Das Mikrobiom – die unplanbare Größe zukünftiger Therapien

Zusammenfassung

Unter Mikrobiom versteht man die Gesamtheit der bakteriellen, parasitären, viralen oder anderen zellulären Mikroorganismen, die den menschlichen Körper oder ein anderes Lebewesen besiedeln. Das Mikrobiom zeigt in den anatomischen Bereichen der Hals-Nasen-Ohrenheilkunde eine deutliche regionale Varianz. Für die Bereiche von Ohr, Nase, Rachen, Larynx und Haut sind jeweils verschiedene Interaktionen des Mikrobiomes mit allgemeinen Faktoren wie Alter, Diät und Lebensstilfaktoren (z. B. Rauchen) in den letzten Jahren bekannt geworden. Zudem liegen eine Reihe von Erkenntnissen vor, dass das Mikrobiom an der Pathogenese verschiedener Erkrankungen auch im HNO-Bereich beteiligt ist. Der vorgestellte Übersichtsartikel fasst die wesentlichen Erkenntnisse dieses sich aktuell äußerst rasch entwickelnden Forschungsgebietes überblickartig zusammen.

Schlüsselwörter

Mikrobiom - Sinusitis - Kopf-Hals-Tumoren - Otitis

• Literatur

• 1 Smith K, McCoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol 2007; 19: 59-69
• 2 Sears CL, Pardoll DM. Perspective: alpha-bugs, their microbial partners, and the link to colon cancer. J Infect Dis 2011; 203: 306-311
• 3 Zhu L, Baker SS, Gill C. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57: 601-609
• 4 Zhu Q, Gao R, Wu W . et al. The role of gut microbiota in the pathogenesis of colorectal cancer. Tumour Biol 2013; 34: 1285-1300
• 5 Sheflin AM, Whitney AK, Weir TL. Cancer-promoting effects of microbial dysbiosis. Curr Oncol Rep 2014; 16: 406
• 6 Boone DR, Castenholz RW, Garrity GM. et al. Bergey's Manual^® of Systematic Bacteriology. Springer; 2001
• 7 Stallmach A, Vehreschild MJGT. Mikrobiom: Wissensstand und Perspektiven. Walter de Gruyter GmbH & Co KG; 2016
• 8 Roesch LF, Casella G, Simell O. et al. Influence of fecal sample storage on bacterial community diversity. Open Microbiol J 2009; 3: 40-46
• 9 Tal M, Verbrugghe A, Gomez DE. et al. The effect of storage at ambient temperature on the feline fecal microbiota. BMC. Vet Res 2017; 13: 256
• 10 Carroll IM, Ringel-Kulka T, Siddle JP. et al. Characterization of the fecal microbiota using high-throughput sequencing reveals a stable microbial community during storage. PLoS One 2012; 7: e46953
• 11 Kia E, Wagner Mackenzie B, Middleton D. et al. Integrity of the Human Faecal Microbiota following Long-Term Sample Storage. PLoS One 2016; 11: e0163666
• 12 Bai G, Gajer P, Nandy M. et al. Comparison of storage conditions for human vaginal microbiome studies. PLoS One 2012; 7: e36934
• 13 Hanshew AS, Jette ME, Tadayon S. et al. A comparison of sampling methods for examining the laryngeal microbiome. PLoS One 2017; 12: e0174765
• 14 Bassiouni A, Cleland EJ, Psaltis AJ. et al. Sinonasal microbiome sampling: a comparison of techniques. PLoS One 2015; 10: e0123216
• 15 Kumar R, Eipers P, Little RB. et al. Getting started with microbiome analysis: sample acquisition to bioinformatics. Curr Protoc Hum Genet 2014; 82: 18 18 11-18 18 29
• 16 Goodrich JK, Di Rienzi SC, Poole AC. et al. Conducting a microbiome study. Cell 2014; 158: 250-262
• 17 Navas-Molina JA, Peralta-Sanchez JM, Gonzalez A. et al. Advancing our understanding of the human microbiome using QIIME. Methods Enzymol 2013; 531: 371-444
• 18 Caporaso JG, Kuczynski J, Stombaugh J. et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010; 7: 335-336
• 19 Kuczynski J, Stombaugh J, Walters WA. et al. Using QIIME to analyze 16S rRNA gene sequences from microbial communities. Curr Protoc Microbiol 2012; Chapter 1: Unit 1E 5
• 20 Leray M, Knowlton N. Visualizing Patterns of Marine Eukaryotic Diversity from Metabarcoding Data Using QIIME. Methods Mol Biol 2016; 1452: 219-235
• 21 Lawley B, Tannock GW. Analysis of 16S rRNA Gene Amplicon Sequences Using the QIIME Software Package. Methods Mol Biol 2017; 1537: 153-163
• 22 Schloss PD, Westcott SL, Ryabin T. et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 2009; 75: 7537-7541
• 23 Yang S, Liebner S, Alawi M. et al. Taxonomic database and cut-off value for processing mcrA gene 454 pyrosequencing data by MOTHUR. J Microbiol Methods 2014; 103: 3-5
• 24 Maidak BL, Olsen GJ, Larsen N. et al. The Ribosomal Database Project (RDP). Nucleic Acids Res 1996; 24: 82-85
• 25 Maidak BL, Cole JR, Lilburn TG. et al. The RDP-II (Ribosomal Database Project). Nucleic Acids Res 2001; 29: 173-174
• 26 Cole JR, Chai B, Farris RJ. et al. The Ribosomal Database Project (RDP-II): sequences and tools for high-throughput rRNA analysis. Nucleic Acids Res 2005; 33: D294-D296
• 27 Bacci G, Bani A, Bazzicalupo M. et al. Evaluation of the Performances of Ribosomal Database Project (RDP) Classifier for Taxonomic Assignment of 16S rRNA Metabarcoding Sequences Generated from Illumina-Solexa NGS. J Genomics 2015; 3: 36-39
• 28 Huse SM, Mark Welch DB, Voorhis A. et al. VAMPS: a website for visualization and analysis of microbial population structures. BMC Bioinformatics 2014; 15: 41
• 29 Suzuk Yildiz S, Kaskatepe B, Altinok S. et al. [Comparison of MALDI-TOF and 16S rRNA methods in identification of viridans group streptococci]. Mikrobiyol Bul 2017; 51: 1-9
• 30 Barberis C, Almuzara M, Join-Lambert O. et al. Comparison of the Bruker MALDI-TOF mass spectrometry system and conventional phenotypic methods for identification of Gram-positive rods. PLoS One 2014; 9: e106303
• 31 Funke G, von Graevenitz A, Clarridge 3rd JE. et al. Clinical microbiology of coryneform bacteria. Clin Microbiol Rev 1997; 10: 125-159
• 32 Allali I, Arnold JW, Roach J. et al. A comparison of sequencing platforms and bioinformatics pipelines for compositional analysis of the gut microbiome. BMC Microbiol 2017; 17: 194
• 33 Hawinkel S, Mattiello F, Bijnens L. et al. A broken promise: microbiome differential abundance methods do not control the false discovery rate. Brief Bioinform 2017;
• 34 Lemos LN, Fulthorpe RR, Triplett EW. et al. Rethinking microbial diversity analysis in the high throughput sequencing era. J Microbiol Methods 2011; 86: 42-51
• 35 Stulberg E, Fravel D, Proctor LM. et al. An assessment of US microbiome research. Nat Microbiol 2016; 1: 15015
• 36 Spor A, Koren O, Ley R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol 2011; 9: 279-290
• 37 Slifierz MJ, Friendship RM, Weese JS. Longitudinal study of the early-life fecal and nasal microbiotas of the domestic pig. BMC Microbiol 2015; 15: 184
• 38 Thevaranjan N, Whelan FJ, Puchta A. et al. Streptococcus pneumoniae Colonization Disrupts the Microbial Community within the Upper Respiratory Tract of Aging Mice. Infect Immun 2016; 84: 906-916
• 39 Renteria AE, Mfuna Endam L, Desrosiers M. Do Aging Factors Influence the Clinical Presentation and Management of Chronic Rhinosinusitis?. Otolaryngol Head Neck Surg 2017; 156: 598-605
• 40 Whelan FJ, Verschoor CP, Stearns JC. et al. The loss of topography in the microbial communities of the upper respiratory tract in the elderly. Ann Am Thorac Soc 2014; 11: 513-521
• 41 Biagi E, Nylund L, Candela M. et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 2010; 5: e10667
• 42 van Beek AA, Hugenholtz F, Meijer B. et al. Frontline Science: Tryptophan restriction arrests B cell development and enhances microbial diversity in WT and prematurely aging Ercc1-/Delta7 mice. J Leukoc Biol 2017; 101: 811-821
• 43 Schneeberger M, Everard A, Gomez-Valades AG. et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep 2015; 5: 16643
• 44 Gomez A, Luckey D, Taneja V. The gut microbiome in autoimmunity: Sex matters. Clin Immunol 2015; 159: 154-162
• 45 Mueller S, Saunier K, Hanisch C. et al. Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study. Appl Environ Microbiol 2006; 72: 1027-1033
• 46 Wu J, Peters BA, Dominianni C. et al. Cigarette smoking and the oral microbiome in a large study of American adults. ISME J 2016; 10: 2435-2446
• 47 Charlson ES, Chen J, Custers-Allen R. et al. Disordered microbial communities in the upper respiratory tract of cigarette smokers. PLoS One 2010; 5: e15216
• 48 Lee J, Taneja V, Vassallo R. Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dent Res 2012; 91: 142-149
• 49 Verna L, Whysner J, Williams GM. N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacol Ther 1996; 71: 57-81
• 50 Wang L, Ganly I. The oral microbiome and oral cancer. Clin Lab Med 2014; 34: 711-719
• 51 Labriola A, Needleman I, Moles DR. Systematic review of the effect of smoking on nonsurgical periodontal therapy. Periodontol 2000 2005; 37: 124-137
• 52 Coretti L, Cuomo M, Florio E. et al. Subgingival dysbiosis in smoker and nonsmoker patients with chronic periodontitis. Mol Med Rep 2017; 15: 2007-2014
• 53 Yu G, Phillips S, Gail MH. et al. The effect of cigarette smoking on the oral and nasal microbiota. Microbiome 2017; 5: 3
• 54 Peralbo-Molina A, Calderon-Santiago M, Jurado-Gamez B. et al. Exhaled breath condensate to discriminate individuals with different smoking habits by GC-TOF/MS. Sci Rep 2017; 7: 1421
• 55 Filipiak W, Ruzsanyi V, Mochalski P. et al. Dependence of exhaled breath composition on exogenous factors, smoking habits and exposure to air pollutants. J Breath Res 2012; 6: 036008
• 56 Falana K, Knight R, Martin CR. et al. Short Course in the Microbiome. J Circ Biomark 2015; 4: 8
• 57 Greenberg D, Givon-Lavi N, Broides A. et al. The contribution of smoking and exposure to tobacco smoke to Streptococcus pneumoniae and Haemophilus influenzae carriage in children and their mothers. Clin Infect Dis 2006; 42: 897-903
• 58 Turnbaugh PJ, Backhed F, Fulton L. et al. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008; 3: 213-223
• 59 Kaczmarek JL, Musaad SM, Holscher HD. Time of day and eating behaviors are associated with the composition and function of the human gastrointestinal microbiota. Am J Clin Nutr 2017; 106: 1220-1231
• 60 Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995; 125: 1401-1412
• 61 Staudacher HM, Whelan K. Altered gastrointestinal microbiota in irritable bowel syndrome and its modification by diet: probiotics, prebiotics and the low FODMAP diet. Proc Nutr Soc 2016; 75: 306-318
• 62 Walsh CJ, Guinane CM, O'Toole PW. et al. Beneficial modulation of the gut microbiota. FEBS Lett 2014; 588: 4120-4130
• 63 De Vadder F, Kovatcheva-Datchary P, Goncalves D. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014; 156: 84-96
• 64 Cleland EJ, Drilling A, Bassiouni A. et al. Probiotic manipulation of the chronic rhinosinusitis microbiome. Int Forum Allergy Rhinol 2014; 4: 309-314
• 65 Iwase T, Uehara Y, Shinji H. et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature 2010; 465: 346-349
• 66 Manning J, Dunne EM, Wescombe PA. et al. Investigation of Streptococcus salivarius-mediated inhibition of pneumococcal adherence to pharyngeal epithelial cells. BMC Microbiol 2016; 16: 225
• 67 World Cancer Research Fund / American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR 2007. Nachlesbar unter http://www.aicr.org/assets/docs/pdf/reports/Second_Expert_Report.pdf; ISBN: 978-0-9722522-2-5
• 68 Muto M, Hitomi Y, Ohtsu A. et al. Acetaldehyde production by non-pathogenic Neisseria in human oral microflora: implications for carcinogenesis in upper aerodigestive tract. Int J Cancer 2000; 88: 342-350
• 69 Dubinkina VB, Tyakht AV, Odintsova VY. et al. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease. Microbiome 2017; 5: 141
• 70 Mangin I, Leveque C, Magne F. et al. Long-term changes in human colonic Bifidobacterium populations induced by a 5-day oral amoxicillin-clavulanic acid treatment. PLoS One 2012; 7: e50257
• 71 De La Cochetiere MF, Durand T, Lepage P. et al. Resilience of the dominant human fecal microbiota upon short-course antibiotic challenge. J Clin Microbiol 2005; 43: 5588-5592
• 72 Pols DHJ, Nielen MMJ, Bohnen AM. et al. Atopic children and use of prescribed medication: A comprehensive study in general practice. PLoS One 2017; 12: e0182664
• 73 Feazel LM, Santorico SA, Robertson CE. et al. Effects of Vaccination with 10-Valent Pneumococcal Non-Typeable Haemophilus influenza Protein D Conjugate Vaccine (PHiD-CV) on the Nasopharyngeal Microbiome of Kenyan Toddlers. PLoS One 2015; 10: e0128064
• 74 Jespersen L, Tarnow I, Eskesen D. et al. Effect of Lactobacillus paracasei subsp. paracasei, L. casei 431 on immune response to influenza vaccination and upper respiratory tract infections in healthy adult volunteers: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Clin Nutr 2015; 101: 1188-1196
• 75 Chan CL, Wabnitz D, Bardy JJ. et al. The microbiome of otitis media with effusion. Laryngoscope 2016; 126: 2844-2851
• 76 Krueger A, Val S, Perez-Losada M. et al. Relationship of the Middle Ear Effusion Microbiome to Secretory Mucin Production in Pediatric Patients With Chronic Otitis Media. Pediatr Infect Dis J 2017; 36: 635-640
• 77 Jervis-Bardy J, Rogers GB, Morris PS. et al. The microbiome of otitis media with effusion in Indigenous Australian children. Int J Pediatr Otorhinolaryngol 2015; 79: 1548-1555
• 78 Liu CM, Cosetti MK, Aziz M. et al. The otologic microbiome: a study of the bacterial microbiota in a pediatric patient with chronic serous otitis media using 16SrRNA gene-based pyrosequencing. Arch Otolaryngol Head Neck Surg 2011; 137: 664-668
• 79 Santos-Cortez RL, Hutchinson DS, Ajami NJ. et al. Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene. Infect Dis Poverty 2016; 5: 97
• 80 Fokkens WJ, Lund VJ, Mullol J. et al. European Position Paper on Rhinosinusitis and Nasal Polyps. 2012; Rhinol Suppl 2012; 23: 3 p preceding table of contents, 1-298
• 81 Zuliani G, Carron M, Gurrola J. et al. Identification of adenoid biofilms in chronic rhinosinusitis. Int J Pediatr Otorhinolaryngol 2006; 70: 1613-1617
• 82 Beule AG, Hosemann W. [Bacterial biofilms]. Laryngorhinootologie 2007; 86: 886-895 quiz 896–889
• 83 Subtil J, Rodrigues JC, Reis L. et al. Adenoid bacterial colonization in a paediatric population. Eur Arch Otorhinolaryngol 2017; 274: 1933-1938
• 84 Taylan I, Ozcan I, Mumcuoglu I. et al. Comparison of the surface and core bacteria in tonsillar and adenoid tissue with Beta-lactamase production. Indian J Otolaryngol Head Neck Surg 2011; 63: 223-228
• 85 Perez GF, Perez-Losada M, Isaza N. et al. Nasopharyngeal microbiome in premature infants and stability during rhinovirus infection. J Investig Med 2017; 65: 984-990
• 86 Perez-Losada M, Alamri L, Crandall KA. et al. Nasopharyngeal Microbiome Diversity Changes over Time in Children with Asthma. PLoS One 2017; 12: e0170543
• 87 Rosas-Salazar C, Shilts MH, Tovchigrechko A. et al. Differences in the Nasopharyngeal Microbiome During Acute Respiratory Tract Infection With Human Rhinovirus and Respiratory Syncytial Virus in Infancy. J Infect Dis 2016; 214: 1924-1928
• 88 Rosas-Salazar C, Shilts MH, Tovchigrechko A. et al. Nasopharyngeal Microbiome in Respiratory Syncytial Virus Resembles Profile Associated with Increased Childhood Asthma Risk. Am J Respir Crit Care Med 2016; 193: 1180-1183
• 89 Teo SM, Mok D, Pham K. et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 2015; 17: 704-715
• 90 Xu L, Zhu Y, Ren L. et al. Characterization of the nasopharyngeal viral microbiome from children with community-acquired pneumonia but negative for Luminex xTAG respiratory viral panel assay detection. J Med Virol 2017;
• 91 Lysholm F, Wetterbom A, Lindau C. et al. Characterization of the viral microbiome in patients with severe lower respiratory tract infections, using metagenomic sequencing. PLoS One 2012; 7: e30875
• 92 Cremers AJ, Zomer AL, Gritzfeld JF. et al. The adult nasopharyngeal microbiome as a determinant of pneumococcal acquisition. Microbiome 2014; 2: 44
• 93 Lal D, Keim P, Delisle J. et al. Mapping and comparing bacterial microbiota in the sinonasal cavity of healthy, allergic rhinitis, and chronic rhinosinusitis subjects. Int Forum Allergy Rhinol 2017; 7: 561-569
• 94 Ivanchenko OA, Karpishchenko SA, Kozlov RS. et al. The microbiome of the maxillary sinus and middle nasal meatus in chronic rhinosinusitis. Rhinology 2016; 54: 68-74
• 95 Cleland EJ, Bassiouni A, Boase S. et al. The fungal microbiome in chronic rhinosinusitis: richness, diversity, postoperative changes and patient outcomes. Int Forum Allergy Rhinol 2014; 4: 259-265
• 96 Martensson A, Greiff L, Lamei SS. et al. Effects of a honeybee lactic acid bacterial microbiome on human nasal symptoms, commensals, and biomarkers. Int Forum Allergy Rhinol 2016; 6: 956-963
• 97 Noverr MC, Huffnagle GB. The 'microflora hypothesis' of allergic diseases. Clin Exp Allergy 2005; 35: 1511-1520
• 98 Bisgaard H, Li N, Bonnelykke K. et al. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J Allergy Clin Immunol 2011; 128: 646-652 e641–645
• 99 Sjogren YM, Jenmalm MC, Bottcher MF. et al. Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin Exp Allergy 2009; 39: 518-526
• 100 Abrahamsson TR, Jakobsson HE, Andersson AF. et al. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy 2014; 44: 842-850
• 101 Huang YJ. Asthma microbiome studies and the potential for new therapeutic strategies. Curr Allergy Asthma Rep 2013; 13: 453-461
• 102 Hansel TT, Johnston SL, Openshaw PJ. Microbes and mucosal immune responses in asthma. Lancet 2013; 381: 861-873
• 103 Suzaki H, Watanabe S, Pawankar R. Rhinosinusitis and asthma-microbiome and new perspectives. Curr Opin Allergy Clin Immunol 2013; 13: 45-49
• 104 Herbst T, Sichelstiel A, Schar C. et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am J Respir Crit Care Med 2011; 184: 198-205
• 105 Cait A, Hughes MR, Antignano F. et al. Microbiome-driven allergic lung inflammation is ameliorated by short-chain fatty acids. Mucosal Immunol 2017;
• 106 Marsland BJ. Regulation of inflammatory responses by the commensal microbiota. Thorax 2012; 67: 93-94
• 107 Ramakrishnan VR, Feazel LM, Gitomer SA. et al. The microbiome of the middle meatus in healthy adults. PLoS One 2013; 8: e85507
• 108 Ramakrishnan VR, Gitomer S, Kofonow JM. et al. Investigation of sinonasal microbiome spatial organization in chronic rhinosinusitis. Int Forum Allergy Rhinol 2017; 7: 16-23
• 109 Du Q, Li M, Zhou X. et al. A comprehensive profiling of supragingival bacterial composition in Chinese twin children and their mothers. Antonie Van Leeuwenhoek 2017; 110: 615-627
• 110 Abusleme L, Dupuy AK, Dutzan N. et al. The subgingival microbiome in health and periodontitis and its relationship with community biomass and inflammation. ISME J 2013; 7: 1016-1025
• 111 Ai D, Huang R, Wen J. et al. Integrated metagenomic data analysis demonstrates that a loss of diversity in oral microbiota is associated with periodontitis. BMC Genomics 2017; 18: 1041
• 112 Adriaens LM, Alessandri R, Sporri S. et al. Does pregnancy have an impact on the subgingival microbiota?. J Periodontol 2009; 80: 72-81
• 113 Zhang M, Chen Y, Xie L. et al. Pyrosequencing of Plaque Microflora In Twin Children with Discordant Caries Phenotypes. PLoS One 2015; 10: e0141310
• 114 Ling Z, Kong J, Jia P. et al. Analysis of oral microbiota in children with dental caries by PCR-DGGE and barcoded pyrosequencing. Microb Ecol 2010; 60: 677-690
• 115 Jiang W, Zhang J, Chen H. Pyrosequencing analysis of oral microbiota in children with severe early childhood dental caries. Curr Microbiol 2013; 67: 537-542
• 116 Xu H, Hao W, Zhou Q. et al. Plaque bacterial microbiome diversity in children younger than 30 months with or without caries prior to eruption of second primary molars. PLoS One 2014; 9: e89269
• 117 Ahn J, Yang L, Paster BJ. et al. Oral microbiome profiles: 16S rRNA pyrosequencing and microarray assay comparison. PLoS One 2011; 6: e22788
• 118 Hasan NA, Young BA, Minard-Smith AT. et al. Microbial community profiling of human saliva using shotgun metagenomic sequencing. PLoS One 2014; 9: e97699
• 119 Abeles SR, Jones MB, Santiago-Rodriguez TM. et al. Microbial diversity in individuals and their household contacts following typical antibiotic courses. Microbiome 2016; 4: 39
• 120 Ling Z, Liu X, Wang Y. et al. Pyrosequencing analysis of the salivary microbiota of healthy Chinese children and adults. Microb Ecol 2013; 65: 487-495
• 121 Guerrero-Preston R, Godoy-Vitorino F, Jedlicka A. et al. 16S rRNA amplicon sequencing identifies microbiota associated with oral cancer, human papilloma virus infection and surgical treatment. Oncotarget 2016; 7: 51320-51334
• 122 Goodson JM, Hartman ML, Shi P. et al. The salivary microbiome is altered in the presence of a high salivary glucose concentration. PLoS One 2017; 12: e0170437
• 123 Zhou J, Jiang N, Wang Z. et al. Influences of pH and Iron Concentration on the Salivary Microbiome in Individual Humans with and without Caries. Appl Environ Microbiol 2017; 83: e02412-e02416
• 124 Foxman B, Luo T, Srinivasan U. et al. The effects of family, dentition, and dental caries on the salivary microbiome. Ann Epidemiol 2016; 26: 348-354
• 125 Mashima I, Theodorea CF, Thaweboon B. et al. Exploring the salivary microbiome of children stratified by the oral hygiene index. PLoS One 2017; 12: e0185274
• 126 Hamuro K, Kotani Y, Toba M. et al. Comparison of salivary IgA secretion rate collected by the aspiration method and swab method. Biosci Microbiota Food Health 2013; 32: 107-112
• 127 Takayasu L, Suda W, Takanashi K. et al. Circadian oscillations of microbial and functional composition in the human salivary microbiome. DNA Res 2017; 24: 261-270
• 128 Cameron SJ, Huws SA, Hegarty MJ. et al. The human salivary microbiome exhibits temporal stability in bacterial diversity. FEMS Microbiol Ecol 2015; 91: fiv091
• 129 Belstrom D, Holmstrup P, Bardow A. et al. Temporal Stability of the Salivary Microbiota in Oral Health. PLoS One 2016; 11: e0147472
• 130 Shaw L, Ribeiro ALR, Levine AP. et al. The Human Salivary Microbiome Is Shaped by Shared Environment Rather than Genetics: Evidence from a Large Family of Closely Related Individuals. MBio 2017; 8(5): e01237-17
• 131 Lazarevic V, Whiteson K, Gaia N. et al. Analysis of the salivary microbiome using culture-independent techniques. J Clin Bioinforma 2012; 2: 4-4 doi: 10.1186/2043-9113-2-4
• 132 Abrao AL, Falcao DP, de Amorim RF. et al. Salivary proteomics: A new adjuvant approach to the early diagnosis of familial juvenile systemic lupus erythematosus. Med Hypotheses 2016; 89: 97-100
• 133 Wolf A, Moissl-Eichinger C, Perras A. et al. The salivary microbiome as an indicator of carcinogenesis in patients with oropharyngeal squamous cell carcinoma: A pilot study. Sci Rep 2017; 7: 5867
• 134 Coit P, Mumcu G, Ture-Ozdemir F. et al. Sequencing of 16S rRNA reveals a distinct salivary microbiome signature in Behcet's disease. Clin Immunol 2016; 169: 28-35
• 135 Asama T, Arima TH, Gomi T. et al. Lactobacillus kunkeei YB38 from honeybee products enhances IgA production in healthy adults. J Appl Microbiol 2015; 119: 818-826
• 136 Hasslof P, West CE, Videhult FK. et al. Early intervention with probiotic Lactobacillus paracasei F19 has no long-term effect on caries experience. Caries Res 2013; 47: 559-565
• 137 Dos Santos AL, Jorge AO, Dos Santos SS. et al. Influence of probiotics on Candida presence and IgA anti-Candida in the oral cavity. Braz J Microbiol 2009; 40: 960-964
• 138 Dassi E, Ballarini A, Covello G. et al. Enhanced microbial diversity in the saliva microbiome induced by short-term probiotic intake revealed by 16S rRNA sequencing on the IonTorrent PGM platform. J Biotechnol 2014; 190: 30-39
• 139 Soderling E, ElSalhy M, Honkala E. et al. Effects of short-term xylitol gum chewing on the oral microbiome. Clin Oral Investig 2015; 19: 237-244
• 140 Gong HL, Shi Y, Zhou L. et al. The Composition of Microbiome in Larynx and the Throat Biodiversity between Laryngeal Squamous Cell Carcinoma Patients and Control Population. PLoS One 2013; 8: e66476
• 141 Gong H, Shi Y, Zhou X. et al. Microbiota in the Throat and Risk Factors for Laryngeal Carcinoma. Appl Environ Microbiol 2014; 80: 7356-7363
• 142 Gong H, Wang B, Shi Y. et al. Composition and abundance of microbiota in the pharynx in patients with laryngeal carcinoma and vocal cord polyps. J Microbiol 2017; 55: 648-654
• 143 Humphreys GJ, McBain AJ. Continuous culture of sessile human oropharyngeal microbiotas. J Med Microbiol 2013; 62: 906-916
• 144 Jensen A, Fago-Olsen H, Sorensen CH. et al. Molecular mapping to species level of the tonsillar crypt microbiota associated with health and recurrent tonsillitis. PLoS One 2013; 8: e56418
• 145 Watanabe H, Goto S, Mori H. et al. Comprehensive microbiome analysis of tonsillar crypts in IgA nephropathy. Nephrol Dial Transplant 2016;
• 146 Tejesvi MV, Uhari M, Tapiainen T. et al. Tonsillar microbiota in children with PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome. Eur J Clin Microbiol Infect Dis 2016; 35: 963-970
• 147 Khadilkar MN, Ankle NR. Anaerobic Bacteriological Microbiota in Surface and Core of Tonsils in Chronic Tonsillitis. J Clin Diagn Res 2016; 10: MC01-MC03
• 148 Gul M, Okur E, Ciragil P. et al. The comparison of tonsillar surface and core cultures in recurrent tonsillitis. Am J Otolaryngol 2007; 28: 173-176
• 149 Iwamura Y, Hayashi J, Sato T. et al. Assessment of oral malodor and tonsillar microbiota after gargling with benzethonium chloride. J Oral Sci 2016; 58: 83-91
• 150 Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016; 535: 75-84
• 151 Thaiss CA, Zmora N, Levy M. et al. The microbiome and innate immunity. Nature 2016; 535: 65-74
• 152 Sonnenberg GF, Monticelli LA, Alenghat T. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 2012; 336: 1321-1325
• 153 Sawahata M, Nakamura Y, Sugiyama Y. Appendectomy, tonsillectomy, and risk for sarcoidosis – A hospital-based case-control study in Japan. Respir Investig 2017; 55: 196-202
• 154 Hanshew AS, Jette ME, Thibeault SL. Characterization and comparison of bacterial communities in benign vocal fold lesions. Microbiome 2014; 2: 43
• 155 Gong H, Shi Y, Xiao X. et al. Alterations of microbiota structure in the larynx relevant to laryngeal carcinoma. Sci Rep 2017; 7: 5507
• 156 Lohmann P, Luna RA, Hollister EB. et al. The airway microbiome of intubated premature infants: characteristics and changes that predict the development of bronchopulmonary dysplasia. Pediatr Res 2014; 76: 294-301
• 157 Kelly BJ, Imai I, Bittinger K. et al. Composition and dynamics of the respiratory tract microbiome in intubated patients. Microbiome 2016; 4: 7
• 158 Hotterbeekx A, Xavier BB, Bielen K. et al. The endotracheal tube microbiome associated with Pseudomonas aeruginosa or Staphylococcus epidermidis. Sci Rep 2016; 6: 36507
• 159 Perez-Losada M, Graham RJ, Coquillette M. et al. The temporal dynamics of the tracheal microbiome in tracheostomised patients with and without lower respiratory infections. PLoS One 2017; 12: e0182520
• 160 Jette ME, Dill-McFarland KA, Hanshew AS. et al. The human laryngeal microbiome: effects of cigarette smoke and reflux. Sci Rep 2016; 6: 35882
• 161 Castellani C, Singer G, Kashofer K. et al. The Influence of Proton Pump Inhibitors on the Fecal Microbiome of Infants with Gastroesophageal Reflux-A Prospective Longitudinal Interventional Study. Front Cell Infect Microbiol 2017; 7: 444
• 162 Yang L, Chaudhary N, Baghdadi J. et al. Microbiome in reflux disorders and esophageal adenocarcinoma. Cancer J 2014; 20: 207-210
• 163 Lagergren J, Bergstrom R, Lindgren A. et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999; 340: 825-831
• 164 Yang H, Gu J, Wang KK. et al. MicroRNA expression signatures in Barrett's esophagus and esophageal adenocarcinoma. Clin Cancer Res 2009; 15: 5744-5752
• 165 Maret-Ouda J, Wahlin K, Artama M. et al. Cohort profile: the Nordic Antireflux Surgery Cohort (NordASCo). BMJ Open 2017; 7: e016505
• 166 Pevsner-Fischer M, Tuganbaev T, Meijer M. et al. Role of the microbiome in non-gastrointestinal cancers. World J Clin Oncol 2016; 7: 200-213
• 167 Kilkkinen A, Rissanen H, Klaukka T. et al. Antibiotic use predicts an increased risk of cancer. Int J Cancer 2008; 123: 2152-2155
• 168 Schmidt BL, Kuczynski J, Bhattacharya A. et al. Changes in abundance of oral microbiota associated with oral cancer. PLoS One 2014; 9: e98741
• 169 Zeng XT, Deng AP, Li C. et al. Periodontal disease and risk of head and neck cancer: a meta-analysis of observational studies. PLoS One 2013; 8: e79017
• 170 Shin JM, Luo T, Kamarajan P. et al. Microbial Communities Associated with Primary and Metastatic Head and Neck Squamous Cell Carcinoma - A High Fusobacterial and Low Streptococcal Signature. Sci Rep 2017; 7: 9934
• 171 Schollkopf C, Melbye M, Munksgaard L. et al. Borrelia infection and risk of non-Hodgkin lymphoma. Blood 2008; 111: 5524-5529
• 172 Chang CM, Landgren O, Koshiol J. et al. Borrelia and subsequent risk of solid tumors and hematologic malignancies in Sweden. Int J Cancer 2012; 131: 2208-2209
• 173 Aigelsreiter A, Leitner E, Deutsch AJ. et al. Chlamydia psittaci in MALT lymphomas of ocular adnexals: the Austrian experience. Leuk Res 2008; 32: 1292-1294
• 174 Aigelsreiter A, Gerlza T, Deutsch AJ. et al. Chlamydia psittaci Infection in nongastrointestinal extranodal MALT lymphomas and their precursor lesions. Am J Clin Pathol 2011; 135: 70-75
• 175 Topalian SL, Taube JM, Anders RA. et al. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016; 16: 275-287
• 176 Lipson EJ, Forde PM, Hammers HJ. et al. Antagonists of PD-1 and PD-L1 in Cancer Treatment. Semin Oncol 2015; 42: 587-600
• 177 Okazaki T, Chikuma S, Iwai Y. et al. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 2013; 14: 1212-1218
• 178 Lazar-Molnar E, Yan Q, Cao E. et al. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci U S A 2008; 105: 10483-10488
• 179 Xu J, Sun HH, Fletcher CD. et al. Expression of Programmed Cell Death 1 Ligands (PD-L1 and PD-L2) in Histiocytic and Dendritic Cell Disorders. Am J Surg Pathol 2016; 40: 443-453
• 180 Yamazaki T, Akiba H, Iwai H. et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002; 169: 5538-5545
• 181 Jiao Q, Liu C, Li W. et al. Programmed death-1 ligands 1 and 2 expression in cutaneous squamous cell carcinoma and their relationship with tumour-infiltrating dendritic cells. Clin Exp Immunol 2017; 188: 420-429
• 182 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252-264
• 183 Pardoll D. Cancer and the Immune System: Basic Concepts and Targets for Intervention. Semin Oncol 2015; 42: 523-538
• 184 Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 2007; 13: 5271-5279
• 185 Iida N, Dzutsev A, Stewart CA. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013; 342: 967-970
• 186 Vetizou M, Pitt JM, Daillere R. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350: 1079-1084
• 187 Dubin K, Callahan MK, Ren B. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun 2016; 7: 10391
• 188 Sivan A, Corrales L, Hubert N. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350: 1084-1089