INTRODUCTION: Patients with ulcerative colitis (UC) have a less diverse microbiome than healthy subjects. Multiple studies have evaluated fecal microbiota transfer (FMT) in these patients using different methods of product preparation, doses, and routes of administration. A systematic review and meta-analysis was performed to compare the efficacy of single-donor (SDN) and multidonor (MDN) strategies for product preparation. METHODS: Systematic searches were performed in Web of Science, Scopus, PubMed, and Orbit Intelligence for studies comparing FMT products manufactured using SDN or MDN strategies to placebo in patients with UC. Fourteen controlled studies were selected for meta-analysis (10 randomized and 4 nonrandomized). The treatment response was assessed by using fixed- and random-effects models, and the significance of the indirect difference between the interventions was assessed using a network approach. RESULTS: Considering all 14 studies, MDN and SDN were superior to placebo in terms of treatment response (risk ratios [RRs]: 4.41 and 1.57, respectively [P ≤ 0.001 for both]), and MDN was superior to SDN (RR: 2.81, P = 0.005). Meta-analysis of the 10 studies with high quality of evidence showed that MDN was superior to SDN in terms of treatment response (RR: 2.31, P = 0.042). Results were identical for both models. DISCUSSION: There was a significant clinical benefit (remission) for patients with UC who received FMT with products manufactured by MDN strategies. Reduction of donor effect may lead to a gain in microbial diversity that could improve response to treatment. These results may have implications in the treatment approach of other diseases amenable to microbiome manipulation. JOURNAL/cltg/04.03/01720094-202305000-00002/2FFU1/v/2023-08-14T034823Z/r/image-tiff

ABSTRACT Growing evidence demonstrates the key role of the gut microbiota in human health and disease. The recent success of microbiotherapy products to treat recurrent Clostridioides difficile infection has shed light on its potential in conditions associated with gut dysbiosis, such as acute graft-versus-host disease, intestinal bowel diseases, neurodegenerative diseases, or even cancer. However, the difficulty in defining a “good” donor as well as the intrinsic variability of donor-derived products’ taxonomic composition limits the translatability and reproducibility of these studies. Thus, the pooling of donors’ feces has been proposed to homogenize product composition and achieve higher taxonomic richness and diversity. In this study, we compared the metagenomic profile of pooled products to corresponding single donor-derived products. We demonstrated that pooled products are more homogeneous, diverse, and enriched in beneficial bacteria known to produce anti-inflammatory short chain fatty acids compared to single donor-derived products. We then evaluated pooled products’ efficacy compared to corresponding single donor-derived products in Salmonella and C. difficile infectious mouse models. We were able to demonstrate that pooled products decreased pathogenicity by inducing a structural change in the intestinal microbiota composition. Single donor-derived product efficacy was variable, with some products failing to control disease progression. We further performed in vitro growth inhibition assays of two extremely drug-resistant bacteria, Enterococcus faecium vanA and Klebsiella pneumoniae oxa48, supporting the use of pooled microbiotherapies. Altogether, these results demonstrate that the heterogeneity of donor-derived products is corrected by pooled fecal microbiotherapies in several infectious preclinical models. IMPORTANCE Growing evidence demonstrates the key role of the gut microbiota in human health and disease. Recent Food and Drug Administration approval of fecal microbiotherapy products to treat recurrent Clostridioides difficile infection has shed light on their potential to treat pathological conditions associated with gut dysbiosis. In this study, we combined metagenomic analysis with in vitro and in vivo studies to compare the efficacy of pooled microbiotherapy products to corresponding single donor-derived products. We demonstrate that pooled products are more homogeneous, diverse, and enriched in beneficial bacteria compared to single donor-derived products. We further reveal that pooled products decreased Salmonella and Clostridioides difficile pathogenicity in mice, while single donor-derived product efficacy was variable, with some products failing to control disease progression. Altogether, these findings support the development of pooled microbiotherapies to overcome donor-dependent treatment efficacy.

Les infections ostéo-articulaires (IOA) nécessitent souvent un traitement antibiotique à forte dose prolongé 6 à 12 semaines. L’impact d’une telle exposition aux antibiotiques sur le microbiote intestinal n’a jamais été évaluée. Nous avons constitué une cohorte nationale prospective observationnelle multicentrique de patients avec une IOA pour évaluer la dynamique de la composition du microbiote intestinal et l’apparition de résistance au cours et à l’issue du traitement antibiotique. Les données cliniques ainsi qu’un prélèvement de selles ont été recueillis dans les 24 h avant le début des antibiotiques (I), à la fin du traitement (FT) et 2 semaines après l’arrêt de l’antibiotique (S). La composition du microbiote a été déterminée par séquençage métagénomique Shot-Gun. Les marqueurs biologiques de l’inflammation systémique et intestinale ont également été évalués aux différents temps. Soixante-deux patients ont été inclus : 27 IOA natives, 14 IOA sur matériel d’ostéosynthèse (IMO) et 21 infections de prothèses (IP). À FT, la diversité du microbiote intestinale (alpha-diversité) était significativement diminuée quel que soit la durée de traitement, les antibiotiques utilisées ou le type d’IOA. Deux semaines après l’arrêt des antibiotiques, l’alpha-diversité du microbiote retrouvait un niveau semblable à celui de la visite initiale chez les patients atteints d’IP et d’IOA natives, mais pas chez les patients avec IMO ( p < 0,05, test de Wilcoxon). L’analyse en composantes principales (PCoA) de la distance de Bray Curtis, a montré une modification significative de la composition du microbiote intestinal à la fin du traitement ( p < 0,01, PERMANOVA) avec une récupération significative dès 15 jours post-traitement (S) et une composition alors semblable à celle pré-traitement. L’analyse taxonomique au niveau du genre a montré que cette résilience observée dans la composition du microbiote à S ne différait pas significativement entre les patients traités pendant 6 semaines et ceux traités pendant 12 semaines. Il n’y avait également pas de différence significative en terme de colonisation par bactéries multi-résistantes ou d’infection à C . difficile suivant la durée de traitement. Aucun antibiotique particulier (notamment les fluoroquinolones) n’a été associé à une perte accrue d’alpha-diversité ou à une dynamique de récupération distincte du microbiote intestinal en fin de traitement. L’analyse PCoA de la distance de Bray Curtis montrait que les patients présentant un taux plasmatique élevé de CRP (≥ 5 mg/L) à FT, sans argument pour une récidive de l’IOA, avaient un microbiote intestinal distinct par rapport aux autres. Le niveau de CRP à FT était corrélé à des marqueurs d’inflammation colique augmentés (néoptérine, Pearson r 2 = 0.32, p < 0,0007). La durée de traitement antibiotique entre 6 et 12 semaines n’influe pas sur les modifications microbiologiques et la récupération précoce de la composition du microbiote intestinal en fin de traitement dans les IOA. Un syndrome inflammatoire biologique persistant sans argument pour une récidive de l’IOA à l’arrêt du traitement était associé à une altération du microbiote intestinal.

There is a growing interest in the potentially deleterious impact of antibiotics on gut microbiota. Patients with bone and joint infection (BJI) require prolonged treatment that may impact significantly the gut microbiota. We collected samples from patients with BJI at baseline, end of antibiotics (EOT), and 2 weeks after antibiotic withdrawal (follow-up, FU) in a multicenter prospective cohort in France. Microbiota composition was determined by shotgun metagenomic sequencing. Fecal markers of gut permeability and inflammation as well as multi-drug-resistant bacteria (MDRB) and Clostridioides difficile carriage were assessed at each time point. Sixty-two patients were enrolled: 27 native BJI, 14 osteosynthesis-related BJI, and 21 prosthetic joint infections (PJI). At EOT, there was a significant loss of alpha-diversity that recovered at FU in patients with native BJI and PJI, but not in patients with osteosynthesis-related BJI. At EOT, we observed an increase of Proteobacteria and Bacteroidetes that partially recovered at FU. The principal component analysis (PCoA) of the Bray–Curtis distance showed a significant change of the gut microbiota at the end of treatment compared to baseline that only partially recover at FU. Microbiota composition at FU does not differ significantly at the genus level when comparing patients treated for 6 weeks vs. those treated for 12 weeks. The use of fluoroquinolones was not associated with a lower Shannon index at the end of treatment; however, the PCoA of the Bray–Curtis distance showed a significant change at EOT, compared to baseline, that fully recovered at FU. Levels of fecal neopterin were negatively correlated with the Shannon index along with the follow-up (r2 = 0.17; p < 0.0001). The PCoA analysis of the Bray–Curtis distance shows that patients with an elevated plasma level of C-reactive protein (≥5 mg/L) at EOT had a distinct gut microbial composition compared to others. MDRB and C. difficile acquisition at EOT and FU represented 20% (7/35) and 37.1% (13/35) of all MDRB/C. difficile-free patients at the beginning of the study, respectively. In patients with BJI, antibiotics altered the gut microbiota diversity and composition with only partial recovery, mucosal inflammation, and permeability and acquisition of MDRB carriage. Microbiome interventions should be explored in patients with BJI to address these issues.

Abstract Background There is growing interest about the deleterious impact of antibiotics on loss of gut symbiosis, called dysbiosis. As patients with BJI require antibiotics usually during 6 to 12 weeks, it is of interest to determine whether dysbiosis is frequent in this population, and if it could potentially reversible or not. Methods Multicentric prospective cohort study in France (EudraCT 2016-003247-10) including patients with 3 categories of BJI: native, osteosynthesis-related and prosthetic joint infection (PJI). At the time of suspicion (V1), at the end of therapy (V2) and then 2 weeks after stopping therapy (V3), blood and fecal samples were collected. Extracted DNA from stool was sequenced using shotgun metagenomic sequencing based on illumina library and Iseq instrumentation. Data run through a dedicated pipeline in order to produce microbiome indexes such as Sympson or Shannon diversities indexes. Gut microbiome and inflammation markers were analyzed including fecal neopterin, a maker of gut inflammation. Results Concerning the 62 patients included (mean age, 60 years; mean duration of antibiotics, 66 days), 27 had native, 14 had osteosynthesis and 21 had PJI. The most frequently prescribed drug was a fluoroquinolone, followed by a third-generation cephalosporin and vancomycin. Stools from 42 of them were analyzed as per protocol. Overall, the mean Shannon richness index decreased from 0.904 at V1 to 0.845 at V2; the Bray-Curtis index underlined the difference in microbiome reconstitution at V3 in comparison with V1. We report significant microbiome loss of diversity at V2, that was reversible at V3 in patients with native BJI and osteosynthesis-related BJI, but not in patients with PJI (figure). Fecal neopterin increased between V1 and V2 (mean 221.6 and 698.1 pmol/g of feces, respectively) and then decreased at V3 (422.5 pmol/g), and could be a potential surrogate marker of gut dysbiosis. Of note, patients with abnormal CRP at the end of antibiotics had high neopterin values, that raises the hypothesis that abnormal CRP at the end of antibiotics could be in relation with gut dysbiosis rather than uncured BJI. Conclusion The impact of antibiotics on the gut microbiota of patients with BJI seems to be significant, especially in patients with PJI who could be candidate for fecal microbiota transplantation. Disclosures All authors: No reported disclosures.

The intestinal microbiota is the reservoir for most multidrug-resistant bacterial pathogens (MDRB, such as extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenemase-producing Enterobacteriaceae, and vancomycin-resistant enterococci) that can be involved in infections. One of the most interesting properties exerted by our intestinal microbiota is colonization resistance, also referred to as the barrier effect [[1]Buffie C.G. Pamer E.G. Microbiota-mediated colonization resistance against intestinal pathogens.Nat Rev Immunol. 2013; 13: 790-801Crossref PubMed Scopus (832) Google Scholar] (Fig. 1). Colonization resistance is defined by the capacity of the intestinal microbiota to prevent durable colonization by exogenous bacteria (including the MDR ones) via direct pathways (bacteriocins and competition for nutrients) and/or close collaboration with the host immune system. The commensal bacteria of the intestine exert essential functions for their host, among them production of vitamins, differentiation of intestinal epithelial cells, and degradation of toxin precursors. While there is no consensus yet to qualify a healthy microbiota, dysbiosis could be defined as an alteration of the balanced dialogue between the host and gut bacteria. Hence, even slight differences in the abundance of healthy gut bacteria have been implicated in diverse systemic diseases with structural functions (mucous layer maturation and immunoglobulin A production) and immunoprotection (colonization resistance, mucosal innate and adaptive immunity, and inflammatory cytokine oversite) [[2]Grenham S. Clarke G. Cryan J.F. Dinan T.G. Brain-gut-microbe communication in health and disease.Front Physiol. 2011; 2: 94Crossref PubMed Scopus (629) Google Scholar]. Antibiotic exposure potentially alters the microbiota, favouring the settlement and growth of resistant bacteria over the susceptible ones [[3]Lankelma J.M. van Vught L.A. Belzer C. Schultz M.J. van der Poll T. de Vos W.M. et al.Critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation: a pilot study.Intens Care Med. 2017; 43: 59-68Crossref PubMed Scopus (137) Google Scholar], which could in turn increase the risk of infections [[4]Ruppé E. Lixandru B. Cojocaru R. Büke C. Paramythiotou E. Angebault C. et al.Relative fecal abundance of extended-spectrum-β-lactamase-producing Escherichia coli strains and their occurrence in urinary tract infections in women.Antimicrob Agents Chemother. 2013; 57: 4512-4517Crossref PubMed Scopus (76) Google Scholar] and dissemination of MDRB in the environment [[5]Lerner A. Adler A. Abu-Hanna J. Percia S.C. Matalon M.K. Carmeli Y. Spread of KPC-producing carbapenem-resistant Enterobacteriaceae: the importance of super-spreaders and rectal KPC concentration.Clin Microbiol Infect. 2015; 21: 470.e1-470.e7Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. Dysbiosis might be associated with poor outcome in ICU patients [[6]Wischmeyer P.E. McDonald D. Knight R. Role of the microbiome, probiotics, and “dysbiosis therapy” in critical illness.Curr Opin Crit Care. 2016; 22: 347-353Crossref PubMed Scopus (108) Google Scholar]. While the composition of the microbiota seems to be restored a couple of weeks after antibiotic exposure, it appears to be slightly different from the pre-antibiotic one [[7]de Gunzburg J. Ghozlane A. Ducher A. Le Chatelier E. Duval X. Ruppé E. et al.Protection of the human gut microbiome from antibiotics.J Infect Dis. 2018; 217: 628-636Crossref PubMed Scopus (85) Google Scholar]. Accordingly, re-establishing the functions of the intestinal microbiota after antibiotic exposure appears to be a promising lead to prevent a high burden of colonization with MDRB and possibly to improve patient outcome [[8]Wei Y. Yang J. Wang J. Yang Y. Huang J. Gong H. et al.Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis.Crit Care. 2016; 20: 332Crossref PubMed Scopus (85) Google Scholar]. Faecal microbiota transplantation (FMT) consists of administering faecal material from a healthy donor into the intestinal tract of a patient with an altered gut microbiota to restore its functions. Clinicians' interest in this treatment was renewed in 2013 with publication of the results of a randomized control trial showing the substantial superiority of FMT over standard care in the treatment of recurrent Clostridium difficile infections (CDI) [[9]van Nood E. Vrieze A. Nieuwdorp M. Fuentes S. Zoetendal E.G. de Vos W.M. et al.Duodenal infusion of donor feces for recurrent Clostridium difficile.N Engl J Med. 2013; 368: 407-415Crossref PubMed Scopus (2564) Google Scholar]. Today in healthcare structures that harbour a FMT supply chain [[10]Terveer E.M. van Beurden Y.H. Goorhuis A. Seegers J.F.M.L. Bauer M.P. van Nood E. et al.How to: establish and run a stool bank.Clin Microbiol Infect. 2017; 23: 924-930Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar], FMT has become the treatment of choice in recurrent CDI [[11]Cammarota G. Ianiro G. Tilg H. Rajilić-Stojanović M. Kump P. Satokari R. et al.European consensus conference on faecal microbiota transplantation in clinical practice.Gut. 2017; 66: 569-580Crossref PubMed Scopus (625) Google Scholar]. As for other possible indications, FMT was shown to be effective in ulcerative colitis, but to a lesser extent than in CDI [12Paramsothy S. Kamm M.A. Kaakoush N.O. Walsh A.J. van den Bogaerde J. Samuel D. et al.Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.Lancet. 2017; 389: 1218-1228Abstract Full Text Full Text PDF PubMed Scopus (730) Google Scholar, 13Young V.B. Therapeutic manipulation of the microbiota: past, present, and considerations for the future.Clin Microbiol Infect. 2016; 22: 905-909Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. Interestingly, in several cases where FMT was used in the context of recurrent CDI, authors observed the intestinal clearance of MDRB [[14]Manges A.R. Steiner T.S. Wright A.J. Fecal microbiota transplantation for the intestinal decolonization of extensively antimicrobial-resistant opportunistic pathogens: a review.Infect Dis. 2016; 48: 587-592Crossref PubMed Scopus (87) Google Scholar], likely through re-establishment of CR-driving intestinal bacteria. Two recent single-centre studies suggest that FMT could be an effective means to decrease MDRB carriage [15Bilinski J. Grzesiowski P. Sorensen N. Madry K. Muszynski J. Robak K. et al.Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study.Clin Infect Dis. 2017; 65: 364-370Crossref PubMed Scopus (177) Google Scholar, 16Dinh A. Fessi H. Duran C. Batista R. Michelon H. Bouchand F. et al.Clearance of carbapenem-resistant Enterobacteriaceae vs vancomycin-resistant enterococci carriage after faecal microbiota transplant: a prospective comparative study.J Hosp Infect. 2018; (pii: S0195-6701(18)30111-7. [Epub ahead of print])https://doi.org/10.1016/j.jhin.2018.02.018Abstract Full Text Full Text PDF Scopus (52) Google Scholar]. Given the results obtained with CDI and the preliminary data on the eradication of MDRB, using FMT where both the antibiotic pressure and the risk of infections are high, such as in ICUs, is an appealing solution to limit the circulation of intestinal MDRB and to prevent or cure CDI. Indeed, the faecal transplants selected for FMT are devoid from MDRB pathogens, and FMT is expected to lower the intestinal concentrations of MDRB or even eradicate them from the gut, thereby lowering the risks of infections caused by MDRB and the risk of cross-transmission. This could trigger a virtuous circle where there is less MDRB intestinal colonization, fewer drug-resistant infections, a lower consumption of broad-spectrum antibiotics, a better prognosis, and a shorter length of stay for the patient (Fig. 1). Then, what are the issues that need to be tackled before using FMT in an ICU setting? First, a choice has to be made between autologous versus heterologous FMT. Autologous FMT comes with the advantage of preventing the transmission of putative pathogens which were undetected during the screening process of heterologous transplants. It may be suitable for patients with no previous alteration of the intestinal microbiota, such as patients scheduled for chemotherapy for cancer or prolonged antimicrobial therapy. Yet as for ICU patients, they have often taken antibiotics before their admission and their intestinal microbiota may already be altered. Moreover, recovering enough faeces for autologous FMT during the first days of admission would be challenging. Hence, we believe that in the specific context of ICU, FMT should be performed with heterologous donors to ensure the unaltered composition of the transplant. Another challenge is to set up a safe supply chain of faecal transplant material [[10]Terveer E.M. van Beurden Y.H. Goorhuis A. Seegers J.F.M.L. Bauer M.P. van Nood E. et al.How to: establish and run a stool bank.Clin Microbiol Infect. 2017; 23: 924-930Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. Obtaining donor transplant material may not be easy, but in the ICU context we may assume that relatives of the patients would be more willing to donate. Nonetheless, they would still have to pass the exhaustive and time-consuming clinical and biological screening tests requested for donation [[11]Cammarota G. Ianiro G. Tilg H. Rajilić-Stojanović M. Kump P. Satokari R. et al.European consensus conference on faecal microbiota transplantation in clinical practice.Gut. 2017; 66: 569-580Crossref PubMed Scopus (625) Google Scholar]. Then, the hospital should harbour or be in relation with a laboratory trained in the preparation of FMT with good manufacturing practices (GMP) standards. Of note, frozen transplants have been shown to be as effective as fresh transplants [[17]Lee C.H. Steiner T. Petrof E.O. Smieja M. Roscoe D. Nematallah A. et al.Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: a randomized clinical trial.JAMA. 2016; 315: 142-149Crossref PubMed Scopus (453) Google Scholar], which would considerably ease the overall logistics of the process. The route of administration does not seem to significantly affect efficacy and safety of FMT (with regards to CDI). Two gastrointestinal routes can be considered: the upper route (oral (with capsules), naso-gastric or naso-duodenal) and the lower route (enema or colonoscopy). FMT has mostly been performed via nasogastric tubes which are commonly used in intubated patients, but the risk of reflux or vomiting in such patients cannot be ruled out [[18]Nseir S. Zerimech F. Fournier C. Lubret R. Ramon P. Durocher A. et al.Continuous control of tracheal cuff pressure and microaspiration of gastric contents in critically ill patients.Am J Respir Crit Care Med. 2011; 184: 1041-1047Crossref PubMed Scopus (173) Google Scholar]. Accordingly, the lower route would be more appropriate for ICU patients. Indeed, administration of FMT by colonoscopy has been successfully performed in patients with severe CDI without significant adverse effects such as intestinal perforation [19Cammarota G. Ianiro G. Magalini S. Gasbarrini A. Gui D. Decrease in surgery for Clostridium difficile infection after starting a program to transplant fecal microbiota.Ann Intern Med. 2015; 163: 487-488Crossref PubMed Scopus (43) Google Scholar, 20Fischer M. Sipe B. Cheng Y.-W. Phelps E. Rogers N. Sagi S. et al.Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: a promising treatment approach.Gut Microbes. 2017; 8: 289-302Crossref PubMed Scopus (111) Google Scholar]. Nonetheless, ICU patients may not be able to retain the transplant when using enema, therefore colonoscopy would be required to administer the transplant in the most proximal parts of the colon. An intermediate solution could be administration of the transplant via a flexible Foley catheter up into the transverse colon as recommended for administration of vancomycin in patients with severe CDI [[21]Gerding D.N. Muto C.A. Owens R.C. Treatment of Clostridium difficile infection.Clin Infect Dis. 2008; 46: S32-S42Crossref PubMed Scopus (249) Google Scholar]. Yet, safe and efficient administration of faecal material via a Foley catheter remains to be assessed. Who should benefit from FMT? As FMT is aimed at restoring the functions of the microbiota after an alteration, we believe that eligible patients should be those having received antibiotics, possibly even before admission to the ICU. Conversely, patients in whom FMT should not be used as of now should be patients having abdominal surgery and septic shock until FMT is demonstrated to be safe in these contexts. When should FMT be performed in the ICU? As antibiotics would destroy the transplant, it would make sense to start performing FMT after discontinuation of antibiotics. Indeed, FMT was shown to be less efficient for eradication of MDRB when patients were exposed to antibiotics in the week after [[15]Bilinski J. Grzesiowski P. Sorensen N. Madry K. Muszynski J. Robak K. et al.Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study.Clin Infect Dis. 2017; 65: 364-370Crossref PubMed Scopus (177) Google Scholar] or within 8 weeks after FMT [[22]Allegretti J.R. Kao D. Sitko J. Fischer M. Kassam Z. Early antibiotic use after fecal microbiota transplantation increases risk of treatment failure.Clin Infect Dis. 2018; 66: 134-135Crossref PubMed Scopus (31) Google Scholar]. Yet, as ICU patients are frequently receiving antibiotic treatments, FMT would only be feasible during a fraction of the stay. During antibiotic therapy, the patient would remain at risk for MDRB acquisition, infection, and cross-transmission. Besides, ICU patients would have more severe and complicated CDI infections and more antecedents of CDI, which are both risk factors for inefficacy of a single FMT [20Fischer M. Sipe B. Cheng Y.-W. Phelps E. Rogers N. Sagi S. et al.Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: a promising treatment approach.Gut Microbes. 2017; 8: 289-302Crossref PubMed Scopus (111) Google Scholar, 23Ianiro G. Valerio L. Masucci L. Pecere S. Bibbò S. Quaranta G. et al.Predictors of failure after single faecal microbiota transplantation in patients with recurrent Clostridium difficile infection: results from a 3-year, single-centre cohort study.Clin Microbiol Infect. 2017; 23: 337.e1-337.e3Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. Hence, iterative FMT for ICU patients could be required to address both the antibiotic exposure and the treatment of severe CDI, questioning the availability of a sufficient number of faecal transplants. Lastly, what about the safety of FMT? The occurrence of adverse effects following FMT in non-ICU patients was recently reviewed [[24]Wang S. Xu M. Wang W. Cao X. Piao M. Khan S. et al.Systematic review: adverse events of fecal microbiota transplantation.PLoS One. 2016; 11Google Scholar]. Briefly, adverse events (AEs) after FMT seem to occur more often when FMT is given via the upper route (43.6%) than via the lower route (17.7%), with the most common AEs being abdominal discomfort and transient fever. Conversely, serious adverse effects (including death, infections, irritable bowel disease flare, auto-immune diseases and FMT procedure related injury) seem to occur more often when the FMT is given via the lower route (6.1%) than via the upper route (2.0%). Death after FMT has been reported in up to 3.5% of patients, but the attributable role of FMT is certain in only one case (aspiration pneumonia [[25]Kelly C.R. Ihunnah C. Fischer M. Khoruts A. Surawicz C. Afzali A. et al.Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients.Am J Gastroenterol. 2014; 109: 1065-1071Crossref PubMed Scopus (464) Google Scholar]). To date, possible long-term effects of FMT remain unexplored. In conclusion, preliminary data from non-ICU patients support the evaluation of FMT in critically ill patients. Currently, 151 active trials are listed by clinicaltrials.gov (update May 2018) using FMT in multiple conditions, with seven of those aiming at further investigating its use for prevention or recovery of intestinal carriage of MDRB. To the best of our knowledge, none of them targets specifically ICU patients. Various concerns specific to ICU patients are raised in addition to other unanswered questions regarding FMT itself (e.g. transmission of pathogens, dose, route, and long-term safety). However, we believe that the potential benefits from FMT (with regards to the control of MDRB and CDI) now justify investigating this promising approach in ICU patients. ER, AR, IML, TF and JFT are consultant for MaaT Pharma. BL is an employee of MaaT Pharma. We thank Cyrielle Gasc, Corentin Le Camus (MaaT Pharma, Lyon, France) and Joël Doré (INRA, Jouy-en-Josas, France) for helpful discussions and careful reading.