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Therefore, we aimed to map the genomic content of, and the biological pathways encoded by, the microbiomes associated with these clinical phenotypes. We also estimated the extent to which these biomes are governed by the Anna Karenina principle (AKP), which states that eubiotic communities are similar between individuals while disease-associated communities are highly individualized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We collected subgingival plaque from 25 periodontally healthy individuals and diseased sites of 59 subjects with stage 3 periodontitis and used shotgun metagenomics to characterize the aggregate of bacterial genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Beta-dispersion metrics demonstrated that AKP was most evident in CP, followed by GAP and LAP. We discovered broad dysbiotic signatures spanning the three phenotypes, with over-representation of pathways that facilitate life in an oxygen-poor, protein- and heme-rich, pro-oxidant environment and enhance capacity for attachment and biofilm formation. Phenotype-specific indicators were more readily evident in LAP microbiome than GAP or CP. Genes that enable acetate-scavenging lifestyle, utilization of alternative nutritional sources, oxidative and nitrosative stress responses, and siderophore production were unique to LAP. An attenuation of virulence-related functionalities and stress response from LAP to GAP to CP was apparent. We also discovered that clinical phenotypes of disease resolved variance in the microbiome with greater clarity than the newly established grading system. Importantly, we observed that one third of the metagenome of LAP is unique to this phenotype while GAP shares significant functional and taxonomic features with both LAP and CP, suggesting either attenuation of an aggressive disease or an early-onset chronic disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Within the limitations of a small sample size and a cross-sectional study design, the distinctive features of the microbiomes associated with LAP and CP strongly persuade us that these are discrete disease entities, while calling into question whether GAP is a separate disease, or an artifact induced by cross-sectional study designs. Further studies on phenotype-specific microbial genes are warranted to explicate their role in disease etiology.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s40168-021-01056-3","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T08:24:43Z","timestamp":1620030283000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Anna Karenina and the subgingival microbiome associated with periodontitis"],"prefix":"10.1186","volume":"9","author":[{"given":"Khaled","family":"Altabtbaei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Maney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukirth M.","family":"Ganesan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shareef M.","family":"Dabdoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haikady N.","family":"Nagaraja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5844-1341","authenticated-orcid":false,"given":"Purnima S.","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,30]]},"reference":[{"issue":"11","key":"1056_CR1","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1177\/0022034514552491","volume":"93","author":"NJ Kassebaum","year":"2014","unstructured":"Kassebaum NJ, Bernabe E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. 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