{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:26:24Z","timestamp":1791462384057,"version":"4.3.4"},"reference-count":42,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Clean Cells","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Introduction: The growing resistance of bacteria to antibiotics is a major global public health concern. An important reservoir of this resistance is the gut microbiota. However, limited data are available on the ability of phage therapy to reduce the digestive carriage of multidrug-resistant bacteria. Materials and methods: Four novel lytic phages were isolated in vitro for efficacy against an extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli strain also resistant to carbapenems through a carbapenemase OXA-48. The first step was to develop models of ESBL E. coli digestive carriage in mice. The second step was to test the efficacy of an oral and rectal phage therapy (a cocktail of four phages or microencapsulated phage) to reduce this carriage. Results: The two most intense models of digestive carriage were obtained by administering amoxicillin (0.5 g\u00b7L\u22121) continuously in the drinking water (Model 1) or pantoprazole (0.1 g\u00b7L\u22121) continuously in the drinking water, combined with amoxicillin (0.5 g\u00b7L\u22121), for the first 8 days (Model 2). Oral administration of the phage cocktail to Model 1 resulted in a transient reduction in the concentration of ESBL E. coli in the faeces 9 days after the bacterial challenge (median = 5.33 \u00d7 108 versus 2.76 \u00d7 109 CFU\u00b7g\u22121, p = 0.02). In contrast, in Model 2, oral or oral + rectal administration of this cocktail did not alter the bacterial titre compared to the control (area under the curve, AUC, 3.49 \u00d7 109; 3.41 \u00d7 109 and 3.82 \u00d7 109 for the control, oral and oral + rectal groups, respectively; p-value &gt; 0.8 for each two-by-two group comparison), as well as the administration of an oral microencapsulated phage in Model 1 (AUC = 8.93 \u00d7 109 versus 9.04 \u00d7 109, p = 0.81). Conclusions: Oral treatment with amoxicillin promoted digestive carriage in mice, which was also the case for the addition of pantoprazole. However, our study confirms the difficulty of achieving efficacy with phage therapy to reduce multidrug-resistant bacterial digestive carriage in vivo.<\/jats:p>","DOI":"10.3390\/microorganisms9122580","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T01:22:05Z","timestamp":1639444925000},"page":"2580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Impact of Phage Therapy on Multidrug-Resistant Escherichia coli Intestinal Carriage in a Murine Model"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7728-2320","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Javaudin","sequence":"first","affiliation":[{"name":"MiHAR Laboratary, EE1701, University of Nantes, 44200 Nantes, France"},{"name":"Emergency Department, Nantes University Hospital, 44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5892-2946","authenticated-orcid":false,"given":"Pascale","family":"B\u00e9mer","sequence":"additional","affiliation":[{"name":"MiHAR Laboratary, EE1701, University of Nantes, 44200 Nantes, France"},{"name":"Department of Bacteriology, Nantes University Hospital, 44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Batard","sequence":"additional","affiliation":[{"name":"MiHAR Laboratary, EE1701, University of Nantes, 44200 Nantes, France"},{"name":"Emergency Department, Nantes University Hospital, 44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2313-1172","authenticated-orcid":false,"given":"Emmanuel","family":"Montassier","sequence":"additional","affiliation":[{"name":"MiHAR Laboratary, EE1701, University of Nantes, 44200 Nantes, France"},{"name":"Emergency Department, Nantes University Hospital, 44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,13]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2021, November 07). Global Priority List of Antibiotic-Resistant Bacteria to Guide Researach, Discovery and Development of New Antibiotics. Available online: https:\/\/www.who.int\/medicines\/publications\/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S209","DOI":"10.1093\/infdis\/jiaa497","article-title":"The gut microbiome as a reservoir for antimicrobial resistance","volume":"223","author":"Anthony","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3389\/fmicb.2013.00087","article-title":"The human microbiome as a reservoir of antimicrobial resistance","volume":"4","author":"Penders","year":"2013","journal-title":"Front. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41385-018-0053-0","article-title":"Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them","volume":"12","author":"Sorbara","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1128\/AAC.50.4.1257-1262.2006","article-title":"Clinical and economic impact of bacteremia with extended- spectrum-beta-lactamase-producing Enterobacteriaceae","volume":"50","author":"Schwaber","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijid.2015.07.010","article-title":"Prevalence, risk factors, and impact on clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteraemia: A five-year study","volume":"39","author":"Denis","year":"2015","journal-title":"Int. J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/jac\/dkq412","article-title":"Burden of antimicrobial resistance in European hospitals: Excess mortality and length of hospital stay associated with bloodstream infections due to Escherichia coli resistant to third-generation cephalosporins","volume":"66","author":"Wolkewitz","year":"2011","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13756-020-0685-1","article-title":"The role of hospital environment in transmissions of multidrug-resistant gram-negative organisms","volume":"9","author":"Chia","year":"2020","journal-title":"Antimicrob. Resist. Infect. Control."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.cmi.2019.01.005","article-title":"ESCMID-EUCIC clinical guidelines on decolonization of multidrug-resistant Gram-negative bacteria carriers","volume":"25","author":"Tacconelli","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1057\/s41599-020-0478-4","article-title":"Phage therapy as a potential solution in the fight against AMR: Obstacles and possible futures","volume":"6","author":"Brives","year":"2020","journal-title":"Palgrave Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/1462-2920.13574","article-title":"Oral application of Escherichia coli bacteriophage: Safety tests in healthy and diarrheal children from Bangladesh","volume":"19","author":"Sarker","year":"2017","journal-title":"Environ. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Divya Ganeshan, S., and Hosseinidoust, Z. (2019). Phage therapy with a focus on the human microbiota. Antibiotics, 8.","DOI":"10.3390\/antibiotics8030131"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1128\/MMBR.00016-10","article-title":"Origins and evolution of antibiotic resistance","volume":"74","author":"Davies","year":"2010","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrmicro2315","article-title":"Bacteriophage resistance mechanisms","volume":"8","author":"Labrie","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1111\/1462-2920.13284","article-title":"Bacteriophages to reduce gut carriage of antibiotic resistant uropathogens with low impact on microbiota composition","volume":"18","author":"Galtier","year":"2016","journal-title":"Environ. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vinner, G.K., Richards, K., Leppanen, M., Sagona, A.P., and Malik, D.J. (2019). Microencapsulation of enteric bacteriophages in a pH-Responsive solid oral dosage formulation using a scalable membrane emulsification process. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11090475"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3905","DOI":"10.1128\/AAC.00522-06","article-title":"Suppression of gastric acid production by proton pump inhibitor treatment facilitates colonization of the large intestine by vancomycin-resistant Enterococcus spp. and Klebsiella pneumoniae in clindamycin-treated mice","volume":"50","author":"Stiefel","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.virol.2009.03.009","article-title":"T4 phages against Escherichia coli diarrhea: Potential and problems","volume":"388","author":"Denou","year":"2009","journal-title":"Virology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1128\/AAC.02782-14","article-title":"Gastrointestinal colonization with a cephalosporinase-producing bacteroides species preserves colonization resistance against vancomycin-resistant enterococcus and Clostridium difficile in cephalosporin-treated mice","volume":"58","author":"Stiefel","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6139","DOI":"10.1128\/AAC.03021-14","article-title":"Antibiotic selection of Escherichia coli sequence type 131 in a mouse intestinal colonization model","volume":"58","author":"Hertz","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1001\/jamainternmed.2020.0009","article-title":"Evaluation of the association between gastric acid suppression and risk of intestinal colonization with multidrug-resistant microorganisms: A systematic review and meta-analysis","volume":"180","author":"Willems","year":"2020","journal-title":"JAMA Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1136\/gutjnl-2015-310376","article-title":"Proton pump inhibitors affect the gut microbiome","volume":"65","author":"Imhann","year":"2016","journal-title":"Gut"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/apt.14451","article-title":"Systematic review: Human gut dysbiosis induced by non-antibiotic prescription medications","volume":"47","author":"Chapelet","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1111\/j.1462-2920.2011.02644.x","article-title":"Intestinal colonization by enteroaggregative Escherichia coli supports long-term bacteriophage replication in mice","volume":"14","author":"Maura","year":"2012","journal-title":"Environ. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.virol.2009.07.020","article-title":"In vivo replication of T4 and T7 bacteriophages in germ-free mice colonized with Escherichia coli","volume":"393","author":"Weiss","year":"2009","journal-title":"Virology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1128\/AAC.48.7.2558-2569.2004","article-title":"In vitro and in vivo bacteriolytic activities of Escherichia coli phages: Implications for phage therapy","volume":"48","author":"Sidoti","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1263\/jbb.100.280","article-title":"Therapeutic use of phage cocktail for controlling Escherichia coli O157:H7 in gastrointestinal tract of mice","volume":"100","author":"Tanji","year":"2005","journal-title":"J. Biosci. Bioeng."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.3389\/fmicb.2019.01984","article-title":"Bacteriophages reduce pathogenic escherichia coli counts in mice without distorting gut microbiota","volume":"10","author":"Dissanayake","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6235","DOI":"10.1128\/AAC.00602-12","article-title":"Virulent bacteriophages can target O104: H4 enteroaggregative Escherichia coli in the mouse intestine","volume":"56","author":"Maura","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","first-page":"840","article-title":"Bacteriophages targeting adherent invasive escherichia coli strains as a promising new treatment for crohn\u2019s disease","volume":"11","author":"Galtier","year":"2017","journal-title":"J. Crohns Colitis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1099\/jmm.0.001162","article-title":"Myoviridae phage PDX kills enteroaggregative Escherichia coli without human microbiome dysbiosis","volume":"69","author":"Cepko","year":"2020","journal-title":"J. Med. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e0013621","DOI":"10.1128\/CMR.00136-21","article-title":"Intestinal bacteriophage therapy: Looking for optimal efficacy","volume":"34","author":"Javaudin","year":"2021","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1128\/jvi.49.1.273-275.1984","article-title":"Requirement for a fluid host cell membrane in injection of coliphage T5 DNA","volume":"49","author":"Labedan","year":"1984","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/BF00211222","article-title":"The role of capsule as a barrier to bacteriophage adsorption in an encapsulated Staphylococcus simulans strain","volume":"177","author":"Ohshima","year":"1988","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0963-9969(01)00121-1","article-title":"Phage adsorption to Streptococcus thermophilus. Influence of environmental factors and characterization of cell-receptors","volume":"35","author":"Binetti","year":"2002","journal-title":"Food Res. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.chom.2020.06.002","article-title":"The spatial heterogeneity of the gut limits predation and fosters coexistence of bacteria and bacteriophages","volume":"28","author":"Chaffringeon","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"689","DOI":"10.3389\/fmicb.2019.00689","article-title":"Biodistribution of liposome-encapsulated bacteriophages and their transcytosis during oral phage therapy","volume":"10","author":"Otero","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.4315\/0362-028X-73.7.1304","article-title":"Oral delivery systems for encapsulated bacteriophages targeted at Escherichia coli O157:H7 in feedlot cattle","volume":"73","author":"Stanford","year":"2010","journal-title":"J. Food Prot."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1128\/aem.61.1.382-385.1995","article-title":"Growth and survival of Escherichia coli O157:H7 under acidic conditions","volume":"61","author":"Conner","year":"1995","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1089\/fpd.2011.0905","article-title":"Direct feeding of microencapsulated bacteriophages to reduce Salmonella colonization in pigs","volume":"8","author":"Saez","year":"2011","journal-title":"Foodborne Pathog. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1128\/AEM.00785-09","article-title":"Phage therapy to reduce preprocessing Salmonella infections in market-weight swine","volume":"76","author":"Wall","year":"2010","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ebiom.2015.12.023","article-title":"Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: A randomized trial in children from bangladesh","volume":"4","author":"Sarker","year":"2016","journal-title":"EBioMedicine"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/12\/2580\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:47:04Z","timestamp":1760168824000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/12\/2580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,13]]},"references-count":42,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["microorganisms9122580"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms9122580","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,13]]}}}