Fecal microbiota transplantation (FMT) has been used as a treatmentof last resort for recurrent C. difficile infections (CDI) with a cure rate of 85–90% after the first FMT (van Nood et al., 2013; Jiang et al., 2017). Several studies have examined the changes that occur in the bacterial community that leads to reestablishment of the intestinal microbiota (Fuentes et al., 2014; Seekatz et al., 2014; Staley et al., 2016). However, studies that have investigated the role of viruses in FMT are limited (Broecker et al., 2016a,b, 2017; Ott et al., 2017)

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GENERAL COMMENTARYpublished: 04 April 2018doi: 10.3389/fcimb.2018.00104Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 April 2018 | Volume 8 | Article 104Edited by:Till Strowig,Helmholtz-Zentrum fürInfektionsforschung, GermanyReviewed by:Joseph Sorg,Texas A&M University, United StatesXingmin Sun,University of South Florida,United StatesV. K. Viswanathan,University of Arizona, United States*Correspondence:Blessing O. Anonyeb.anonye@warwick.ac.ukReceived: 25 October 2017Accepted: 19 March 2018Published: 04 April 2018Citation:Anonye BO (2018) Commentary:Bacteriophage transfer during faecalmicrobiota transplantation inClostridium difficile infection isassociated with treatment outcome.Front. Cell. Infect. Microbiol. 8:104.doi: 10.3389/fcimb.2018.00104Commentary: Bacteriophage transferduring faecal microbiotatransplantation in Clostridiumdifficile infection is associated withtreatment outcomeBlessing O. Anonye 1,2*1Microbiology and Infection Unit, Division of Biomedical Sciences, Warwick Medical School, Coventry, United Kingdom,2Warwick Integrative Synthetic Biology Centre, School of Life Sciences, University of Warwick, Coventry, United KingdomKeywords: bacteriophages, gut microbiota, fecal microbiota transplantation, C. difficile infection, CaudoviralesA commentary onBacteriophage transfer during faecal microbiota transplantation in Clostridium difficileinfection is associated with treatment outcomeby Zuo T., Wong S. H., Lam K., Lui R., Cheung K., Tang W., et al. (2017). Gut 67, 634–643.doi: 10.1136/gutjnl-2017-313952Fecal microbiota transplantation (FMT) has been used as a treatmentof last resort for recurrentC. difficile infections (CDI) with a cure rate of 85–90% after the first FMT (van Nood et al., 2013;Jiang et al., 2017). Several studies have examined the changes that occur in the bacterial communitythat leads to reestablishment of the intestinal microbiota (Fuentes et al., 2014; Seekatz et al., 2014;Staley et al., 2016). However, studies that have investigated the role of viruses in FMT are limited(Broecker et al., 2016a,b, 2017; Ott et al., 2017).Recently, Zuo and colleagues performed metagenomics sequencing of virus like particles onfecal samples from patients with CDI and healthy controls to determine if bacteriophages wereassociated with restoration of the intestinal microbiota after FMT (Zuo et al., 2017). Prior toFMT, the patients had increased abundance of Caudovirales with decreased diversity, richness andevenness when compared to healthy controls. Longitudinal studies of patients who received FMT(n = 9) and standard therapy, vancomycin (n = 5) demonstrated that FMT led to the transfer ofviruses from the donor to the recipients (Zuo et al., 2017).The patients that were administered FMT were divided into two groups of “responders” and“non-responders” based on whether they were cured of CDI or recurred after FMT. In particular,after FMT, they noticed a significant decrease in the abundance of Caudovirales and increase inrichness of donor-derived Caudovirales in the enteric virome of the patients (Zuo et al., 2017).There was a correlation between donor viral richness and the patients responding to FMT. Of thetwo-thirds that were cured after FMT, four of the donors had higher Caudovirales richness whencompared to the non-responders group where the donor Caudovirales richness was lower (Zuoet al., 2017).When compared to the non-responders, the remaining two donors had a similar (n= 1for non-responder donor) or slightly higher Caudovirale richness.Furthermore, lower abundance of the family, Microviridae was observed in the patients beforeFMT when compared to the controls but this increased after FMT. Fifteen viral species werefound to be enriched between FMT responders and non-responders. Viral species belonging to theMicroviridae family such as Eel River Basin pequenovirus was the most abundant in the responders(Zuo et al., 2017).Anonye Bacteriophage and C. difficile InfectionMoreover, Zuo et al. performed 16S rRNA gene sequencingto determine changes in the bacterial community and notedincrease in Lachnospiraceae and Ruminococcaceae families (Zuoet al., 2017). However, there was no significant differencebetween donor transferred bacteria between FMT respondersand non-responders. Interestingly, vancomycin treatment hadno significant effect on the viral community (Caudovirales)of those who responded to the antibiotic therapy. However,the bacterial community was significantly affected (Zuo et al.,2017).Broecker et al. investigated the long term bacterial andvirome changes in a patient after FMT for recurrent CDI,and found the virome at several months post-FMT relatedto the donor virome (Broecker et al., 2016a,b). Similarly,Ott and colleagues recently demonstrated that sterilefecal filtrates from donor feces was effective in treatingrecurrent CDI in five patients (Ott et al., 2017). Theyshowed that the “phagebiota” of a recipient at 6 weekspost-FMT was similar to the fecal filtrate from the donor(Ott et al., 2017). These findings indicate that apart fromlive bacteria, other components of the microbiota such asbacteriophages, antimicrobial compounds or metabolitescontribute to reestablishment of the intestinal microbiotain FMT.There is no doubt that bacteriophages play a role in theintestinal microbiota with a potential to alter the compositionand function of the host microbiota. The question is whatconstitutes a healthy gut phageome and how do they influencethe human gut microbiota? Most of the phages in healthyhuman gut microbiota belong to the Caudovirales orderand from the family Microviridae which have double andsingle stranded DNA respectively (Kim et al., 2011; Manriqueet al., 2016). As seen above in recurrent CDI, increaseddiversity, richness and evenness of the Caudovirales wasimplicated in the efficacy of FMT. However, in other intestinaldiseases, it is not clear cut as to the role of Caudoviraleslikely due to other risk factors involved (Norman et al.,2015). For example, Caudovirales richness was observed inpatients with inflammatory bowel disease (Norman et al.,2015).The next question one may be tempted to ask is, how stableis the “phagebiota” in individuals and what are the effectsof antibiotic perturbations on the phageome? Research by Lyet al. showed that transmission of viruses was common betweenmembers of the same household over a 6-month period (Ly et al.,2016). Treatment of healthy individuals living in a particularhousehold with the antibiotics, amoxicillin or azithromycin for7 days did not affect the composition of viruses in the intestinalmicrobiota (Ly et al., 2016).These studies have highlighted the underappreciated roleviruses play in addition to bacterial colonization in the intestinalmicrobiota. However, as individual phages are specific in actiontoward their bacterial host, it would be advantageous to isolatephages that target pathogenic bacteria such as C. difficile,though this is not trivial. Indeed, previous work revealed thatusing a single phage, 8CD27 (Meader et al., 2010, 2013) or acombination of phages led to the inhibition of C. difficile growthin vitro and in vivo (Nale et al., 2016a,b). Recently, a combinationof four phages was found to totally inhibit C. difficile growth ina batch fermentation model spiked with feces from four healthyvolunteers (Nale et al., 2018).Much work remains to be done on phage therapy forC. difficile infection. The ability to develop a synthetic mixture ofphages as treatment for infectious diseases, will go a long way inthis era of antibiotic resistance. Not only will this be beneficial insevere CDI, but could also be useful as a therapy for other diseasesrelated to the intestinal microbiota.AUTHOR CONTRIBUTIONSThe author confirms being the sole contributor of this work andapproved it for publication.FUNDINGBA received a small Warwick Integrative Synthetic Biology(WISB) grant. WISB is a BBSRC/EPSRC Synthetic BiologyResearch Centre (grant ref: BB/M017982/1) funded underthe UK Research Councils’ Synthetic Biology for Growthprogramme.REFERENCESBroecker, F., Klumpp, J., and Moelling, K. (2016a). Long-term microbiota andvirome in a Zürich patient after fecal transplantation against Clostridiumdifficile infection. Ann. N. Y. Acad. Sci. 1372, 29–41. doi: 10.1111/nyas.13100Broecker, F., Klumpp, J., Schuppler, M., Russo, G., Biedermann, L., Hombach,M., et al. (2016b). Long-term changes of bacterial and viral compositionsin the intestine of a recovered Clostridium difficile patient after fecalmicrobiota transplantation. Cold Spring Harb. Mol. Case Stud. 2:a000448.doi: 10.1101/mcs.a000448Broecker, F., Russo, G., Klumpp, J., and Moelling, K. (2017). Stable core viromedespite variable microbiome after fecal transfer. Gut Microbes 8, 214–220.doi: 10.1080/19490976.2016.1265196Fuentes, S., van Nood, E., Tims, S., Heikamp-de Jong, I., ter Braak, C. J., Keller,J. J., et al. (2014). Reset of a critically disturbed microbial ecosystem: faecaltransplant in recurrent Clostridium difficile infection. ISME J. 8, 1621–1633.doi: 10.1038/ismej.2014.13Jiang, Z. D., Ajami, N. J., Petrosino, J. F., Jun, G., Hanis, C. L., Shah,M., et al. (2017).Randomised clinical trial: faecal microbiota transplantation for recurrentClostridum difficile infection – fresh, or frozen, or lyophilised microbiota froma small pool of healthy donors delivered by colonoscopy. Aliment. Pharmacol.Ther. 45, 899–908. doi: 10.1111/apt.13969Kim, M. S., Park, E. J., Roh, S. W., and Bae, J. W. (2011). Diversity and abundanceof single-stranded DNA viruses in human feces. Appl. Environ. Microbiol. 77,8062–8070. doi: 10.1128/aem.06331-11Ly, M., Jones, M. B., Abeles, S. R., Santiago-Rodriguez, T. M., Gao, J., Chan, I. C.,et al. (2016). Transmission of viruses via our microbiomes. Microbiome 4, 64.doi: 10.1186/s40168-016-0212-zManrique, P., Bolduc, B., Walk, S. T., van der Oost, J., de Vos, W. M., and Young,M. J. (2016). Healthy human gut phageome. Proc. Natl. Acad. Sci. U.S.A. 113,10400–10405. doi: 10.1073/pnas.1601060113Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 2 April 2018 | Volume 8 | Article 104Anonye Bacteriophage and C. difficile InfectionMeader, E., Mayer, M. J., Gasson, M. J., Steverding, D., Carding, S. R., and Narbad,A. (2010). Bacteriophage treatment significantly reduces viable Clostridiumdifficile and prevents toxin production in an in vitro model system. Anaerobe16, 549–554. doi: 10.1016/j.anaerobe.2010.08.006Meader, E., Mayer, M. J., Steverding, D., Carding, S. R., and Narbad, A. (2013).Evaluation of bacteriophage therapy to control Clostridium difficile and toxinproduction in an in vitro human colon model system. Anaerobe 22, 25–30.doi: 10.1016/j.anaerobe.2013.05.001Nale, J. Y., Chutia, M., Carr, P., Hickenbotham, P. T., and Clokie, M. R. 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H., Rehman, A., Moltzau-Anderson, J., Bharti, R., Grasis,J. A., et al. (2017). Efficacy of sterile fecal filtrate transfer for treating patientswith Clostridium difficile Infection. Gastroenterology 152, 799.e797–811.e797.doi: 10.1053/j.gastro.2016.11.010Seekatz, A. M., Aas, J., Gessert, C. E., Rubin, T. A., Saman, D. M., Bakken, J.S., et al. (2014). Recovery of the gut microbiome following fecal microbiotatransplantation.MBio 5:e00893-14. doi: 10.1128/mBio.00893-14Staley, C., Kelly, C. R., Brandt, L. J., Khoruts, A., and Sadowsky, M. J. (2016).Complete microbiota engraftment is not essential for recovery from recurrentClostridium difficile infection following fecal microbiota transplantation.MBio7:e01965-16. doi: 10.1128/mBio.01965-16van Nood, E., Vrieze, A., Nieuwdorp, M., Fuentes, S., Zoetendal, E. G., deVos, W. M.,et al. (2013). Duodenal infusion of donor feces for recurrentClostridium difficile. N. Engl. J. Med. 368, 407–415. doi: 10.1056/NEJMoa1205037Zuo, T., Wong, S. H., Lam, K., Lui, R., Cheung, K., Tang, W., et al. (2017).Bacteriophage transfer during faecal microbiota transplantation in Clostridiumdifficile infection is associated with treatment outcome. Gut 67, 634–643.doi: 10.1136/gutjnl-2017-313952Conflict of Interest Statement: The author declares that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2018 Anonye. This is an open-access article distributed under the termsof the Creative Commons Attribution License (CC BY). The use, distribution orreproduction in other forums is permitted, provided the original author(s) and thecopyright owner are credited and that the original publication in this journal is cited,in accordance with accepted academic practice. No use, distribution or reproductionis permitted which does not comply with these terms.Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 3 April 2018 | Volume 8 | Article 104

Commentary : Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome

Blessing O. Anonye

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