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。     

Factors Related to Outcomes of Fecal Microbiota Transplantation in Patients with Clostridioides difficile Infection

Background/AimsThe aim of this study was to evaluate factors related to outcomes of fecal microbiota transplantation (FMT) in patients with Clostridioides difficile infection (CDI) and viability of frozen stock for FMT.MethodsClinical data of patients who had received FMT for CDI were prospectively collected. Next-generation 16S rRNA gene sequencing of bacteria was performed from donors’ and recipients’ stool. Colony-forming units (CFUs) of cultures from frozen stock solutions for FMT were measured at 0, 4, 8, 12, 24, 48 weeks after preparation of the solutions.ResultsIn total, 25 FMT procedures were performed in 20 cases (14 fresh and 11 frozen FMT). Forty-five percent of cases involved fulminant CDI. The overall success rate was 55% after the 1st FMT and 75% after the 2nd FMT. The success rate was significantly higher in partially treated CDI than in refractory CDI (100% vs 71.4%; p=0.001). In successful cases only, the decrease in alpha-diversity in the recipient stool microbiomes was recovered after FMT to a level similar to that in donor stools. There was a significant difference in the microbiome composition in pre-FMT recipients’ stool between successful and failed cases (p=0.001). The CFUs of frozen solution for FMT did not decrease for 48 weeks in both aerobic and anaerobic cultures.ConclusionsFMT is highly effective in partially treated CDI but not in refractory CDI. The microbiome differs between failed and successful cases. Frozen stock for FMT is viable up to 48 weeks.     

In search of stool donors: a multicenter study of prior knowledge,perceptions, motivators,and deterrents among potential donors for fecal microbiota transplantation

ABSTRACT

Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridioides difficile infection. Stool donors are essential, but difficult to recruit and retain. We aimed to identify factors influencing willingness to donate stool. This multi-center study with a 32-item questionnaire targeted young adults and health care workers via social media and university email lists in Edmonton and Kingston, Canada; London and Nottingham, England; and Indianapolis and Boston, USA. Items included baseline demographics and FMT knowledge and perception. Investigated motivators and deterrents included economic compensation, screening process, time commitment, and stool donation logistics. Logistic regression and linear regression models estimated associations of study variables with self-assessed willingness to donate stool. 802 respondents completed our questionnaire: 387 (48.3%) age 21-30 years, 573 (71.4%) female, 323 (40%) health care workers. Country of residence, age and occupation were not associated with willingness to donate stool. Factors increasing willingness to donate were: already a blood donor (OR 1.64), male, altruism, economic benefit, knowledge of how FMT can help patients (OR 1.32), and positive attitudes towards FMT (OR 1.39). Factors decreasing willingness to donate were: stool collection unpleasant (OR 0.92), screening process invasive (OR 0.92), higher stool donation frequency, negative social perception of stool, and logistics of collection/transporting feces. We conclude that 1) blood donors and males are more willing to consider stool donation; 2) altruism, economic compensation, and positive feedback are motivators; and 3) screening process, high donation frequency, logistics of collection/transporting feces, lack of public awareness, and negative social perception are deterrents. Considering these variables could maximize donor recruitment and retention.     

Successful treatment of fulminant Clostridioides difficile infection with emergent fecal microbiota transplantation in a patient with acute myeloid leukemia and prolonged,severe neutropenia

We present a patient with acute myeloid leukemia and prolonged, severe neutropenia who developed fulminant Clostridioides difficile infection refractory to medical therapy and was high‐risk for surgical intervention. He was treated with fecal microbiota transplantation (FMT) for life‐saving cure. The patient had subsequent clinical improvement, however, developed multidrug‐resistant Pseudomonas aeruginosa bacteremia 2 days post‐procedure. We describe subsequent investigation of this event that found this bacteremia was not related to the donor stool administered during FMT. This case adds to the literature that FMT could be considered in heavily immunocompromised patients with fulminant Clostridioides difficile infection where maximal medical therapy has been ineffective and surgery may carry an excessively high mortality risk.     

Therapeutic methods of gut microbiota modification in colorectal cancer management – fecal microbiota transplantation,prebiotics, probiotics,and synbiotics

ABSTRACT

The link between gut microbiota and the development of colorectal cancer has been investigated. An imbalance in the gut microbiota promotes the progress of colorectal carcinogenesis via multiple mechanisms, including inflammation, activation of carcinogens, and tumorigenic pathways as well as damaging host DNA. Several therapeutic methods are available with which to alter the composition and the activity of gut microbiota, such as administration of prebiotics, probiotics, and synbiotics; these can confer various benefits for colorectal cancer patients. Nowadays, fecal microbiota transplantation is the most modern way of modulating the gut microbiota. Even though data regarding fecal microbiota transplantation in colorectal cancer patients are still rather limited, it has been approved as a clinical method of treatment-recurrent Clostridium difficile infection, which may also occur in these patients. The major benefits of fecal microbiota transplantation include modulation of immunotherapy efficacy, amelioration of bile acid metabolism, and restoration of intestinal microbial diversity. Nonetheless, more studies are needed to assess the long-term effects of fecal microbiota transplantation. In this review, the impact of gut microbiota on the efficiency of anti-cancer therapy and colorectal cancer patients’ overall survival is also discussed.     

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.     

Immunological mechanisms of fecal microbiota transplantation in recurrent Clostridioides difficile infection

Fecal microbiota transplantation (FMT) is a successful method for treating recurrent Clostridioides difficile (C. difficile) infection (rCDI) with around 90% efficacy. Due to the relative simplicity of this approach, it is being widely used and currently, thousands of patients have been treated with FMT worldwide. Nonetheless, the mechanisms underlying its effects are just beginning to be understood. Data indicate that FMT effectiveness is due to a combination of microbiological direct mechanisms against C. difficile, but also through indirect mechanisms including the production of microbiota-derived metabolites as secondary bile acids and short chain fatty acids. Moreover, the modulation of the strong inflammatory response triggered by C. difficile after FMT seems to rely on a pivotal role of regulatory T cells, which would be responsible for the reduction of several cells and soluble inflammatory mediators, ensuing normalization of the intestinal mucosal immune system. In this minireview, we analyze recent advances in these immunological aspects associated with the efficacy of FMT.     

Inflammatory bowel disease: The role of commensal microbiome in immune regulation

The incidence of inflammatory bowel disease (IBD) is increasing. Microbiome is one of the most important factors in its development and affects the different clinical outcomes of IBD patients depending on its composition and different alterations. We conducted a systematic review to discuss the association between microbiome and IBD in terms of immune regulation, and therapies that can modify microbiota. A comprehensive systematic literature search was performed through April 2020 in PubMed, Web of Science, the Cochrane Library, and clinicaltrials.gov. Inclusion criteria required IBD immune regulation and alternate therapeutics for IBD. This analysis helps explain the multifactorial origin of microbiome diversity including normal immune regulation, immune pathophysiology of IBD, and shows the evidence of several therapeutic targets to change microbiome in patients with IBD, such as prebiotics, probiotics, antibiotics, fecal microbiota transplant, and others.     

Freeze-dried fecal samples are biologically active after long-lasting storage and suited to fecal microbiota transplantation in a preclinical murine model of Clostridioides difficile infection

ABSTRACT

Fecal microbiota transplantation is now recommended for treating recurrent forms of Clostridioides difficile infection. Recent studies have reported protocols using capsules of either frozen or freeze-dried stool allowing oral administration in in- and out-patient settings. However, a central question remains the viability, engraftment, and efficacy of the microbiome over time during storage life. This study shows that both the freeze-drying and freezing procedures for fecal samples allowed preserving viability, short-chain fatty acids concentration, and anti-Clostridioides difficile properties of microbiota without significant alteration after storage for 12 months. Fecal transplantation with freeze-dried microbiota allowed engraftment of microbiota leading to clearance of Clostridioides difficile infection in a preclinical murine model with a survival rate of 70% versus 53-60% in mice treated with frozen inocula, and 20% in the untreated group. Moreover, the freeze-dried powder can be used to fill oral hard capsules using a very low amount (0.5%) of glidant excipient, allowing oral formulation. Altogether, this study showed that freeze-dried inocula can be used for the treatment of Clostridioides difficile infection with long-lasting stability of the fecal microbiota. This formulation facilitates biobanking and allows the use of hard capsules, an essential step to simplify patient access to treatment.     

Five years of fecal microbiota transplantation——an update of the Israeli experience

AIM To evaluate and describe the efficacy of fecal microbiota transplantation(FMT) for Clostridium difficile infection(CDI) in a national Israeli cohort.METHODS All patients who received FMT for recurrent(recurrence within 8 wk of the previous treatment) or refractory CDI from 2013 through 2017 in all the five medical centers in Israel currently performing FMT were included. Stool donors were screened according to the Israeli Ministry of Health guidelines. Clinical and laboratory data of patients were collected from patients' medical files, and they included indications for FMT, risk factors for CDI and disease severity. Primary outcome was FMT success(at least 2 mo free of CDI-related diarrhea post-FMT). Secondary outcomes included initial response to FMT(cessation of diarrhea within 7 d) and recurrence at 6 mo.RESULTS There were 111 FMTs for CDI, with a median age of 70 years [interquartile range(IQR): 53-82], and 42%(47) males. Fifty patients(45%) were treated via the lower gastrointestinal(LGI, represented only by colonoscopy) route, 37(33%) via capsules, and 24(22%) via the upper gastrointestinal(UGI) route. The overall success rate was 87.4%(97 patients), with no significant difference between routes of administration(P = 0.338). In the univariant analysis, FMT success correlated with milder disease(P = 0.01), ambulatory setting(P 0.05) and lower Charlson comorbidity score(P 0.05). In the multivariant analysis, only severe CDI [odd ratio(OR) = 0.14, P 0.05] and inpatient FMT(OR = 0.19, P 0.05) were each independently inversely related to FMT success. There were 35(32%) patients younger than 60 years of age, and 14(40%) of them had a background of inflammatory bowel disease.CONCLUSION FMT is a safe and effective treatment for CDI, with capsules emerging as a successful and well-tolerated route. Severe CDI is less likely to respond to FMT.     

肠道微生物群组与肠道免疫的关系

人类肠道是一个生态系统,存在大量的微生物。肠道微生物群与肠道天然免疫及获得性免疫之间存在动态的相互作用,影响着肠道免疫系统的形成和功能。当这种相互作用中的一步或多步失效时,自身免疫性疾病和炎症性疾病就会发生。回顾肠道微生物群组与肠道免疫功能的关系,有助于提高微生物对免疫系统失调相关的肠道疾病治疗应用的认识。     

Fecal microbiota transplantation in the metabolic diseases: Current status and perspectives

With the development of microbiology and metabolomics, the relationship between the intestinal microbiome and intestinal diseases has been revealed. Fecal microbiota transplantation (FMT), as a new treatment method, can affect the course of many chronic diseases such as metabolic syndrome, malignant tumor, autoimmune disease and nervous system disease. Although the mechanism of action of FMT is now well understood, there is some controversy in metabolic diseases, so its clinical application may be limited. Microflora transplantation is recommended by clinical medical guidelines and consensus for the treatment of recurrent or refractory Clostridium difficile infection, and has been gradually promoted for the treatment of other intestinal and extraintestinal diseases. However, the initial results are varied, suggesting that the heterogeneity of the donor stools may affect the efficacy of FMT. The success of FMT depends on the microbial diversity and composition of donor feces. Therefore, clinical trials may fail due to the selection of ineffective donors, and not to faulty indication selection for FMT. A new understanding is that FMT not only improves insulin sensitivity, but may also alter the natural course of type 1 diabetes by modulating autoimmunity. In this review, we focus on the main mechanisms and deficiencies of FMT, and explore the optimal design of FMT research, especially in the field of cardiometabolic diseases.     

Faecal microbiota transplantation for eradication of co-infection with Clostridioides difficile and extensively drug-resistant KPC-producing Klebsiella pneumoniae

Abstract

Clostridioides difficile infection may be complicated by co-infection with other pathogens. We here describe the successful use of faecal microbiota transplantation to eradicate concomitant C. difficile and extensively drug-resistant (XDR) KPC-producing Klebsiella pneumoniae. Donor microbiota efficiently engrafted in the patient, and a donor-like microbial assemblage persisted in the patient during six months follow-up. The report explores the potential for the donor microbiota to eradicate and replace multi-resistant microorganisms.