The field of human microbiome research has undergone a revolution in its approach toward understanding how microorganisms influence the physiology of their host. 1 Development of culture-independent methods has resulted in increased detection and classification of microbial species within microbial communities. 2 technologies, biomarker sequencing, and shotgun metagenomics have become standard tools used to determine the composition and genetic makeup of the human microbiome. 3 Other "-omics" technologies, such as proteomics and metabolomics, support mechanistic hypotheses involved in causal microbial pathways that are related to states of health and disease. 4,5 Since Antonie van Leeuwenhoek first discovered the existence of microbes in the 1700s while analyzing dental plaque under a microscope, the composition of oral microbial communities has been extensively studied. 6 Over 250 species from the oral cavity have been isolated in culture and characterized, including several key pathogens, such as Streptococcus mutans, Porphyromonas gingivalis, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans, involved in the etiology of dental caries and periodontal disease. [7][8][9] An integrated approach toward understanding states of oral disease from the polymicrobial perspective has emerged over time, attributing disease pathology not only to key pathogens but rather to networks of co-occurring microbes, the collective activities of which contribute to pathogenesis. [9][10][11][12] As such, the importance of understanding the divergences, between oral health and disease, in the microbes comprising the system as well as their relative abundance and functional activity, in addition to genetic factors and ecological pressures that drive such changes, is a primary focus of research within the field of oral health research. 9,[13][14][15][16][17] In recent decades, genetic approaches have shed light on the functional capacity of members of oral microbiomes, the mechanistic underpinnings of caries and periodontal disease pathogenesis, and the complex dynamics and fitness factors of key organisms in oral microbiomes. 3,18 The oral microbial ecosystem is constantly exposed to exogenous foreign substances. 17 Such circumstances are defining factors for founding microbes and their ability to persist in this environment, and make for distinct relationships between microbe and host that rely on selective pressures. Pioneer microbial colonizers of the oral cavity, such as Streptococcus mitis, Streptococcus sanguinis, Streptococcus gordonii, and Streptococcus salivarius, display core characteristics that make them well suited to this specific niche as they are able to bind selectively to tongue and cheek cells before the teeth emerge and can outcompete other microbial species. 17,19 Emerging teeth acquire a protective glycoprotein coat, which sets in motion successional microbial colonization, resulting in the development of complex polymicrobial biofilm communities, namely dental plaque. 20 These complex dental plaque m...

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Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite reports that P-gp expression depends on the microbiome, the mechanisms responsible and their physiological relevance remain unclear. Surprisingly, we found that the cardiac drug-metabolizing gut ActinobacteriumEggerthella lentaincreases drug absorption in mice through post-translational inhibition of P-gp ATPase efflux activity. P-gp inhibition is conserved in theEggerthellaceaefamily but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics identified a cluster of isoflavonoids produced byE. lentarelated to plant-derived P-gp inhibitors. These results highlight the unexpected overlap between diet- and microbiome-derived compounds, and the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism.

RATIONALE: Severity assessment is essential for asthma management. DNA methylation (DNAm) plays a critical role in asthma pathogenesis. The purpose of this study was to identify nasal epithelial DNAm differences associated with asthma severity in children and explore the effect of environmental exposures. METHODS: This study included 33 non-severe and 22 severe asthmatic children. Nasal epithelial DNA methylation modification (all children) and gene expression (17 children) were analyzed. The correlation between DNAm and gene expression was assessed. Computational approaches were performed to evaluate the enrichment of binding of transcription factors (TFs) and histone modifications. Differentially methylated CpG positions (DMPs) associated with environmental exposures and predictive of severe asthma were explored. RESULTS: We found 816 DMPs and 10 differentially methylated regions associated with asthma severity. The DNAm levels of 39 DMPs significantly correlated with gene expression. Three DMPs that predict asthma severity were identified. Out of 816 DMPs, 11 DMPs were associated with exposure to air pollution and 16 DMPs were associated with exposure to secondhand smoke. Six DMPs were simultaneously associated with asthma status, allergy asthma, total IgE, environment IgE, and fractional exhaled nitric oxide (FeNO) in an independent cohort of children. Around the 816 DMPs, 3 histone marks and several TFs known to be involved in asthma were enriched. CONCLUSIONS: DNAm marks in nasal epithelium were associated with asthma severity in children and some marks were also associated with clinical characteristics in previous studies. As promising markers for predicting severity, these DMPs may be influenced by environmental exposures and regulate gene expression.

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