Voltar
Artigo Acesso aberto Revisado por pares
BIBTEX RIS

Antibiotic Perturbation of Gut Microbiota Dysregulates Osteoimmune Cross Talk in Postpubertal Skeletal Development

2019; Elsevier BV; Volume: 189; Issue: 2 Linguagem: Inglês

10.1016/j.ajpath.2018.10.017

ISSN

1525-2191

Autores

Jessica D. Hathaway‐Schrader, Heidi M. Steinkamp, M.B. Chavez, Nicole Poulides, Joy E. Kirkpatrick, Michael E. Chew, Emily Huang, Alexander V. Alekseyenko, J. Ignacio Aguirre, Chad M. Novince,

Tópico(s)

Bone Metabolism and Diseases

Resumo

Commensal gut microbiota–host immune responses are experimentally delineated via gnotobiotic animal models or alternatively by antibiotic perturbation of gut microbiota. Osteoimmunology investigations in germ-free mice, revealing that gut microbiota immunomodulatory actions critically regulate physiologic skeletal development, highlight that antibiotic perturbation of gut microbiota may dysregulate normal osteoimmunological processes. We investigated the impact of antibiotic disruption of gut microbiota on osteoimmune response effects in postpubertal skeletal development. Sex-matched C57BL/6T mice were administered broad-spectrum antibiotics or vehicle-control from the age of 6 to 12 weeks. Antibiotic alterations in gut bacterial composition and skeletal morphology were sex dependent. Antibiotics did not influence osteoblastogenesis or endochondral bone formation, but notably enhanced osteoclastogenesis. Unchanged Tnf or Ccl3 expression in marrow and elevated tumor necrosis factor-α and chemokine (C-C motif) ligand 3 in serum indicated that the pro-osteoclastic effects of the antibiotics are driven by increased systemic inflammation. Antibiotic-induced broad changes in adaptive and innate immune cells in mesenteric lymph nodes and spleen demonstrated that the perturbation of gut microbiota drives a state of dysbiotic hyperimmune response at secondary lymphoid tissues draining local gut and systemic circulation. Antibiotics up-regulated the myeloid-derived suppressor cells, immature myeloid progenitor cells known for immunosuppressive properties in pathophysiologic inflammatory conditions. Myeloid-derived suppressor cell–mediated immunosuppression can be antigen specific. Therefore, antibiotic-induced broad suppression of major histocompatibility complex class II antigen presentation genes in bone marrow discerns that antibiotic perturbation of gut microbiota dysregulates critical osteoimmune cross talk. Commensal gut microbiota–host immune responses are experimentally delineated via gnotobiotic animal models or alternatively by antibiotic perturbation of gut microbiota. Osteoimmunology investigations in germ-free mice, revealing that gut microbiota immunomodulatory actions critically regulate physiologic skeletal development, highlight that antibiotic perturbation of gut microbiota may dysregulate normal osteoimmunological processes. We investigated the impact of antibiotic disruption of gut microbiota on osteoimmune response effects in postpubertal skeletal development. Sex-matched C57BL/6T mice were administered broad-spectrum antibiotics or vehicle-control from the age of 6 to 12 weeks. Antibiotic alterations in gut bacterial composition and skeletal morphology were sex dependent. Antibiotics did not influence osteoblastogenesis or endochondral bone formation, but notably enhanced osteoclastogenesis. Unchanged Tnf or Ccl3 expression in marrow and elevated tumor necrosis factor-α and chemokine (C-C motif) ligand 3 in serum indicated that the pro-osteoclastic effects of the antibiotics are driven by increased systemic inflammation. Antibiotic-induced broad changes in adaptive and innate immune cells in mesenteric lymph nodes and spleen demonstrated that the perturbation of gut microbiota drives a state of dysbiotic hyperimmune response at secondary lymphoid tissues draining local gut and systemic circulation. Antibiotics up-regulated the myeloid-derived suppressor cells, immature myeloid progenitor cells known for immunosuppressive properties in pathophysiologic inflammatory conditions. Myeloid-derived suppressor cell–mediated immunosuppression can be antigen specific. Therefore, antibiotic-induced broad suppression of major histocompatibility complex class II antigen presentation genes in bone marrow discerns that antibiotic perturbation of gut microbiota dysregulates critical osteoimmune cross talk. The gut is colonized by diverse microorganisms (ie, bacteria, fungi, and viruses) that collectively form a microbial community known as the gut microbiota. Early life host-microbe interactions direct the development of immunity and the establishment of a stable complex microbial community, commonly referred to as the commensal microbiota.1Round J.L. Mazmanian S.K. The gut microbiota shapes intestinal immune responses during health and disease.Nat Rev Immunol. 2009; 9: 313-323Crossref PubMed Scopus (2273) Google Scholar, 2Ivanov II, Honda K. Intestinal commensal microbes as immune modulators.Cell Host Microbe. 2012; 12: 496-508Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 3Brestoff J.R. Artis D. Commensal bacteria at the interface of host metabolism and the immune system.Nat Immunol. 2013; 14: 676-684Crossref PubMed Scopus (371) Google Scholar, 4Clemente J.C. Ursell L.K. Parfrey L.W. Knight R. The impact of the gut microbiota on human health: an integrative view.Cell. 2012; 148: 1258-1270Abstract Full Text Full Text PDF PubMed Scopus (1359) Google Scholar, 5Sommer F. Backhed F. The gut microbiota: masters of host development and physiology.Nat Rev Microbiol. 2013; 11: 227-238Crossref PubMed Scopus (1207) Google Scholar Extensive research has focused on commensal gut microbiota–host immune response effects in the context of protection against pathogenic gut microbes6Buffie C.G. Pamer E.G. Microbiota-mediated colonization resistance against intestinal pathogens.Nat Rev Immunol. 2013; 13: 790-801Crossref PubMed Scopus (481) Google Scholar, 7Kamada N. Chen G.Y. Inohara N. Nunez G. Control of pathogens and pathobionts by the gut microbiota.Nat Immunol. 2013; 14: 685-690Crossref PubMed Scopus (534) Google Scholar, 8Baumler A.J. Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut.Nature. 2016; 535: 85-93Crossref PubMed Google Scholar and the pathophysiology of chronic inflammatory/autoimmune gastrointestinal disease states.9Kamada N. Seo S.U. Chen G.Y. Nunez G. Role of the gut microbiota in immunity and inflammatory disease.Nat Rev Immunol. 2013; 13: 321-335Crossref PubMed Scopus (826) Google Scholar, 10Dalal S.R. Chang E.B. The microbial basis of inflammatory bowel diseases.J Clin Invest. 2014; 124: 4190-4196Crossref PubMed Scopus (104) Google Scholar, 11Pickard J.M. Zeng M.Y. Caruso R. Nunez G. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease.Immunol Rev. 2017; 279: 70-89Crossref PubMed Scopus (112) Google Scholar Timely investigations have delineated that indigenous gut microbiota immunomodulatory effects not only influence pathologic conditions centered in the gut, but also at distant anatomical sites (ie, liver, brain, heart, and skeleton).12Leung C. Rivera L. Furness J.B. Angus P.W. The role of the gut microbiota in NAFLD.Nat Rev Gastroenterol Hepatol. 2016; 13: 412-425Crossref PubMed Scopus (191) Google Scholar, 13Yu L.X. Schwabe R.F. The gut microbiome and liver cancer: mechanisms and clinical translation.Nat Rev Gastroenterol Hepatol. 2017; 14: 527-539Crossref PubMed Scopus (68) Google Scholar, 14Berer K. Mues M. Koutrolos M. Rasbi Z.A. Boziki M. Johner C. Wekerle H. Krishnamoorthy G. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination.Nature. 2011; 479: 538-541Crossref PubMed Scopus (636) Google Scholar, 15Sampson T.R. Debelius J.W. Thron T. Janssen S. Shastri G.G. Ilhan Z.E. Challis C. Schretter C.E. Rocha S. Gradinaru V. Chesselet M.F. Keshavarzian A. Shannon K.M. Krajmalnik-Brown R. Wittung-Stafshede P. Knight R. Mazmanian S.K. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease.Cell. 2016; 167: 1469-1480.e1412Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar, 16Troseid M. Ueland T. Hov J.R. Svardal A. Gregersen I. Dahl C.P. Aakhus S. Gude E. Bjorndal B. Halvorsen B. Karlsen T.H. Aukrust P. Gullestad L. Berge R.K. Yndestad A. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure.J Intern Med. 2015; 277: 717-726Crossref PubMed Scopus (158) Google Scholar, 17Jie Z. Xia H. Zhong S.L. Feng Q. Li S. Liang S. et al.The gut microbiome in atherosclerotic cardiovascular disease.Nat Commun. 2017; 8: 845Crossref PubMed Scopus (167) Google Scholar, 18Wu H.J. Ivanov II, Darce J. Hattori K. Shima T. Umesaki Y. Littman D.R. Benoist C. Mathis D. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.Immunity. 2010; 32: 815-827Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar, 19Li J.Y. Chassaing B. Tyagi A.M. Vaccaro C. Luo T. Adams J. Darby T.M. Weitzmann M.N. Mulle J.G. Gewirtz A.T. Jones R.M. Pacifici R. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics.J Clin Invest. 2016; 126: 2049-2063Crossref PubMed Scopus (123) Google Scholar Not well understood and central to this report, the immunomodulation of commensal gut microbiota critically influences the normal growth and development of extragastrointestinal tissues.4Clemente J.C. Ursell L.K. Parfrey L.W. Knight R. The impact of the gut microbiota on human health: an integrative view.Cell. 2012; 148: 1258-1270Abstract Full Text Full Text PDF PubMed Scopus (1359) Google Scholar, 5Sommer F. Backhed F. The gut microbiota: masters of host development and physiology.Nat Rev Microbiol. 2013; 11: 227-238Crossref PubMed Scopus (1207) Google Scholar, 20Schroeder B.O. Backhed F. Signals from the gut microbiota to distant organs in physiology and disease.Nat Med. 2016; 22: 1079-1089Crossref PubMed Scopus (297) Google Scholar, 21Blander J.M. Longman R.S. Iliev I.D. Sonnenberg G.F. Artis D. Regulation of inflammation by microbiota interactions with the host.Nat Immunol. 2017; 18: 851-860Crossref PubMed Scopus (145) Google Scholar After birth, microbial colonization of the infant gut is primarily determined by the method of delivery and the mother's indigenous microbiota.22Dominguez-Bello M.G. Costello E.K. Contreras M. Magris M. Hidalgo G. Fierer N. Knight R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.Proc Natl Acad Sci U S A. 2010; 107: 11971-11975Crossref PubMed Scopus (1939) Google Scholar, 23Backhed F. Roswall J. Peng Y. Feng Q. Jia H. Kovatcheva-Datchary P. Li Y. Xia Y. Xie H. Zhong H. Khan M.T. Zhang J. Li J. Xiao L. Al-Aama J. Zhang D. Lee Y.S. Kotowska D. Colding C. Tremaroli V. Yin Y. Bergman S. Xu X. Madsen L. Kristiansen K. Dahlgren J. Wang J. Dynamics and stabilization of the human gut microbiome during the first year of life.Cell Host Microbe. 2015; 17: 690-703Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 24Chu D.M. Ma J. Prince A.L. Antony K.M. Seferovic M.D. Aagaard K.M. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery.Nat Med. 2017; 23: 314-326Crossref PubMed Scopus (251) Google Scholar Throughout life, exogenous factors (ie, lifestyle, hygiene, diet, and medications) induce shifts/changes in the gut microbiota composition, which have indirect effects on host immunity and physiology.5Sommer F. Backhed F. The gut microbiota: masters of host development and physiology.Nat Rev Microbiol. 2013; 11: 227-238Crossref PubMed Scopus (1207) Google Scholar, 25Cho I. Blaser M.J. The human microbiome: at the interface of health and disease.Nat Rev Genet. 2012; 13: 260-270Crossref PubMed Scopus (1314) Google Scholar, 26Ananthakrishnan A.N. Epidemiology and risk factors for IBD.Nat Rev Gastroenterol Hepatol. 2015; 12: 205-217Crossref PubMed Scopus (437) Google Scholar, 27Sommer F. Anderson J.M. Bharti R. Raes J. Rosenstiel P. The resilience of the intestinal microbiota influences health and disease.Nat Rev Microbiol. 2017; 15: 630-638Crossref PubMed Scopus (143) Google Scholar In line with this premise, antibiotic perturbation of the indigenous gut microbiota induces lasting alterations in the host immune response, which has implications for health and disease.28Keeney K.M. Yurist-Doutsch S. Arrieta M.C. Finlay B.B. Effects of antibiotics on human microbiota and subsequent disease.Annu Rev Microbiol. 2014; 68: 217-235Crossref PubMed Scopus (119) Google Scholar, 29Blaser M.J. Antibiotic use and its consequences for the normal microbiome.Science. 2016; 352: 544-545Crossref PubMed Google Scholar, 30Ianiro G. Tilg H. Gasbarrini A. Antibiotics as deep modulators of gut microbiota: between good and evil.Gut. 2016; 65: 1906-1915Crossref PubMed Scopus (98) Google Scholar, 31Becattini S. Taur Y. Pamer E.G. Antibiotic-induced changes in the intestinal microbiota and disease.Trends Mol Med. 2016; 22: 458-478Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Antibiotics can induce hyperimmune proinflammatory response states, which have been purported to be driven by dysbiotic shifts in the gut microbiota composition, increased intestinal permeability, translocation of gut microbes/microbial ligands, and/or overgrowth of drug-resistant opportunistic pathogens.21Blander J.M. Longman R.S. Iliev I.D. Sonnenberg G.F. Artis D. Regulation of inflammation by microbiota interactions with the host.Nat Immunol. 2017; 18: 851-860Crossref PubMed Scopus (145) Google Scholar, 31Becattini S. Taur Y. Pamer E.G. Antibiotic-induced changes in the intestinal microbiota and disease.Trends Mol Med. 2016; 22: 458-478Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 32Knoop K.A. McDonald K.G. Kulkarni D.H. Newberry R.D. Antibiotics promote inflammation through the translocation of native commensal colonic bacteria.Gut. 2016; 65: 1100-1109Crossref PubMed Scopus (69) Google Scholar, 33Lewis J.D. Chen E.Z. Baldassano R.N. Otley A.R. Griffiths A.M. Lee D. Bittinger K. Bailey A. Friedman E.S. Hoffmann C. Albenberg L. Sinha R. Compher C. Gilroy E. Nessel L. Grant A. Chehoud C. Li H. Wu G.D. Bushman F.D. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn's disease.Cell Host Microbe. 2015; 18: 489-500Abstract Full Text Full Text PDF PubMed Google Scholar, 34Lichtman J.S. Ferreyra J.A. Ng K.M. Smits S.A. Sonnenburg J.L. Elias J.E. Host-microbiota interactions in the pathogenesis of antibiotic-associated diseases.Cell Rep. 2016; 14: 1049-1061Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 35Grasa L. Abecia L. Forcen R. Castro M. de Jalon J.A. Latorre E. Alcalde A.I. Murillo M.D. Antibiotic-induced depletion of murine microbiota induces mild inflammation and changes in toll-like receptor patterns and intestinal motility.Microb Ecol. 2015; 70: 835-848Crossref PubMed Scopus (10) Google Scholar, 36Belkaid Y. Harrison O.J. Homeostatic immunity and the microbiota.Immunity. 2017; 46: 562-576Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 37Underhill D.M. Iliev I.D. The mycobiota: interactions between commensal fungi and the host immune system.Nat Rev Immunol. 2014; 14: 405-416Crossref PubMed Scopus (246) Google Scholar, 38Abt M.C. McKenney P.T. Pamer E.G. Clostridium difficile colitis: pathogenesis and host defence.Nat Rev Microbiol. 2016; 14: 609-620Crossref PubMed Scopus (116) Google Scholar, 39Burrello C. Garavaglia F. Cribiu F.M. Ercoli G. Bosari S. Caprioli F. Facciotti F. Short-term oral antibiotics treatment promotes inflammatory activation of colonic invariant natural killer T and conventional CD4(+) T cells.Front Med. 2018; 5: 21Crossref Scopus (6) Google Scholar, 40Zeng M.Y. Inohara N. Nunez G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut.Mucosal Immunol. 2017; 10: 18-26Crossref PubMed Scopus (94) Google Scholar, 41Edelblum K.L. Sharon G. Singh G. Odenwald M.A. Sailer A. Cao S. Ravens S. Thomsen I. El Bissati K. McLeod R. Dong C. Gurbuxani S. Prinz I. Mazmanian S.K. Turner J.R. The microbiome activates CD4 T-cell-mediated immunity to compensate for increased intestinal permeability.Cell Mol Gastroenterol Hepatol. 2017; 4: 285-297Abstract Full Text Full Text PDF PubMed Google Scholar, 42Tulstrup M.V. Christensen E.G. Carvalho V. Linninge C. Ahrne S. Hojberg O. Licht T.R. Bahl M.I. Antibiotic treatment affects intestinal permeability and gut microbial composition in Wistar rats dependent on antibiotic class.PLoS One. 2015; 10: e0144854Crossref PubMed Scopus (0) Google Scholar, 43Romick-Rosendale L.E. Legomarcino A. Patel N.B. Morrow A.L. Kennedy M.A. Prolonged antibiotic use induces intestinal injury in mice that is repaired after removing antibiotic pressure: implications for empiric antibiotic therapy.Metabolomics. 2014; 10: 8-20Crossref PubMed Scopus (3) Google Scholar The field of osteoimmunology has shown that the immune cell interactions with bone cells regulate skeletal development and homeostasis, under physiological and pathophysiologic conditions.44Li Y. Toraldo G. Li A. Yang X. Zhang H. Qian W.P. Weitzmann M.N. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo.Blood. 2007; 109: 3839-3848Crossref PubMed Scopus (246) Google Scholar, 45Lorenzo J. Horowitz M. Choi Y. Osteoimmunology: interactions of the bone and immune system.Endocr Rev. 2008; 29: 403-440Crossref PubMed Scopus (330) Google Scholar, 46Takayanagi H. Osteoimmunology and the effects of the immune system on bone.Nat Rev Rheumatol. 2009; 5: 667-676Crossref PubMed Scopus (243) Google Scholar, 47Pacifici R. T cells: critical bone regulators in health and disease.Bone. 2010; 47: 461-471Crossref PubMed Scopus (0) Google Scholar, 48Walsh M.C. Takegahara N. Kim H. Choi Y. Updating osteoimmunology: regulation of bone cells by innate and adaptive immunity.Nat Rev Rheumatol. 2018; 14: 146-156Crossref PubMed Scopus (35) Google Scholar Proinflammatory immune response states can suppress osteoblast-mediated bone formation and/or enhance osteoclast-mediated bone resorption, having detrimental effects on the accrual of bone mass in the growing skeleton and the maintenance of bone mass in the mature adult skeleton.49Zaidi M. Skeletal remodeling in health and disease.Nat Med. 2007; 13: 791-801Crossref PubMed Scopus (573) Google Scholar, 50Redlich K. Smolen J.S. Inflammatory bone loss: pathogenesis and therapeutic intervention.Nat Rev Drug Discov. 2012; 11: 234-250Crossref PubMed Scopus (313) Google Scholar, 51Weitzmann M.N. Ofotokun I. Physiological and pathophysiological bone turnover: role of the immune system.Nat Rev Endocrinol. 2016; 12: 518-532Crossref PubMed Scopus (0) Google Scholar Recent osteoimmunology reports in the germ-free mouse model, disclosing that gut microbiota immunomodulatory actions potently regulate and promote the development and homeostasis of skeletal tissues,52Sjogren K. Engdahl C. Henning P. Lerner U.H. Tremaroli V. Lagerquist M.K. Backhed F. Ohlsson C. The gut microbiota regulates bone mass in mice.J Bone Miner Res. 2012; 27: 1357-1367Crossref PubMed Scopus (210) Google Scholar, 53Schwarzer M. Makki K. Storelli G. Machuca-Gayet I. Srutkova D. Hermanova P. Martino M.E. Balmand S. Hudcovic T. Heddi A. Rieusset J. Kozakova H. Vidal H. Leulier F. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition.Science. 2016; 351: 854-857Crossref PubMed Scopus (170) Google Scholar, 54Yan J. Herzog J.W. Tsang K. Brennan C.A. Bower M.A. Garrett W.S. Sartor B.R. Aliprantis A.O. Charles J.F. Gut microbiota induce IGF-1 and promote bone formation and growth.Proc Natl Acad Sci U S A. 2016; 113: E7554-E7563Crossref PubMed Scopus (119) Google Scholar, 55Novince C.M. Whittow C.R. Aartun J.D. Hathaway J.D. Poulides N. Chavez M.B. Steinkamp H.M. Kirkwood K.A. Huang E. Westwater C. Kirkwood K.L. Commensal gut microbiota immunomodulatory actions in bone marrow and liver have catabolic effects on skeletal homeostasis in health.Sci Rep. 2017; 7: 5747Crossref PubMed Scopus (8) Google Scholar highlight that antibiotic perturbation of commensal gut microbiota may dysregulate normal osteoimmunological processes. Considering that antibiotic disruption of the indigenous gut microbiota has been reported to induce proinflammatory hyperimmune response states,21Blander J.M. Longman R.S. Iliev I.D. Sonnenberg G.F. Artis D. Regulation of inflammation by microbiota interactions with the host.Nat Immunol. 2017; 18: 851-860Crossref PubMed Scopus (145) Google Scholar, 31Becattini S. Taur Y. Pamer E.G. Antibiotic-induced changes in the intestinal microbiota and disease.Trends Mol Med. 2016; 22: 458-478Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 32Knoop K.A. McDonald K.G. Kulkarni D.H. Newberry R.D. Antibiotics promote inflammation through the translocation of native commensal colonic bacteria.Gut. 2016; 65: 1100-1109Crossref PubMed Scopus (69) Google Scholar, 33Lewis J.D. Chen E.Z. Baldassano R.N. Otley A.R. Griffiths A.M. Lee D. Bittinger K. Bailey A. Friedman E.S. Hoffmann C. Albenberg L. Sinha R. Compher C. Gilroy E. Nessel L. Grant A. Chehoud C. Li H. Wu G.D. Bushman F.D. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn's disease.Cell Host Microbe. 2015; 18: 489-500Abstract Full Text Full Text PDF PubMed Google Scholar, 34Lichtman J.S. Ferreyra J.A. Ng K.M. Smits S.A. Sonnenburg J.L. Elias J.E. Host-microbiota interactions in the pathogenesis of antibiotic-associated diseases.Cell Rep. 2016; 14: 1049-1061Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 35Grasa L. Abecia L. Forcen R. Castro M. de Jalon J.A. Latorre E. Alcalde A.I. Murillo M.D. Antibiotic-induced depletion of murine microbiota induces mild inflammation and changes in toll-like receptor patterns and intestinal motility.Microb Ecol. 2015; 70: 835-848Crossref PubMed Scopus (10) Google Scholar, 36Belkaid Y. Harrison O.J. Homeostatic immunity and the microbiota.Immunity. 2017; 46: 562-576Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 37Underhill D.M. Iliev I.D. The mycobiota: interactions between commensal fungi and the host immune system.Nat Rev Immunol. 2014; 14: 405-416Crossref PubMed Scopus (246) Google Scholar, 38Abt M.C. McKenney P.T. Pamer E.G. Clostridium difficile colitis: pathogenesis and host defence.Nat Rev Microbiol. 2016; 14: 609-620Crossref PubMed Scopus (116) Google Scholar, 39Burrello C. Garavaglia F. Cribiu F.M. Ercoli G. Bosari S. Caprioli F. Facciotti F. Short-term oral antibiotics treatment promotes inflammatory activation of colonic invariant natural killer T and conventional CD4(+) T cells.Front Med. 2018; 5: 21Crossref Scopus (6) Google Scholar, 40Zeng M.Y. Inohara N. Nunez G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut.Mucosal Immunol. 2017; 10: 18-26Crossref PubMed Scopus (94) Google Scholar, 41Edelblum K.L. Sharon G. Singh G. Odenwald M.A. Sailer A. Cao S. Ravens S. Thomsen I. El Bissati K. McLeod R. Dong C. Gurbuxani S. Prinz I. Mazmanian S.K. Turner J.R. The microbiome activates CD4 T-cell-mediated immunity to compensate for increased intestinal permeability.Cell Mol Gastroenterol Hepatol. 2017; 4: 285-297Abstract Full Text Full Text PDF PubMed Google Scholar, 42Tulstrup M.V. Christensen E.G. Carvalho V. Linninge C. Ahrne S. Hojberg O. Licht T.R. Bahl M.I. Antibiotic treatment affects intestinal permeability and gut microbial composition in Wistar rats dependent on antibiotic class.PLoS One. 2015; 10: e0144854Crossref PubMed Scopus (0) Google Scholar, 43Romick-Rosendale L.E. Legomarcino A. Patel N.B. Morrow A.L. Kennedy M.A. Prolonged antibiotic use induces intestinal injury in mice that is repaired after removing antibiotic pressure: implications for empiric antibiotic therapy.Metabolomics. 2014; 10: 8-20Crossref PubMed Scopus (3) Google Scholar antibiotic administration could notably have unintended pathophysiologic effects impairing the attainment and maintenance of peak skeletal bone mass. Low-dose (subtherapeutic) antibiotics have been administered to agricultural animals since the 1940s for growth-promoting effects, which have been largely attributed to gut microbiota alterations in nutrient metabolism.56Gaskins H.R. Collier C.T. Anderson D.B. Antibiotics as growth promotants: mode of action.Anim Biotechnol. 2002; 13: 29-42Crossref PubMed Scopus (286) Google Scholar, 57Cox L.M. Blaser M.J. Antibiotics in early life and obesity.Nat Rev Endocrinol. 2015; 11: 182-190Crossref PubMed Google Scholar, 58Stokstad E.L. Antibiotics in animal nutrition.Physiol Rev. 1954; 34: 25-51Crossref PubMed Scopus (10) Google Scholar, 59Taylor J.H. Antibiotics and other growth-promoting substances.Proc Nutr Soc. 1962; 21: 73-80Crossref PubMed Scopus (0) Google Scholar Despite decades of agricultural research evaluating antibiotic perturbation of the gut microbiota in relation to animal growth effects, the initial skeletal outcomes were reported by a recent early-life antibiotic treatment study in female C57BL/6J mice.60Cho I. Yamanishi S. Cox L. Methe B.A. Zavadil J. Li K. Gao Z. Mahana D. Raju K. Teitler I. Li H. Alekseyenko A.V. Blaser M.J. Antibiotics in early life alter the murine colonic microbiome and adiposity.Nature. 2012; 488: 621-626Crossref PubMed Scopus (777) Google Scholar This timely investigation evaluated antibiotic alterations in gut microbiota composition, relative to host metabolism and growth outcomes.60Cho I. Yamanishi S. Cox L. Methe B.A. Zavadil J. Li K. Gao Z. Mahana D. Raju K. Teitler I. Li H. Alekseyenko A.V. Blaser M.J. Antibiotics in early life alter the murine colonic microbiome and adiposity.Nature. 2012; 488: 621-626Crossref PubMed Scopus (777) Google Scholar Continuous low-dose antibiotic administration, beginning at age 28 days of life, transiently increased whole animal bone mineral density scores in 7-week–old mice.60Cho I. Yamanishi S. Cox L. Methe B.A. Zavadil J. Li K. Gao Z. Mahana D. Raju K. Teitler I. Li H. Alekseyenko A.V. Blaser M.J. Antibiotics in early life alter the murine colonic microbiome and adiposity.Nature. 2012; 488: 621-626Crossref PubMed Scopus (777) Google Scholar Eleven-week–old antibiotic- versus vehicle-treated mice had similar whole-animal bone mineral density scores.60Cho I. Yamanishi S. Cox L. Methe B.A. Zavadil J. Li K. Gao Z. Mahana D. Raju K. Teitler I. Li H. Alekseyenko A.V. Blaser M.J. Antibiotics in early life alter the murine colonic microbiome and adiposity.Nature. 2012; 488: 621-626Crossref PubMed Scopus (777) Google Scholar Broad-spectrum antibiotic cocktails (combination of two or more different antibiotic drugs) are commonly administered by researchers evaluating gut microbiota: host response effects in experimental animal models. Broad-spectrum antibiotic cocktail formulation protocols have been developed, which either deplete or disrupt bacterial communities in the murine gut.61Reikvam D.H. Erofeev A. Sandvik A. Grcic V. Jahnsen F.L. Gaustad P. McCoy K.D. Macpherson A.J. Meza-Zepeda L.A. Johansen F.E. Depletion of murine intestinal microbiota: effects on gut mucosa and epithelial gene expression.PLoS One. 2011; 6: e17996Crossref PubMed Scopus (188) Google Scholar, 62Kostic A.D. Howitt M.R. Garrett W.S. Exploring host-microbiota interactions in animal models and humans.Genes Dev. 2013; 27: 701-718Crossref PubMed Scopus (195) Google Scholar, 63Ericsson A.C. Franklin C.L. Manipulating the gut microbiota: methods and challenges.ILAR J. 2015; 56: 205-217Crossref PubMed Scopus (30) Google Scholar, 64Hansen A.K. Krych L. Nielsen D.S. Hansen C.H. A review of applied aspects of dealing with gut microbiota impact on rodent models.ILAR J. 2015; 56: 250-264Crossref PubMed Scopus (7) Google Scholar, 65Franklin C.L. Ericsson A.C. Microbiota and reproducibility of rodent models.Lab Anim (NY). 2017; 46: 114-122Crossref PubMed Scopus (52) Google Scholar Experimental depletion protocols are commonly used as an alternative to the germ-free mouse model, whereas experimental disruption protocols are used to delineate how perturbations in the indigenous gut microbiota impact host physiology. Highly relevant to the current study, Guss et al66Guss J.D. Horsfield M.W. Fontenele F.F. Sandoval T.N. Luna M. Apoorva F. Lima S.F. Bicalho R.C. Singh A. Ley R.E. van der Meulen M.C. Goldring S.R. Hernandez C.J. Alterations to the gut microbiome impair bone strength and tissue material properties.J Bone Miner Res. 2017; 32: 1343-1353Crossref PubMed Scopus (0) Google Scholar published the first known report evaluating broad-spectrum antibiotic disruption of gut microbiota effects on skeletal outcomes. Continuous broad-spectrum antibiotic administration in male C57BL/6J mice (from 4 to 16 weeks of age) decreased whole bone mechanical properties, which were unrelated to inferior cortical bone morphologic parameters.66Guss J.D. Horsfield M.W. Fontenele F.F. Sandoval T.N. Luna M. Apoorva F. Lima S.F. Bicalho R.C. Singh A. Ley R.E. van der Meulen M.C. Goldring S.R. Hernandez C.J. Alterations to the gut microbiome impair bone strength and tissue material properties.J Bone Miner Res. 2017; 32: 1343-1353Crossref PubMed Scopus (0) Google Scholar Antibiotic perturbation of the normal gut microbiota during postnatal skeletal development has been shown to influence bone mass accrual60Cho I. Yamanishi S. Cox L. Methe B.A. Zavadil J. Li K. Gao Z. Mahana D. Raju K. Teitler I. Li H. Alekseyenko A.V. Blaser M.J. Antibiotics in early life alter the murine colonic microbiome and adiposity.Nature. 2012; 488: 621-626Crossref PubMed Scopus (777) Google Scholar, 66Guss J.D. Horsfield M.W. Fontenele F.F. Sandoval T.N. Luna M. Apoorva F. Lima S.F. Bicalho R.C. Singh A. Ley R.E. van der Meulen M.C. Goldring S.R. Hernandez C.J. Alterations to the gut microbiome impair bone strength and tissue material properties.J Bone Miner Res. 2017; 32: 1343-1353Crossref PubMed Scopus (0) Google Scholar and bone mechanical properties,66Guss J.D. Horsfield M.W. Fontenele F.F. Sandoval T.N. Luna M. Apoorva F. Lima S.

Referência(s)