Toward revision of antimicrobial therapies in hematopoietic stem cell transplantation: target the pathogens, but protect the indigenous microbiota

      Host microbiota plays important roles in providing colonization resistance to pathogens and instructing development and function of the immune system. Antibiotic treatments intended to target pathogens further weaken the host defenses and may paradoxically increase the risk of systemic infections. This consequence is especially problematic in patients undergoing hematopoietic stem cell transplantation, where the mucosal defenses are already weakened by the conditioning regimens. This review discusses the roles that indigenous microbiota plays in protecting the host and maintaining immune homeostasis. In addition, we highlight possible strategies that are being developed to allow targeted antimicrobial therapy against pathogens, while minimizing the harm to indigenous microbiota.


      CDI (Clostridium difficile infection), GVHD (graft-vs-host disease), HCT (hematopoietic stem cell transplantation), ILC (innate lymphoid cell), iNKT (invariant natural killer T cell), TLR (Toll-like receptor)
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        • Freifeld A.G.
        • Bow E.J.
        • Sepkowitz K.A.
        • et al.
        Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America.
        Clin Infect Dis. 2011; 52: e56-e93
        • Bruminhent J.
        • Wang Z.X.
        • Hu C.
        • et al.
        Clostridium difficile colonization and disease in patients undergoing hematopoietic stem cell transplantation.
        Biol Blood Marrow Transplant. 2014; 20: 1329-1334
        • Jain T.
        • Croswell C.
        • Urday-Cornejo V.
        • et al.
        Clostridium Difficile Colonization in Hematopoietic Stem Cell Transplant Recipients: A Prospective Study of the Epidemiology and Outcomes Involving Toxigenic and Nontoxigenic Strains.
        Biol Blood Marrow Transplant. 2016; 22: 157-163
        • Huang A.M.
        • Marini B.L.
        • Frame D.
        • Aronoff D.M.
        • Nagel J.L.
        Risk factors for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients.
        Transpl Infect Dis. 2014; 16: 744-750
        • Backhed F.
        • Ley R.E.
        • Sonnenburg J.L.
        • Peterson D.A.
        • Gordon J.I.
        Host-bacterial mutualism in the human intestine.
        Science. 2005; 307: 1915-1920
        • Cummings J.H.
        • Macfarlane G.T.
        Role of intestinal bacteria in nutrient metabolism.
        JPEN J Parenter Enteral Nutr. 1997; 21: 357-365
        • Stevens C.E.
        • Hume I.D.
        Contributions of microbes in vertebrate gastrointestinal tract to production and conservation of nutrients.
        Physiol Rev. 1998; 78: 393-427
        • Ochman H.
        • Worobey M.
        • Kuo C.H.
        • et al.
        Evolutionary relationships of wild hominids recapitulated by gut microbial communities.
        PLoS Biol. 2010; 8: e1000546
        • Van den Abbeele P.
        • Van de Wiele T.
        • Verstraete W.
        • Possemiers S.
        The host selects mucosal and luminal associations of coevolved gut microorganisms: a novel concept.
        FEMS Microbiol Rev. 2011; 35: 681-704
        • Bloomfield S.F.
        • Stanwell-Smith R.
        • Crevel R.W.
        • Pickup J.
        Too clean, or not too clean: the hygiene hypothesis and home hygiene.
        Clin Exp Allergy. 2006; 36: 402-425
        • Bohnhoff M.
        • Drake B.L.
        • Miller C.P.
        Effect of streptomycin on susceptibility of intestinal tract to experimental Salmonella infection.
        Proc Soc Exp Biol Med. 1954; 86: 132-137
        • Miller C.P.
        • Bohnhoff M.
        Changes in the Mouse's Enteric Microflora Associated with Enhanced Susceptibility to Salmonella Infection Following Streptomycin Treatment.
        J Infect Dis. 1963; 113: 59-66
        • Ng K.M.
        • Ferreyra J.A.
        • Higginbottom S.K.
        • et al.
        Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens.
        Nature. 2013; 502: 96-99
        • Diaz-Ochoa V.E.
        • Jellbauer S.
        • Klaus S.
        • Raffatellu M.
        Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis.
        Front Cell Infect Microbiol. 2014; 4: 2
        • Vaishnava S.
        • Behrendt C.L.
        • Ismail A.S.
        • Eckmann L.
        • Hooper L.V.
        Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface.
        Proc Natl Acad Sci U S A. 2008; 105: 20858-20863
        • Vaishnava S.
        • Yamamoto M.
        • Severson K.M.
        • et al.
        The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine.
        Science. 2011; 334: 255-258
        • Bordin M.
        • D'Atri F.
        • Guillemot L.
        • Citi S.
        Histone deacetylase inhibitors up-regulate the expression of tight junction proteins.
        Mol Cancer Res. 2004; 2: 692-701
        • Al-Asmakh M.
        • Hedin L.
        Microbiota and the control of blood-tissue barriers.
        Tissue Barriers. 2015; 3: e1039691
        • Nigro G.
        • Rossi R.
        • Commere P.H.
        • Jay P.
        • Sansonetti P.J.
        The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration.
        Cell Host Microbe. 2014; 15: 792-798
        • Rakoff-Nahoum S.
        • Paglino J.
        • Eslami-Varzaneh F.
        • Edberg S.
        • Medzhitov R.
        Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.
        Cell. 2004; 118: 229-241
        • Brandl K.
        • Sun L.
        • Neppl C.
        • et al.
        MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands.
        Proc Natl Acad Sci U S A. 2010; 107: 19967-19972
        • Dudakov J.A.
        • Hanash A.M.
        • van den Brink M.R.
        Interleukin-22: immunobiology and pathology.
        Annu Rev Immunol. 2015; 33: 747-785
        • Ivanov I.I.
        • Atarashi K.
        • Manel N.
        • et al.
        Induction of intestinal Th17 cells by segmented filamentous bacteria.
        Cell. 2009; 139: 485-498
        • Qiu J.
        • Guo X.
        • Chen Z.M.
        • et al.
        Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora.
        Immunity. 2013; 39: 386-399
        • Hasegawa M.
        • Kamada N.
        • Jiao Y.
        • Liu M.Z.
        • Nunez G.
        • Inohara N.
        Protective role of commensals against Clostridium difficile infection via an IL-1beta-mediated positive-feedback loop.
        J Immunol. 2012; 189: 3085-3091
        • Taur Y.
        • Xavier J.B.
        • Lipuma L.
        • et al.
        Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation.
        Clin Infect Dis. 2012; 55: 905-914
        • Caballero S.
        • Carter R.
        • Ke X.
        • et al.
        Distinct but Spatially Overlapping Intestinal Niches for Vancomycin-Resistant Enterococcus faecium and Carbapenem-Resistant Klebsiella pneumoniae.
        PLoS Pathog. 2015; 11: e1005132
        • Satlin M.J.
        • Vardhana S.
        • Soave R.
        • et al.
        Impact of Prophylactic Levofloxacin on Rates of Bloodstream Infection and Fever in Neutropenic Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation.
        Biol Blood Marrow Transplant. 2015; 21: 1808-1814
        • Round J.L.
        • Mazmanian S.K.
        The gut microbiota shapes intestinal immune responses during health and disease.
        Nat Rev Immunol. 2009; 9: 313-323
        • Strachan D.P.
        Hay fever, hygiene, and household size.
        BMJ. 1989; 299: 1259-1260
        • Dominguez-Bello M.G.
        • Blaser M.J.
        Asthma: Undoing millions of years of coevolution in early life?.
        Sci Transl Med. 2015; 7: 307fs39
        • Blaser M.J.
        • Falkow S.
        What are the consequences of the disappearing human microbiota?.
        Nat Rev Microbiol. 2009; 7: 887-894
        • Olszak T.
        • An D.
        • Zeissig S.
        • et al.
        Microbial exposure during early life has persistent effects on natural killer T cell function.
        Science. 2012; 336: 489-493
        • An D.
        • Oh S.F.
        • Olszak T.
        • et al.
        Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells.
        Cell. 2014; 156: 123-133
        • Round J.L.
        • Lee S.M.
        • Li J.
        • et al.
        The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota.
        Science. 2011; 332: 974-977
        • Stefka A.T.
        • Feehley T.
        • Tripathi P.
        • et al.
        Commensal bacteria protect against food allergen sensitization.
        Proc Natl Acad Sci U S A. 2014; 111: 13145-13150
        • Atarashi K.
        • Tanoue T.
        • Oshima K.
        • et al.
        Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota.
        Nature. 2013; 500: 232-236
        • Waldecker M.
        • Kautenburger T.
        • Daumann H.
        • Busch C.
        • Schrenk D.
        Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon.
        J Nutr Biochem. 2008; 19: 587-593
        • Arpaia N.
        • Campbell C.
        • Fan X.
        • et al.
        Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.
        Nature. 2013; 504: 451-455
        • Smith P.M.
        • Howitt M.R.
        • Panikov N.
        • et al.
        The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.
        Science. 2013; 341: 569-573
        • Mathewson N.D.
        • Jenq R.
        • Mathew A.V.
        • et al.
        Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease.
        Nat Immunol. 2016; 17: 505-513
        • Khoruts A.
        • Fraser J.M.
        A causal link between lymphopenia and autoimmunity.
        Immunol Lett. 2005; 98: 23-31
        • van Bekkum D.W.
        • Roodenburg J.
        • Heidt P.J.
        • van der Waaij D.
        Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora.
        J Natl Cancer Inst. 1974; 52: 401-404
        • Jones J.M.
        • Wilson R.
        • Bealmear P.M.
        Mortality and gross pathology of secondary disease in germfree mouse radiation chimeras.
        Radiat Res. 1971; 45: 577-588
        • Vriesendorp H.M.
        • Heidt P.J.
        • Zurcher C.
        Gastrointestinal decontamination of dogs treated with total body irradiation and bone marrow transplantation.
        Exp Hematol. 1981; 9: 904-916
        • Beelen D.W.
        • Elmaagacli A.
        • Muller K.D.
        • Hirche H.
        • Schaefer U.W.
        Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial.
        Blood. 1999; 93: 3267-3275
        • Vossen J.M.
        • Guiot H.F.
        • Lankester A.C.
        • et al.
        Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation.
        PLoS One. 2014; 9: e105706
        • Vossen J.M.
        • Heidt P.J.
        • van den Berg H.
        • Gerritsen E.J.
        • Hermans J.
        • Dooren L.J.
        Prevention of infection and graft-versus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation.
        Eur J Clin Microbiol Infect Dis. 1990; 9: 14-23
        • Storb R.
        • Thomas E.D.
        Graft-versus-host disease in dog and man: the Seattle experience.
        Immunol Rev. 1985; 88: 215-238
        • Shono Y.
        • Docampo M.D.
        • Peled J.U.
        • et al.
        Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice.
        Sci Transl Med. 2016; 8: 339ra71
        • Jenq R.R.
        • Ubeda C.
        • Taur Y.
        • et al.
        Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation.
        J Exp Med. 2012; 209: 903-911
        • Hippen K.L.
        • Bucher C.
        • Schirm D.K.
        • et al.
        Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes.
        Blood. 2012; 119: 619-628
        • Taur Y.
        • Jenq R.R.
        • Perales M.A.
        • et al.
        The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.
        Blood. 2014; 124: 1174-1182
        • van der Waaij D.
        • Vossen J.M.
        • Altes C.K.
        • Hartgrink C.
        Reconventionalization following antibiotic decontamination in man and animals.
        Am J Clin Nutr. 1977; 30: 1887-1895
        • Hardesty J.S.
        • Juang P.
        Fidaxomicin: a macrocyclic antibiotic for the treatment of Clostridium difficile infection.
        Pharmacotherapy. 2011; 31: 877-886
        • Louie T.J.
        • Miller M.A.
        • Mullane K.M.
        • et al.
        Fidaxomicin versus vancomycin for Clostridium difficile infection.
        N Engl J Med. 2011; 364: 422-431
        • van Nood E.
        • Vrieze A.
        • Nieuwdorp M.
        • et al.
        Duodenal infusion of donor feces for recurrent Clostridium difficile.
        N Engl J Med. 2013; 368: 407-415
        • Hamilton M.J.
        • Weingarden A.R.
        • Unno T.
        • Khoruts A.
        • Sadowsky M.J.
        High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria.
        Gut microbes. 2013; 4: 125-135
        • Weingarden A.
        • Gonzalez A.
        • Vazquez-Baeza Y.
        • et al.
        Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection.
        Microbiome. 2015; 3: 10
        • Seekatz A.M.
        • Aas J.
        • Gessert C.E.
        • et al.
        Recovery of the gut microbiome following fecal microbiota transplantation.
        MBio. 2014; 5: e00893-e00914
        • Shankar V.
        • Hamilton M.J.
        • Khoruts A.
        • et al.
        Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation.
        Microbiome. 2014; 2: 13
        • Hamilton M.J.
        • Weingarden A.R.
        • Sadowsky M.J.
        • Khoruts A.
        Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection.
        Am J Gastroenterol. 2012; 107: 761-767
        • Huynh E.
        • Li J.
        Generation of Lactococcus lactis capable of coexpressing epidermal growth factor and trefoil factor to enhance in vitro wound healing.
        Appl Microbiol Biotechnol. 2015; 99: 4667-4677
        • Welling G.W.
        • Holtrop A.
        • Slootmaker-van der Meulen C.
        • et al.
        Inactivation of ceftriaxone by faecal enzyme preparations during ceftriaxone treatment.
        J Antimicrob Chemother. 1992; 30: 234-236
        • Pitout J.D.
        IPSAT P1A, a class A beta-lactamase therapy for the prevention of penicillin-induced disruption to the intestinal microflora.
        Curr Opin Investig Drugs. 2009; 10: 838-844
        • de Gunzburg J.
        • Ducher A.
        • Modess C.
        • et al.
        Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: A proof of concept study in healthy subjects.
        J Clin Pharmacol. 2015; 55: 10-16