Fecal microbiota transplantation as novel therapy in gastroenterology:A systematic review

AIM:To study the clinical efficacy and safety of Fecal microbiota transplantation(FMT).We systematically reviewed FMT used as clinical therapy.METHODS:We searched MEDLINE,EMBASE,the Cochrane Library and Conference proceedings from inception to July,2013.Treatment effect of FMT was calculated as the percentage of patients who achieved clinical improvement per patient category,on an intention-to-treat basis.RESULTS:We included 45 studies;34 on Clostridium difficile-infection(CDI),7 on inflammatory bowel disease,1 on metabolic syndrome,1 on constipation,1 on pouchitis and 1 on irritable bowel syndrome(IBS).In CDI 90% resolution of diarrhea in 33 case series(n = 867) was reported,and 94% resolution of diarrhea after repeated FMT in a randomized controlled trial(RCT)(n = 16).In ulcerative colitis(UC) remission rates of 0% to 68% were found(n = 106).In Crohn's disease(CD)(n = 6),no benefit was observed.In IBS,70% improvement of symptoms was found(n = 13).100% Reversal of symptoms was observed in constipation(n = 3).In pouchitis,none of the patients(n = 8) achieved remission.One RCT showed significant improvement of insulin sensitivity in metabolic syndrome(n = 10).Serious adverse events were rare.CONCLUSION:FMT is highly effective in CDI,and holds promise in UC.As for CD,chronic constipation,pouchitis and IBS data are too limited to draw conclusions.FMT increases insulin sensitivity in metabolic syndrome.     

Recurrent Clostridium difficile infections: The importance of the intestinal microbiota

Clostridium difficile infections (CDI) are a leading cause of antibiotic-associated and nosocomial diarrhea. Despite effective antibiotic treatments, recurrent infections are common. With the recent emergence of hypervirulent isolates of C. difficile, CDI is a growing epidemic with higher rates of recurrence, increasing severity and mortality. Fecal microbiota transplantation (FMT) is an alternative treatment for recurrent CDI. A better understanding of intestinal microbiota and its role in CDI has opened the door to this promising therapeutic approach. FMT is thought to resolve dysbiosis by restoring gut microbiota diversity thereby breaking the cycle of recurrent CDI. Since the first reported use of FMT for recurrent CDI in 1958, systematic reviews of case series and case report have shown its effectiveness with high resolution rates compared to standard antibiotic treatment. This article focuses on current guidelines for CDI treatment, the role of intestinal microbiota in CDI recurrence and current evidence about FMT efficacy, adverse effects and acceptability.     

A case of Clostridium difficile infection complicated by acute respiratory distress syndrome treated with fecal microbiota transplantation

Acute respiratory distress syndrome is a life-threatening disorder caused mainly by pneumonia. Clostridium difficile infection (CDI) is a common nosocomial diarrheal disease. Disruption of normal intestinal flora by antibiotics is the main risk factor for CDI. The use of broad-spectrum antibiotics for serious medical conditions can make it difficult to treat CDI complicated by acute respiratory distress syndrome. Fecal microbiota transplantation is a highly effective treatment in patients with refractory CDI. Here we report on a patient with refractory CDI and acute respiratory distress syndrome caused by pneumonia who was treated with fecal microbiota transplantation.     

Efficacy and safety of,and patient satisfaction with,colonoscopic-administered fecal microbiota transplantation in relapsing and refractory community- and hospital-acquired Clostridium difficile infection

OBJECTIVE:

To report the efficacy and safety of, and patient satisfaction with, colonoscopic fecal microbiota transplantation (FMT) for community- and hospital-acquired Clostridium difficile infection (CDI).

METHODS:

A retrospective medical records review of patients who underwent FMT between July 1, 2012 and August 31, 2013 was conducted. A total of 22 FMTs were performed on 20 patients via colonoscopy. The patients were divided into ‘community-acquired’ and ‘hospital-acquired’ CDI. Telephone surveys were conducted to determine procedure outcome and patient satisfaction. Primary cure rate was defined as resolution of diarrhea without recurrence within three months of FMT, whereas secondary cure rate described patients who experienced resolution of diarrhea and return of normal bowel function after a second course of FMT.

RESULTS:

Nine patients met the criteria for community-acquired CDI whereas 11 were categorized as hospital-acquired CDI. A female predominance in the community-acquired group (88.89% [eight of nine]) was found (P=0.048). The primary cure rate was 100% (nine of nine) and 81.8% (nine of 11 patients) in community- and hospital-acquired CDI groups, respectively (P=0.189). Two patients in the hospital-acquired group had to undergo a repeat FMT for persistent symptomatic infection; the secondary cure rate was 100%. During the six-month follow-up, all patients were extremely satisfied with the procedure and no complications or adverse events were reported.

CONCLUSION:

FMT was a highly successful and very acceptable treatment modality for treating both community- and hospital-acquired CDI.     

Complicated fecal microbiota transplantation in a tetraplegic patient with severe Clostridium difficile infection

A 65-year-old male suffering from acute spinal cord injury leading to incomplete tetraplegia presented with severe recurrent Clostridium difficile(C. difficile) infection subsequent to antibiotic treatment for pneumonia. After a history of ineffective antimicrobial therapies, including metronidazole, vancomycin, fidaxomicin, rifaximin and tigecycline, leading to several relapses, the patient underwent colonoscopic fecal microbiota transplantation from his healthy son. Four days subsequent to the procedure, the patient showed a systemic inflammation response syndrome. Without detecting an infectious cause, the patient received antimicrobial treatment, including tigecycline, metronidazole, vancomycin via polyethylene glycol and an additional enema for a period of seven days, leading to a prompt recovery and no reported C. difficile infection relapse during a 12 wk follow up.     

Physician attitudes toward the use of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection

BACKGROUND:

Fecal microbiota transplantation (FMT) is a safe and effective, yet infrequently used therapy for recurrent Clostridium difficile infection (CDI).

OBJECTIVE:

To characterize barriers to FMT adoption by surveying physicians about their experiences and attitudes toward the use of FMT.

METHODS:

An electronic survey was distributed to physicians to assess their experience with CDI and attitudes toward FMT.

RESULTS:

A total of 139 surveys were sent and 135 were completed, yielding a response rate of 97%. Twenty-five (20%) physicians had treated a patient with FMT, 10 (8%) offered to treat with FMT, nine (7%) referred a patient to receive FMT, and 83 (65%) had neither offered nor referred a patient for FMT. Physicians who had experience with FMT (performed, offered or referred) were more likely to be male, an infectious diseases specialist, >40 years of age, fellowship trained and practicing in an urban setting. The most common reasons for not offering or referring a patient for FMT were: not having ‘the right clinical situation’ (33%); the belief that patients would find it too unappealing (24%); and institutional or logistical barriers (23%). Only 8% of physicians predicted that the majority of patients would opt for FMT if given the option. Physicians predicted that patients would find all aspects of the FMT process more unappealing than they would as providers.

CONCLUSIONS:

Physicians have limited experience with FMT despite having treated patients with multiple recurrent CDIs. There is a clear discordance between physician beliefs about FMT and patient willingness to accept FMT as a treatment for recurrent CDI.     

粪菌移植的研究现状、存在问题与发展方向

粪菌移植已经用于治疗难治性难辨梭状芽孢杆菌感染、炎症性肠病、腹泻型和便秘型肠易激综合征。但哪些患者适合用,哪些人适合做供体,怎么样是理想的移植方法等问题还没有完全解决,有关其机制、技术标准化、安全性评估等方面尚处于起步阶段,有待于深入研究。本文对FMT的研究现状、存在问题与发展方向作一介绍,并提出粪人工组合菌群移植是未来重要研究方向。     

Future prospect of faecal microbiota transplantation as a potential therapy in asthma

There is convincing evidence from both human and animal studies suggesting that the gut microbiota plays an important role in regulating immune responses associated with the development of asthma. Certain intestinal microbial strains have been demonstrated to suppress or impair immune responsiveness in asthma experimental models, suggesting that specific species among gut commensal microbiota may play either a morbific or phylactic role in the progression of asthma. Evidence to date suggests that the intestinal microbiota represent fertile targets for prevention or management of asthma. The faecal microbiota transplantation (FMT) is a rather straightforward therapy that manipulates the human gastrointestinal (GI) microbiota, by which a healthy donor microbiota is transferred into an existing but disturbed microbial ecosystem. The FMT may therefore represent a therapeutic approach for asthma treatment in the foreseeable future. At present, FMT therapy for asthma is very limited and should be actively studied. Considerable efforts are needed to increase our knowledge in the field of FMT therapy for asthma. In this review, we aimed to provide several insights into the development of FMT therapy for asthma.     

Clostridium difficile and inflammatory bowel disease: Role in pathogenesis and implications in treatment

Clostridium difficile(C.difficile)is the leading cause of antibiotic associated colitis and nosocomial diarrhea.Patients with inflammatory bowel disease(IBD)are at increased risk of developing C.difficile infection(CDI),have worse outcomes of CDI-including higher rates of colectomy and death,and experience higher rates of recurrence.However,it is still not clear whether C.difficile is a cause of IBD or a consequence of the inflammatory state in the intestinal environment.The burden of CDI has increased dramatically over the past decade,with severe outbreaks described in many countries,which have been attributed to a new and more virulent strain.A parallel rise in the incidence of CDI has been noted in patients with IBD.IBD patients with CDI tend be younger,have less prior antibiotic exposure,and most cases of CDI in these patients represent outpatient acquired infections.The clinical presentation of CDI in these patients can be unique-including diversion colitis,enteritis and pouchitis,and typical findings on colonoscopy are often absent.Due to the high prevalence of CDI in patients hospitalized with an IBD exacerbation,and the prognostic implications of CDI in these patients,it is recommended to test all IBD patients hospitalized with a disease flare for C.difficile.Treatment includes general measures such as supportive care and infection control measures.Antibiotic therapy with either oral metronidazole,vancomycin,or the novel antibiotic-fidaxomicin,should be initiated as soon as possible.Fecal macrobiota transplantation constitutes another optional treatment for severe/recurrent CDI.The aim of this paper is to review recent data on CDI in IBD:role in pathogenesis,diagnostic methods,optional treatments,and outcomes of these patients.     

Ulcerative colitis worsened after Clostridium difficile infection:Efficacy of infliximab

The incidence of Clostridium difficile(C.difficile)infection(CDI)is 1.8%-5.7%in admitted patients with ulcerative colitis(UC).CDI can worsen UC and increase the risk for colectomy or even death,thus necessitating therapy escalation,such as increasing the corticoid therapy or starting a biologic treatment.Several reported cases with infliximab therapy have provided favorable outcomes in UC patients with CDI,suggesting that infliximab treatment may be protective;however,the optimal infliximab treatment regimen for UC patients with CDI remains to be established.Here,we report a case of worsening UC in the presence of recurrent CDI.The patient had received prior ciprofloxacin and immunosuppressive therapy during a prolonged hospital stay.The deterioration in the patient’s condition likely resulted from the ability of C.difficile to promote relapsing of UC by activating the immune response.Ultimately,the patient was treated with a high dose of infliximab after a low trough level of infliximab at week 8was identified,yielding better clinical results.Infliximab was found to be safe after repetitive episodes of CDI.The trough level of infliximab was therefore a useful indicator to guide therapy and correlated well with the patient’s outcome.     

Step-up fecal microbiota transplantation (FMT) strategy

Gut dysbiosis is a characteristic of inflammatory bowel disease (IBD) and is believed to play a role in the pathogenesis of IBD. Fecal microbiota transplantation (FMT) is an effective strategy to restore intestinal microbial diversity and has been reported to have a potential therapeutic value in IBD. Our recent study reported a holistic integrative therapy called “step-up FMT strategy,” which was beneficial in treating steroid-dependent IBD patients. This strategy consists of scheduled FMTs combined with steroids, anti-TNF-α antibody treatment or enteral nutrition. Herein, we will elaborate the strategy thoroughly, introducing the concept, potential indication, methodology, and safety of “step-up FMT strategy” in detail.     

Utility of faecal calprotectin analysis in adult inflammatory bowel disease

The inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are chronic relapsing, remitting disorders. Diagnosis, along with assessment of disease activity and prognosis present challenges to managing clinicians. Faecal biomarkers, such as faecal calprotectin, are a non-invasive method which can be used to aid these decisions. Calprotectin is a calcium and zinc binding protein found in the cytosol of human neutrophils and macrophages. It is released extracellularly in times of cell stress or damage and can be detected within faeces and thus can be used as a sensitive marker of intestinal inflammation. Faecal calprotectin has been shown to be useful in the diagnosis of IBD, correlates with mucosal disease activity and can help to predict response to treatment or relapse. With growing evidence supporting its use, over the last decade this faecal biomarker has significantly changed the way IBD is managed.     

Prospects and challenges for intestinal microbiome therapy in pediatric gastrointestinal disorders

Fecal microbiome (microbiota) transplantation is an emerging treatment not only for refractory/recurrent Clostridium difficile infections and chronic gastrointestinal diseases, but also for metabolic syndrome, and even possibly for neurological disorders. This non-conventional therapy has been perhaps more appropriately designated as fecal bacteriotherapy (FB) as well. The employment of FB is spreading into pediatric gastroenterology. This focused review highlights the pediatric applications of FB and discusses hypotheses for its mechanism of action. We propose that intestinal microbiome therapy may be a more appropriate term for FB, which integrates its potential future applications.     

Fecal transplant policy and legislation

Fecal microbiota transplantation(FMT) has garnered significant attention in recent years in the face of a reemerging Clostridium difficile(C.difficile) epidemic.Positive results from the first randomized control trial evaluating FMT have encouraged the medical community to explore the process further and expand its application beyond C.difficile infections and even the gastrointestinal domain.However promising and numerous the prospects of FMT appear,the method remains limited in scope today due to several important barriers,most notably a poorly defined federal regulatory policy.The Food and Drug Administrationhas found it difficult to standardize and regulate the administration of inherently variable,metabolically active,and ubiquitously available fecal material.The current cumbersome policy,which classifies human feces as a drug,has prevented physicians from providing FMT and deserving patients from accessing FMT in a timely fashion,and subsequent modifications seem only to be temporary.The argument for reclassifying fecal material as human tissue is well supported.Essentially,this would allow for a regulatory framework that is sufficiently flexible to expand access to care and facilitate research,but also appropriately restrictive and centralized to ensure patient safety.Such an approach can facilitate the advancement of FMT to a more refined,controlled,and aesthetic process,perhaps in the form of a customized and wellcharacterized stool substitute therapy.     

The potential for emerging therapeutic options for Clostridium difficile infection

Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review.     

A Case of Toxic Megacolon Caused by Clostridium difficile Infection and Treated with Fecal Microbiota Transplantation

Toxic megacolon is a rare clinical complication of fulminant Clostridium difficile infection. The mortality rate of fulminant C. difficile infection is reported to be as high as 50%. Fecal microbiota transplantation is a highly effective treatment in patients with recurrent or refractory C. difficile infection. However, there are few published articles on the use of such transplantation for fulminant C. difficile infection. Here, we report on a patient with toxic megacolon complicated by C. difficile infection who was treated successfully with fecal microbiota transplantation.     

Intestinal microbiota in health and disease: Role of bifidobacteria in gut homeostasis

The pool of microbes inhabiting our body is known as “microbiota” and their collective genomes as “microbiome”. The colon is the most densely populated organ in the human body, although other parts, such as the skin, vaginal mucosa, or respiratory tract, also harbour specific microbiota. This microbial community regulates some important metabolic and physiological functions of the host, and drives the maturation of the immune system in early life, contributing to its homeostasis during life. Alterations of the intestinal microbiota can occur by changes in composition (dysbiosis), function, or microbiota-host interactions and they can be directly correlated with several diseases. The only disease in which a clear causal role of a dysbiotic microbiota has been demonstrated is the case of Clostridium difficile infections. Nonetheless, alterations in composition and function of the microbiota have been associated with several gastrointestinal diseases (inflammatory bowel disease, colorectal cancer, or irritable bowel syndrome), as well as extra-intestinal pathologies, such as those affecting the liver, or the respiratory tract (e.g., allergy, bronchial asthma, and cystic fibrosis), among others. Species of Bifidobacterium genus are the normal inhabitants of a healthy human gut and alterations in number and composition of their populations is one of the most frequent features present in these diseases. The use of probiotics, including bifidobacteria strains, in preventive medicine to maintain a healthy intestinal function is well documented. Probiotics are also proposed as therapeutic agents for gastrointestinal disorders and other pathologies. The World Gastroenterology Organization recently published potential clinical applications for several probiotic formulations, in which species of lactobacilli are predominant. This review is focused on probiotic preparations containing Bifidobacterium strains, alone or in combination with other bacteria, which have been tested in human clinical studies. In spite of extensive literature on and research into this topic, the degree of scientific evidence of the effectiveness of probiotics is still insufficient in most cases. More effort need to be made to design and conduct accurate human studies demonstrating the efficacy of probiotics in the prevention, alleviation, or treatment of different pathologies.     

粪便菌群移植与慢性乙型肝炎

<正>慢性乙型肝炎是全球公共卫生健康问题,大约2.4亿人为血清HBsAg携带者~([1]),其中15%~40%的人将会发展成肝硬化、肝衰竭、肝细胞癌~([2])。粪便菌群移植(faecal microbiota transplantation,FMT)是将正常人的粪便移植到患者的胃肠道以治疗特定疾病,如肠道疾病、艰难梭菌感染等。1 FMT的起源、历史和现状FMT并不是当代一种新的治疗方法,早在公元4世纪的中国就有应用记录。葛洪用绳子悬吊正常人的粪便给患有严重腹泻和食物中毒的患者口服。     

粪菌移植与慢性肝脏疾病

<正>成人胃肠道粘膜表面积达到300 m2,是人体与外界环境发生相互作用最大的区域。在成人胃肠道中定殖着超过1×10~(14)个微生物。各种不同的环境信号和不同的饮食习惯使肠道微生物群产生大量的代谢产物以及脂多糖/内毒素、胆汁酸、短链脂肪酸、三甲胺等物质。肝脏作为肠道营养物质、细菌产物、毒素以及其他各种代谢产物的接受者和过滤者,经受着这些物质的作用,可能造成许多肝脏疾