients, specifically abundances of the above-mentioned Firmicutes, continued to change for at least 16 weeks after FMT, suggesting that full microbiota recovery from RCDI may take much longer than expected based on the disappearance of diarrheal symptoms immediately after FMT.     

Fecal microbiota transplants: emerging social representations in the English-language print media

This study investigates how English-language news sources have represented fecal microbiota transplants (FMT). FMT involves transferring stool from a healthy donor to a recipient with a dysfunctional intestinal flora in order to repopulate their gut microbiome. FMT applications are increasingly moving into mainstream clinical care. We investigate press coverage of stool transplants, as well as broader themes associated with health and the gut microbiome, in order to uncover emerging social representations. Our findings show that print media focused in particular on creating novel, mainly hopeful, social representations of feces through wordplay and punning, side-lining issues of risk and fear. We also identify changing metaphorical framings of microbes and bacteria from “enemies” to “friends”, and ways in which readers are familiarized with FMT through the depiction of the process as both mundane and highly medicalized.     

粪菌移植治疗艰难梭菌感染的研究进展

艰难梭菌感染(Clostridium difficile infection,CDI)是院内抗生素相关性腹泻的最重要因素之一,其主要临床表现包括血便、腹泻、中毒性巨结肠、伪膜性肠炎等。近年来,CDI发病率、复发率、死亡率和治疗费用均明显增加,但其各种治疗方法均有局限性,尤其是抗生素治疗复发性艰难梭菌感染已面临许多棘手问题。目前证实肠道菌群失调和CDI感染关系密切,肠道菌群紊乱后导致艰难梭菌过度繁殖并释放毒素,可导致艰难梭菌感染。粪菌移植作为重建肠道菌群的重要方式,已成为复发性、难治性艰难梭菌感染最有效的治疗方式之一,不良反应极少。本文就国内外粪菌移植治疗艰难梭菌感染的研究进展作一综述。     

三生通便方治疗功能性便秘肠道实热证的随机双盲安慰剂对照临床研究

目的:观察三生通便方治疗功能性便秘肠道实热证的临床疗效、对生活质量的影响和安全性。方法:选取2016年7月至2018年3月我院收治的功能性便秘肠道实热证患者70例,随机分为观察组和对照组各35例,观察组给予三生通便方颗粒剂,对照组给予安慰剂治疗,两组均治疗4周。分别于治疗前、治疗2周和治疗4周时记录评估西医症状积分和中医证候有效率,并于治疗前和治疗4周分别记录评估便秘患者西医单项症状程度和生活质量量表(PAC-QOL)。结果:经4周治疗后,观察组西医症状积分的全分析集(FAS)和符合方案集(PPS)分析均显著低于对照组(P<0.01);观察组中医证候有效率的FAS和PPS分析分别为74.29%和78.79%,均显著高于对照组的34.29%和36.36%(P<0.01);观察组西医单项症状改善的FAS和PPS分析均优于治疗前(P<0.01);观察组PAC-QOL积分的FAS和PPS分析均显著低于对照组(P<0.05)。两组不良事件发生率差异无统计学意义(P>0.05)。结论:三生通便方能有效、安全地改善功能性便秘肠道实热证患者的临床症状和生活质量,值得临床推广应用。     

腰椎后路手术肠道菌群变化的研究

目的探讨腰椎后路手术患者肠道菌群的变化以期更合理的指导临床治疗。方法选择58例腰椎后路手术患者,出现肠道菌群失调症者38例,未出现肠道菌群失调症的20例作为对照组。在腰椎后路手术后,分别取2组患者自然排出的新鲜粪便10 g,采用定性定量检测比较2组患者肠道主要菌群差异及B/E值。肠道菌群失调症患者且与手术前自然排出的新鲜粪便进行相同比较。结果试验组肠道的双歧杆菌、类杆菌数量及B/E值较对照组均减少,分别是:9.21±0.65 vs 10.12±0.85;10.02±0.45 vs 10.23±0.45;1.05±0.17 vs 6.99±1.24,差异有统计学意义(P<0.05);而肠杆菌、肠球菌数量较对照组增加,分别是:9.11±1.09 vs 8.55±0.89;7.80±1.02vs 7.29±0.98,差异有统计学意义(P<0.05)。小梭菌、乳杆菌与对照组相比较,差异无统计学意义(P>0.05)。肠道菌群失调症患者与手术前进行比较,差异无统计学意义(P>0.05)。结论腰椎后路手术出现肠道菌群失调患者专性厌氧菌减少,条件致病菌增加,肠道微生物定植抗力下降。正确及时地去除病因,尽可能地采取微创手术技术,减少医源性损伤,调整机体免疫功能,纠正营养不良,合理使用抗生素是解决腰椎后路手术患者肠道功能障碍的有效办法。     

Fecal Microbiota Transplantation via Colonoscopy for Recurrent C. difficile Infection

Fecal Microbiota Transplantation (FMT) is a safe and highly effective treatment for recurrent and refractory C. difficile infection (CDI). Various methods of FMT administration have been reported in the literature including nasogastric tube, upper endoscopy, enema and colonoscopy. FMT via colonoscopy yields excellent cure rates and is also well tolerated. We have found that patients find this an acceptable and tolerable mode of delivery. At our Center, we have initiated a fecal transplant program for patients with recurrent or refractory CDI. We have developed a protocol using an iterative process of revision and have performed 24 fecal transplants on 22 patients with success rates comparable to the current published literature. A systematic approach to patient and donor screening, preparation of stool, and delivery of the stool maximizes therapeutic success. Here we detail each step of the FMT protocol that can be carried out at any endoscopy center with a high degree of safety and success.     

Low Level Engraftment and Improvement following a Single Colonoscopic Administration of Fecal Microbiota to Patients with Ulcerative Colitis

Objective

Fecal microbiota transplantation (FMT) is an investigational treatment for diseases thought to involve alterations in the intestinal microbiota including ulcerative colitis (UC). Case reports have described therapeutic benefit of FMT in patients with UC, possibly due to changes in the microbiota. We measured the degree to which the transplanted microbiota engraft following FMT in patients with UC using a donor similarity index (DSI).

Methods

Seven patients with mild to moderate UC (UC disease activity index scores 3–10) received a single colonoscopic administration of FMT. Metagenomic sequence data from stool were analyzed using an alignment-free comparison tool, to measure the DSI, and a phylogenetic analysis tool, to characterize taxonomic changes. Clinical, endoscopic, histologic, and fecal calprotectin outcome measures were also collected.

Results

One of 5 patients from whom sequencing data were available achieved the primary endpoint of 50% donor similarity at week 4; an additional 2 patients achieved 40% donor similarity. One patient with 40% donor similarity achieved clinical and histologic remission 1 month after FMT. However, these were lost by 2−3 months, and loss correlated with a decrease in DSI. The remaining patients did not demonstrate clinical response or remission. Histology scores improved in all but 1 patient. No patients remained in remission at 3 months after FMT.

Conclusions

Following a single colonoscopic fecal transplant, a DSI of 40-50% is achieved in about two-thirds of recipients. This level of engraftment correlated with a temporary clinical improvement in only 1/5 patients. Larger sample sizes could further validate this method for measuring engraftment, and changes in transplant frequency or method might improve microbiota engraftment and efficacy.

Trial Registration

ClinicalTrials.gov NCT01742754