Given the importance of gut microbial homeostasis in maintaining health, there has been considerable interest in developing innovative therapeutic strategies for restoring gut microbiota. One such... Show moreGiven the importance of gut microbial homeostasis in maintaining health, there has been considerable interest in developing innovative therapeutic strategies for restoring gut microbiota. One such approach, fecal microbiota transplantation (FMT), is the main “whole gut microbiome replacement” strategy and has been integrated into clinical practice guidelines for treating recurrent Clostridioides difficile infection (rCDI). Furthermore, the potential application of FMT in other indications such as inflammatory bowel disease (IBD), metabolic syndrome, and solid tumor malignancies is an area of intense interest and active research. However, the complex and variable nature of FMT makes it challenging to address its precise functionality and to assess clinical efficacy and safety in different disease contexts. In this review, we outline clinical applications, efficacy, durability, and safety of FMT and provide a comprehensive assessment of its procedural and administration aspects. The clinical applications of FMT in children and cancer immunotherapy are also described. We focus on data from human studies in IBD in contrast with rCDI to delineate the putative mechanisms of this treatment in IBD as a model, including colonization resistance and functional restoration through bacterial engraftment, modulating effects of virome/phageome, gut metabolome and host interactions, and immunoregulatory actions of FMT. Furthermore, we comprehensively review omics technologies, metagenomic approaches, and bioinformatics pipelines to characterize complex microbial communities and discuss their limitations. FMT regulatory challenges, ethical considerations, and pharmacomicrobiomics are also highlighted to shed light on future development of tailored microbiome-based therapeutics. Show less
De ziekte van Crohn (CD) en colitis ulcerosa (UC) zijn chronisch inflammatoire darmziekten (IBD). Ondanks dat er de laatste jaren significante stappen zijn gezet in de medicamenteuze behandeling... Show moreDe ziekte van Crohn (CD) en colitis ulcerosa (UC) zijn chronisch inflammatoire darmziekten (IBD). Ondanks dat er de laatste jaren significante stappen zijn gezet in de medicamenteuze behandeling van IBD, ervaart een groot deel van de IBD patiënten klachten van aanhoudende ontsteking en bijwerkingen van de behandeling, wat de noodzaak voor het zoeken naar nieuwe behandelingsopties onderstreept. Door ons te richten op zowel de ontsteking die de klachten van IBD veroorzaakt, als op de onderliggende pathogenese die deze ontsteking aanstuurt middels het introduceren van een gezond microbioom en een gebalanceerde leefstijl, hopen we een (kleine) stap voorwaarts gezet te hebben richting een toekomst met een betere kwaliteit van leven voor patiënten met IBD. Show less
Wiese, M.; Schuren, F.H.J.; Smits, W.K.; Kuijper, E.J.; Ouwens, A.; Heerikhuisen, M.; ... ; Vossen, J.M.B.M. van der 2022
BackgroundClostridioides difficile is a Gram-positive anaerobic bacterium that can produce the toxins TcdA and/or TcdB and is considered an opportunistic pathogen. C. difficile is mainly... Show moreBackgroundClostridioides difficile is a Gram-positive anaerobic bacterium that can produce the toxins TcdA and/or TcdB and is considered an opportunistic pathogen. C. difficile is mainly transmitted as endospores, which germinate to produce the pathogenic vegetative cells under suitable conditions in the gut. To efficiently screen novel therapeutic- interventions against the proliferation of C. difficile within a complex microbial community, platforms are needed that facilitate parallel experimentation. In order to allow for screening of novel interventions a medium-to-high throughput in vitro system is desirable. To this end, we have developed the 96-well CDi-screen platform that employs an adapted simulated ileal effluent medium (CDi-SIEM) and allows for culturing of pathogenic C. difficile. MethodsC. difficile strain ATCC 43599 was inoculated in the form of vegetative cells and spores into the CDi-screen in the presence and absence of a cultured fecal microbiota and incubated for 48h. To demonstrate its utility, we investigated the effect of the human milk oligosaccharide 2'-Fucosyllactose (2'-FL) at 4 and 8 mg/mL on C. difficile outgrowth and toxin production in the CDi-screen. The test conditions were sampled after 24 and 48 hours. C. difficile -specific primers were used to monitor C. difficile growth via qPCR and barcoded 16S rRNA gene amplicon sequencing facilitated the in-depth analysis of gut microbial community dynamics. ResultsC. difficile ATCC 43599 proliferated in CDi-SIEM, both when inoculated as spores and as vegetative cells. The strain reached cell numbers expressed as C. difficile genome equivalents of up to 10 (8) cells per mL after 24h of incubation. 2'-FL significantly inhibited the outgrowth of the ATTC 43599 strain within a complex human gut microbial community in the CDi-screen. In addition, a dose-dependent modulation of the gut microbial community composition by 2'-FL supplementation was detected, with a significant increase in the relative abundance of the genus Blautia in the presence of 2'-FL. ConclusionThe CDi-screen is suitable for studying C. difficile proliferation in a complex gut ecosystem and for screening for anti-pathogenic interventions that target C. difficile directly and/or indirectly through interactions with the gut microbiota. Different doses of compounds such as in this study the dose of the human milk oligosaccharide 2'-FL can be screened for efficacy in the inhibition of C. difficile proliferation. Show less
Reigadas, E.; Prehn, J. van; Falcone, M.; Fitzpatrick, F.; Vehreschild, M.J.G.T.; Kuijper, E.J.; ... ; Study Grp Host Microbiota Interact 2021
Background: Clostridioides difficile infection (CDI) remains the leading cause of healthcare-associated diarrhoea, despite existing guidelines for infection control measures and antimicrobial... Show moreBackground: Clostridioides difficile infection (CDI) remains the leading cause of healthcare-associated diarrhoea, despite existing guidelines for infection control measures and antimicrobial stewardship. The high associated health and economic burden of CDI calls for novel strategies to prevent the development and spread of CDI in susceptible patients. Objectives: We aim to review CDI prophylactic treatment strategies and their implementation in clinical practice. Sources: We searched PubMed, Embase, Emcare, Web of Science, and the COCHRANE Library databases to identify prophylactic interventions aimed at prevention of CDI. The search was restricted to articles published in English since 2012. Content: A toxin-based vaccine candidate is currently being investigated in a phase III clinical trial. However, a recent attempt to develop a toxin-based vaccine has failed. Conventional probiotics have not yet proved to be an effective strategy for prevention of CDI. New promising microbiota-based interventions that bind and inactivate concomitantly administered antibiotics, such as ribaxamase and DAV-132, have been developed. Prophylaxis of CDI with C. difficile antibiotics should not be performed routinely and should be considered only for secondary prophylaxis in very selected patients who are at the highest imminent risk for recurrent CDI (R-CDI) after a thorough evaluation. Faecal microbiota transplantation (FMT) has proved to be a very effective treatment for patients with multiple recurrences. Bezlotoxumab provides protection against R-CDI, mainly in patients with primary episodes and a high risk of relapse. Implications: There are no proven effective, evidenced-based prophylaxis options for primary CDI. As for secondary prevention, FMT is considered the option of choice in patients with multiple recurrences. Bezlotoxumab can be added to standard treatment for patients at high risk for R-CDI. The most promising strategies are those aimed at reducing changes in intestinal microbiota and development of a new effective non-toxin-based vaccine. Elena Reigadas, Clin Microbiol Infect 2021;27:1777 (c) 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Show less
Wingen-Heimann, S.M.; Prehn, J. van; Kuijper, E.J.; Vehreschild, M.J.G.T. 2021
Antibiotics provided humanity resilience to the majority of bacterial infections. An important trade-off is the emergence of antimicrobial resistance, and a diminished and perturbed microbiota,... Show moreAntibiotics provided humanity resilience to the majority of bacterial infections. An important trade-off is the emergence of antimicrobial resistance, and a diminished and perturbed microbiota, resulting in an increased susceptibility for Clostridioides difficile infections. For both C. difficile and multidrug resistant micro-organisms (MDRO), asymptomatic colonisation of the gut plays an important role in the development of infection. The aim of this thesis is to better understand the role of the microbiota in defence against infections with C. difficile and MDRO. The first part describes the epidemiology and detection of asymptomatically colonized individuals. It concludes that though asymptomatic colonization of MDRO and C. difficile can become a nidus for nosocomial (hospital) infection and transmission, its prevalence is still low in the Netherlands. The second part of this thesis focuses on eradication and/or treatment of these micro-organisms with ‘fecal microbiota transplantation’ of healthy donor feces. It describes the establishment of the Netherlands Donor Feces Bank, and the research, experiences and successes of FMT in the treatment of patients with recurrent C. difficile infections and MDRO. The experience of this thesis may help the establishment, utilization, standardization and maturation of stool banks and research institutes of the next-generation of microbiota modifying therapies. Show less
Czepiel, J.; Krutova, M.; Mizrahi, A.; Khanafer, N.; Enoch, D.A.; Patyi, M.; ... ; Garlicki, A. 2021
We aimed to describe the clinical presentation, treatment, outcome and report on factors associated with mortality over a 90-day period in Clostridioides difficile infection (CDI). Descriptive,... Show moreWe aimed to describe the clinical presentation, treatment, outcome and report on factors associated with mortality over a 90-day period in Clostridioides difficile infection (CDI). Descriptive, univariate, and multivariate regression analyses were performed on data collected in a retrospective case-control study conducted in nine hospitals from seven European countries. A total of 624 patients were included, of which 415 were deceased (cases) and 209 were still alive 90 days after a CDI diagnosis (controls). The most common antibiotics used previously in both groups were beta-lactams; previous exposure to fluoroquinolones was significantly (p = 0.0004) greater in deceased patients. Multivariate logistic regression showed that the factors independently related with death during CDI were older age, inadequate CDI therapy, cachexia, malignancy, Charlson Index, long-term care, elevated white blood cell count (WBC), C-reactive protein (CRP), bacteraemia, complications, and cognitive impairment. In addition, older age, higher levels of WBC, neutrophil, CRP or creatinine, the presence of malignancy, cognitive impairment, and complications were strongly correlated with shortening the time from CDI diagnosis to death. CDI prevention should be primarily focused on hospitalised elderly people receiving antibiotics. WBC, neutrophil count, CRP, creatinine, albumin and lactate levels should be tested in every hospitalised patient treated for CDI to assess the risk of a fatal outcome. Show less
Ooijevaar, R.E.; Nood, E. van; Goorhuis, A.; Terveer, E.M.; Prehn, J. van; Verspaget, H.W.; ... ; Keller, J.J. 2021
Fecal microbiota transplantation (FMT) has become a well-established treatment for recurrent Clostridioides difficile infection (rCDI). While short-term outcomes and adverse events relating to FMT... Show moreFecal microbiota transplantation (FMT) has become a well-established treatment for recurrent Clostridioides difficile infection (rCDI). While short-term outcomes and adverse events relating to FMT have been well documented, there still is a paucity of data with regard to long-term safety. In this report, we describe the long-term follow-up of the prospective cohort of the first randomized controlled trial of FMT for rCDI, and review the existing literature. A total of 34 patients were treated with FMT for rCDI. Seven patients were still alive after a follow-up of more than 10 years and three patients were lost to follow-up. None of the 34 patients had experienced a new-onset autoimmune, gastrointestinal, or malignant disorder during follow-up. We did not find any deterioration or amelioration of pre-existing medical conditions. Furthermore, no deaths directly attributable to FMT could be identified. These findings are in accordance with the data in available literature. In conclusion, no long-term adverse events or complications directly attributable to FMT were found in our prospective cohort. Review of the available literature does not point to long-term risks associated with FMT in this elderly population, provided that carefully screened fecal suspensions are being used. No firm conclusion on the long-term safety of FMT in younger patients could be drawn. Show less
