Protection of the Human Gut Microbiome From Antibiotics Jean de Gunzburg, Amine Ghozlane, Annie Ducher, Emmanuelle Le Chatelier, Xavier Duval, Etienne Ruppé, Laurence Armand-Lefevre, Frédérique Sablier-Gallis, Charles Burdet, Loubna Alavoine, et al. To cite this version: Jean de Gunzburg, Amine Ghozlane, Annie Ducher, Emmanuelle Le Chatelier, Xavier Duval, et al.. Protection of the Human Gut Microbiome From Antibiotics. Journal of Infectious Diseases, Oxford University Press (OUP), 2018, 217 (4), pp.628-636. 10.1093/infdis/jix604. pasteur-02552147 HAL Id: pasteur-02552147 https://hal-pasteur.archives-ouvertes.fr/pasteur-02552147 Submitted on 23 Apr 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. 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Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives| 4.0 International License The Journal of Infectious Diseases MAJOR ARTICLE Protection of the Human Gut Microbiome From Antibiotics Jean de Gunzburg,1,a Amine Ghozlane,2,a Annie Ducher,1,a Emmanuelle Le Chatelier,2,a Xavier Duval,3,4,5 Etienne Ruppé,2,b Laurence Armand-Lefevre,3,4,5 Frédérique Sablier-Gallis,1 Charles Burdet,4,5 Loubna Alavoine,3 Elisabeth Chachaty,6 Violaine Augustin,1 Marina Varastet,1 Florence Levenez,2 Sean Kennedy,2,b Nicolas Pons,2 France Mentré,4,5,c and Antoine Andremont3,4,5,c 1Da Volterra, Paris; 2Metagenopolis, Institut National de la Recherche Agronomique, Jouy-en-Josas; 3Bichat Claude Bernard Hospital, University Paris Diderot, Sorbonne Paris 217 Cité, 4Institut National de la Santé et de la Recherche Médicale, Infection Antimicrobials Modelling Evolution, Unité Mixte de Recherche 1137, and 5University Paris Diderot, Sorbonne Paris Cité, Paris; and 5Institut Gustave-Roussy, Villejuif, France Downloaded from https://academic.oup.com/jid/article-abstract/217/4/628/4653556 by Institut Pasteur user on 23 April 2020 15 Background. Antibiotics are life-saving drugs but severely affect the gut microbiome with short-term consequences including diarrhea and selection of antibiotic-resistant bacteria. Long-term links to allergy and obesity are also suggested. We devised a product, February DAV132, and previously showed its ability to deliver a powerful adsorbent, activated charcoal, in the late ileum of human volunteers. Methods. We performed a randomized controlled trial in 28 human volunteers treated with a 5-day clinical regimen of the fluoroquinolone antibiotic moxifloxacin in 2 parallel groups, with or without DAV132 coadministration. Two control goups of 8 volunteers each receiving DAV132 alone, or a nonactive substitute, were added. Results. The coadministration of DAV132 decreased free moxifloxacin fecal concentrations by 99%, while plasmatic levels were unaffected. Shotgun quantitative metagenomics showed that the richness and composition of the intestinal microbiota were largely preserved in subjects co-treated with DAV132 in addition to moxifloxacin. No adverse effect was observed. In addition, DAV132 efficiently adsorbed a wide range of clinically relevant antibiotics ex vivo. Conclusions. DAV132 was highly effective to protect the gut microbiome of moxifloxacin-treated healthy volunteers and may constitute a clinical breakthrough by preventing adverse health consequences of a wide range of antibiotic treatments. Clinical Trials Registration. NCT02176005. Keywords. microbiome; antibiotics; fluoroquinolones; Clostridium difficile. Antibiotics constitute one of the most medically important and community patients [9–11]. Long-term links to allergy [4] and effective class of drugs. However, during systemic antibiotic treat- obesity [5] have also been suggested. Indeed, burgeoning research ments, the nonabsorbed part of orally administered drugs, as well in recent years has shown that the intestinal microbiome plays an as the possible fraction excreted into the upper intestine via bile important role in many aspects of human physiology and health for both oral and parenteral antibiotics, reaches the cecum and [12]. In particular, it is involved in the production of metabolites STANDARD colon where it can exert devastating effects on the gut microbi- that may affect insulin sensitivity [13] and diet-related obesity ome, with short- and long-term consequences [1–5]. Short-term [14]; this state has been shown to correlate with a gut microbi- effects include diarrhea, Clostridium difficile infection (CDI), and ome of lower bacterial richness than in healthy individuals [15]. selection of antibiotic-resistant microorganisms [6–8]. CDI cur- Strategies that would preserve the intestinal microbiome from rently constitutes a major clinical challenge, and antibiotic treat- deleterious consequences of dysbiosis during antibiotic treat- ments are the key factor for their occurrence in hospitalized and ments would be highly welcome for immediate protection of patients from CDI, and also for long-term public health conse- quences such as dissemination of resistant bacteria and the occur- Received 30 July 2017; editorial decision 15 November 2017; accepted 19 November 2017; rence of metabolic disorders. Oral administration of a β-lactamase published online November 23, 2017. [16–20] prevented the impact of parenteral β-lactams on the Presented in part: IDWeek, San Diego, California, October 2015 (abstract 760). aJ. G., A. G., and A. D. contributed equally to this work. microbiome, which is promising but limited to this class of anti- bPresent affiliation: E.R., INSERM, IAME, UMR 1137, Paris, France; University Paris Diderot, biotics. Delivering a nonspecific adsorbent to the colon partially Sorbonne Paris Cité, 75018 Paris, France; A.G. and S.K., Institut Pasteur, 75015 Paris, France. cF. M. and A. A. contributed equally to this work. decreased fecal concentrations of orally administered ciprofloxa- Correspondence: J. de Gunzburg, PhD, Da Volterra, 75011 Paris, France (gunzburg@davolterra. cin without significantly affecting its plasma pharmacokinetics in com). The Journal of Infectious Diseases® 2018;217:628–36 rats [21]. We devised a product, DAV132, which delivers a pow- © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases erful nonspecific adsorbent, a carefully chosen activated charcoal, Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ to the late ileum in humans, and have shown in healthy volunteers by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any that its administration did not affect the plasma pharmacokinetics medium, provided the original work is not altered or transformed in any way, and that the of amoxicillin, given as a single dose [22]. Here, we performed a work is properly cited. For commercial re-use, please contact [email protected] DOI: 10.1093/infdis/jix604 randomized clinical trial in volunteers receiving a full oral clinical 628 • JID 2018:217 (15 February) • de Gunzburg et al course of the fluoroquinolone antibiotic moxifloxacin (MXF), and evaluations, at the Clinical Investigation Centre of the Bichat assessed DAV132 safety, as well as its resulting effects on MXF Hospital, Paris (France) in respect with Good Clinical plasma concentrations, MXF free fecal concentrations, and intes- Practice and the Declaration of Helsinki as last amended. tinal dysbiosis. We also evaluated ex vivo the capacity of DAV132 Volunteers were randomized (Supplementary Materials) to adsorb a wide range of clinically relevant antibiotics. to receive either MXF alone (n = 14), MXF + DAV132 (n = 14), DAV132 alone (n = 8), or CTL (n = 8) (Figure 1). METHODS The study was carried out after authorizations from French Investigational Products Health Authorities and the Independent Ethics Committee DAV132 was manufactured according to Da Volterra’s specifi- (“Comité de Protection des Personnes Ile-de-France IV,” cations [22] under Good Manufacturing Practice conditions at Paris, France) had been obtained (January and February NextPharma (Bielefeld, Germany). The dosage form, consisting 2014, respectively). It was declared in ClinicalTrials.gov of 7.5 g DAV132, contained 5.11 g activated charcoal as active (identifier NCT02176005) and the French (ID-RCB number Downloaded from https://academic.oup.com/jid/article-abstract/217/4/628/4653556 by Institut Pasteur user on 23 April 2020 adsorbing ingredient. To facilitate oral intake, DAV132 pellets 2013-A01504-41) registers of clinical trials. A study-specific were suspended in an extemporaneously prepared gel suspen- scientific committee (A. A., V. A., A. Duc., A. Duf., X. D., C. F., sion (batch number C1311007). A negative control (CTL) was J. G., F. M., and M. V.) was set up to ensure scientific integrity. made of a product similar to DAV132, in which the adsorb- ent was replaced by microcrystalline cellulose (batch number Treatments C1311006). MXF was from Bayer (Avalox 400 mg Filmtabletten, Moxifloxacin 400 mg was administered orally, once a day (after batch number BXGFBN1). breakfast)