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It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective inhibition of COX-2 on the small intestinal microbiota in the rat. In order to avoid mucosal damage due to topical effects and inflammation-driven microbial alterations, rofecoxib, a nonacidic compound, was used. The direct inhibitory effect of rofecoxib on the growth of bacteria was ruled out in vitro. The mucosa-sparing effect of rofecoxib was confirmed by macroscopic and histological analysis, as well as by measuring the intestinal levels of cytokines and tight junction proteins. Deep sequencing of bacterial 16S rRNA revealed that chronic rofecoxib treatment had no significant influence on the composition and diversity of jejunal microbiota. In conclusion, this is the first demonstration that long-term selective inhibition of COX-2 by rofecoxib does not cause small intestinal dysbiosis in rats. Moreover, inhibition of COX-2 activity is not likely to be responsible per se for microbial alterations caused by some coxibs, but other drug-specific properties may contribute to it.<\/jats:p>","DOI":"10.3390\/cells8030251","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T04:06:55Z","timestamp":1552882015000},"page":"251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Lack of Small Intestinal Dysbiosis Following Long-Term Selective Inhibition of Cyclooxygenase-2 by Rofecoxib in the Rat"],"prefix":"10.3390","volume":"8","author":[{"given":"Bernadette","family":"L\u00e1z\u00e1r","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor B.","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of 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Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.gtc.2009.03.007","article-title":"Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications","volume":"38","author":"Lanas","year":"2009","journal-title":"Gastroenterol. Clin. N. Am."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1053\/j.gastro.2011.06.075","article-title":"Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis","volume":"141","author":"Wallace","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1124\/jpet.112.197475","article-title":"Exacerbation of nonsteroidal anti-inflammatory drug-induced small intestinal lesions by antisecretory drugs in rats: The role of intestinal motility","volume":"343","author":"Satoh","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.3748\/wjg.v19.i12.1861","article-title":"Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy","volume":"19","author":"Wallace","year":"2013","journal-title":"World. J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1093\/toxsci\/kfs310","article-title":"Multiple NSAID-induced hits injure the small intestine: Underlying mechanisms and novel strategies","volume":"131","author":"Boelsterli","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1159\/000374106","article-title":"NSAID-induced small intestinal damage\u2014Roles of various pathogenic factors","volume":"91","author":"Takeuchi","year":"2015","journal-title":"Digestion"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1053\/j.gastro.2017.10.049","article-title":"Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs","volume":"154","author":"Bjarnason","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1053\/gast.1996.v111.pm8690211","article-title":"Characterization of Prostaglandin G\/H Synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts","volume":"111","author":"Kargman","year":"1996","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3228","DOI":"10.1073\/pnas.91.8.3228","article-title":"Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic","volume":"91","author":"Masferrer","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1046\/j.1365-2036.1999.00529.x","article-title":"Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen","volume":"13","author":"Lanza","year":"1999","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1056\/NEJM200011233432103","article-title":"Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group","volume":"343","author":"Bombardier","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1111\/j.1572-0241.2000.02194.x","article-title":"Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor","volume":"95","author":"Goldstein","year":"2000","journal-title":"Am. J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1001\/jama.284.10.1247","article-title":"Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study","volume":"284","author":"Silverstein","year":"2000","journal-title":"JAMA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0002-9343(00)00470-8","article-title":"A randomized trial measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects","volume":"109","author":"Hunt","year":"2000","journal-title":"Am. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1053\/gast.2003.50054","article-title":"Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use","volume":"124","author":"Laine","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0140-6736(10)60673-3","article-title":"Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): A randomised trial","volume":"376","author":"Chan","year":"2010","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S1542-3565(05)00980-8","article-title":"Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflmmatory bowel disease","volume":"4","author":"Takeuchi","year":"2006","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/0092-8674(95)90125-6","article-title":"Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse","volume":"83","author":"Morham","year":"1995","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1053\/gast.2002.33647","article-title":"COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice","volume":"122","author":"Sigthorsson","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.cgh.2007.04.031","article-title":"Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: A cross-sectional capsule enteroscopy study","volume":"5","author":"Maiden","year":"2007","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1172\/JCI119013","article-title":"Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2","volume":"98","author":"Reuter","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1111\/j.1572-0241.2001.03730.x","article-title":"Exacerbation of inflammatory bowel disease associated with use of celecoxib","volume":"96","author":"Bonner","year":"2001","journal-title":"Am. J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1097\/00054725-200407000-00005","article-title":"The spectrum of gastrointestinal toxicity and effect on disease activity of selective cyclooxygenase-2 inhibitors in patients with inflammatory bowel disease","volume":"10","author":"Matuk","year":"2004","journal-title":"Inflamm. Bowel. Dis."},{"key":"ref_26","first-page":"142","article-title":"Rofecoxib and inflammatory bowel disease: Clinical and pathologic observations","volume":"39","author":"Wilcox","year":"2005","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s00535-014-1032-1","article-title":"NSAID enteropathy and bacteria: A complicated relationship","volume":"50","author":"Syer","year":"2015","journal-title":"J. Gastroenterol."},{"key":"ref_28","first-page":"237","article-title":"Small intestinal ulcers and intestinal flora in rats given indomethacin","volume":"54","author":"Kent","year":"1969","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2152\/jmi.51.43","article-title":"Role of unbalanced growth of gram-negative bacteria in ileal ulcer formation in rats treated with a nonsteroidal anti-inflammatory drug","volume":"51","author":"Hagiwara","year":"2004","journal-title":"J. Med. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6707","DOI":"10.1128\/AEM.00378-06","article-title":"Culture-independent analysis of indomethacin-induced alterations in the rat gastrointestinal microbiota","volume":"72","author":"Dalby","year":"2006","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"G994","DOI":"10.1152\/ajpgi.00066.2015","article-title":"Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID","volume":"308","author":"Blackler","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"211","DOI":"10.4161\/gmic.2.4.17863","article-title":"Intestinal dysbiosis in inflammatory bowel disease","volume":"2","author":"Kaur","year":"2011","journal-title":"Gut. Microbes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1158\/1940-6207.CAPR-16-0095","article-title":"Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden","volume":"9","author":"Montrose","year":"2016","journal-title":"Cancer. Prev. Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Whitfield-Cargile, C.M., Chamoun-Emanuelli, A.M., Cohen, N.D., Richardson, L.M., Ajami, N.J., and Dockery, H.J. (2018). Differential effects of selective and non-selective cyclooxygenase inhibitors on fecal microbiota in adult horses. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202527"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.cmi.2016.01.013","article-title":"Celecoxib does not alter intestinal microbiome in a longitudinal diet-controlled study","volume":"22","author":"Bokulich","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1136\/gut.47.6.762","article-title":"Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa","volume":"47","author":"Jackson","year":"2000","journal-title":"Gut"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1080\/01926230590906512","article-title":"Differential expression of COX-1 and COX-2 in the gastrointestinal tract of the rat","volume":"33","author":"Haworth","year":"2005","journal-title":"Toxicol. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"750","DOI":"10.3389\/fmicb.2015.00750","article-title":"Repurposing celecoxib as a topical antimicrobial agent","volume":"6","author":"Thangamani","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1124\/jpet.113.207118","article-title":"NSAID-induced enteropathy: Are the currently available selective COX-2 inhibitors all the same?","volume":"348","author":"Fornai","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/mi.2016.75","article-title":"Mechanisms of inflammation-driven bacterial dysbiosis in the gut","volume":"10","author":"Zeng","year":"2017","journal-title":"Mucosal. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.2165\/00003088-200544120-00004","article-title":"Clinical pharmacology of lumiracoxib: A selective cyclo-oxygenase-2 inhibitor","volume":"44","author":"Rordorf","year":"2005","journal-title":"Clin. Pharmacokinet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ejpb.2008.10.019","article-title":"Computer simulations using GastroPlus to justify a biowaiver for etoricoxib solid oral drug products","volume":"72","author":"Okumu","year":"2009","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.tvjl.2014.07.025","article-title":"The pharmacokinetics and in vitro\/ex vivo cyclooxygenase selectivity of parecoxib and its active metabolite valdecoxib in cats","volume":"202","author":"Kim","year":"2014","journal-title":"Vet. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1365-2036.2007.03348.x","article-title":"Determinants of the short-term gastric damage caused by NSAIDs in man","volume":"26","author":"Bjarnason","year":"2007","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1038\/sj.bjp.0702420","article-title":"Limited anti-inflammatory efficacy of cyclo-oxygenase-2 inhibition in carrageenan-airpouch inflammation","volume":"126","author":"Wallace","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1124\/jpet.104.076877","article-title":"Valdecoxib: Assessment of cyclooxygenase-2 potency and selectivity","volume":"312","author":"Gierse","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1038\/ismej.2013.106","article-title":"Stochastic changes over time and not founder effects drive cage effects in microbial community assembly in a mouse model","volume":"7","author":"McCafferty","year":"2013","journal-title":"ISME J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.3748\/wjg.v20.i10.2641","article-title":"Sodium alginate ameliorates indomethacin-induced gastrointestinal mucosal injury via inhibiting translocation in rats","volume":"20","author":"Yamamoto","year":"2014","journal-title":"World. J. Gastroenterol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1053\/gast.1996.v111.pm8898641","article-title":"Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum","volume":"111","author":"Mantyh","year":"1996","journal-title":"Gastroenterology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/ja.2017.2","article-title":"Lipophilic teicoplanin pseudoaglycon derivatives are active against vancomycin- and teicoplanin-resistant enterococci","volume":"70","author":"Szucs","year":"2017","journal-title":"J. Antibiot."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/nar\/gks808","article-title":"Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies","volume":"41","author":"Klindworth","year":"2013","journal-title":"Nucleic. Acids. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"R46","DOI":"10.1186\/gb-2014-15-3-r46","article-title":"Kraken: Ultrafast metagenomic sequence classification using exact alignments","volume":"15","author":"Wood","year":"2014","journal-title":"Genome. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nmeth.f.303","article-title":"QIIME allows analysis of high-throughput community sequencing data","volume":"7","author":"Caporaso","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s10096-010-0921-3","article-title":"Emergence of a colistin-resistant KPC-2-producing Klebsiella pneumoniae ST258 clone in Hungary","volume":"29","author":"Toth","year":"2010","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"Faseb J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"545","DOI":"10.2165\/00003088-200342060-00004","article-title":"Pharmacokinetics of rofecoxib: A specific cyclo-oxygenase-2 inhibitor","volume":"42","author":"Davies","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.vascn.2015.11.008","article-title":"A novel model for NSAID induced gastroenteropathy in rats","volume":"78","author":"Singh","year":"2016","journal-title":"J. Pharmacol. Toxicol. Methods."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1111\/j.1462-2920.2009.01931.x","article-title":"The role of pH in determining the species composition of the human colonic microbiota","volume":"11","author":"Duncan","year":"2009","journal-title":"Environ. Microbiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"178.e1","DOI":"10.1016\/j.cmi.2015.10.003","article-title":"The influence of non-steroidal anti-inflammatory drugs on the gut microbiome","volume":"22","author":"Rogers","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.crohns.2014.02.001","article-title":"Specific changes of gut commensal microbiota and TLRs during indomethacin-induced acute intestinal inflammation in rats","volume":"8","author":"Aguilera","year":"2014","journal-title":"J. Crohns. Colitis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.3389\/fphar.2018.01340","article-title":"Pathophysiology of NSAID-Associated Intestinal Lesions in the Rat: Luminal Bacteria and Mucosal Inflammation as Targets for Prevention","volume":"9","author":"Colucci","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1017\/S0007114509991553","article-title":"The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition","volume":"103","author":"Makivuokko","year":"2010","journal-title":"Br. J. Nutr."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1002\/ibd.20602","article-title":"Mechanisms of action of probiotics: Recent advances","volume":"15","author":"Ng","year":"2009","journal-title":"Inflamm. Bowel. Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s00535-012-0648-2","article-title":"NSAID enteropathy: Could probiotics prevent it?","volume":"48","author":"Montalto","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1136\/gut.2007.125963","article-title":"Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent","volume":"57","author":"Watanabe","year":"2008","journal-title":"Gut"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nri3430","article-title":"Role of the gut microbiota in immunity and inflammatory disease","volume":"13","author":"Kamada","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1016\/S0140-6736(08)61490-7","article-title":"Cardiovascular events associated with rofecoxib: Final analysis of the APPROVe trial","volume":"372","author":"Baron","year":"2008","journal-title":"Lancet"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s00360-009-0440-7","article-title":"Segmental expression of claudin proteins correlates with tight junction barrier properties in rat intestine","volume":"180","author":"Markov","year":"2010","journal-title":"J. Comp. Physiol. B"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.3748\/wjg.v22.i11.3117","article-title":"Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer","volume":"22","author":"Landy","year":"2016","journal-title":"World. J. Gastroenterol."},{"key":"ref_71","first-page":"1","article-title":"Antimicrobial activity of flurbiprofen and ibuprofen in vitro against six common periodontal pathogens","volume":"3","author":"Hersh","year":"1991","journal-title":"J. Clin. Dent."},{"key":"ref_72","first-page":"1","article-title":"Antibacterial, Anti-biofilm Activity of Some Non-steroidal Anti-Inflammatory Drugs and N-acetyl Cysteine against Some Biofilm Producing Uropathogens","volume":"3","author":"Mohsen","year":"2015","journal-title":"Am. J. Epidemiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"45840","DOI":"10.1038\/srep45840","article-title":"Microbial Biogeography and Core Microbiota of the Rat Digestive Tract","volume":"8","author":"Li","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/3\/251\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:39:15Z","timestamp":1760186355000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/3\/251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,15]]},"references-count":73,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["cells8030251"],"URL":"https:\/\/doi.org\/10.3390\/cells8030251","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,15]]}}}