Project description:Background. Hematopoietic cell transplantation (HCT) is a potentially curative therapy for a wide range of pediatric malignant and nonmalignant diseases. However, complications, including blood stream infection (BSI) remain a major cause of morbidity and mortality. While certain bacteria that are abundant in the oral microbiome, such as S. mitis, can cause BSI, the role of the oral microbial community in the etiology of BSI is not well understood. The finding that the use of xylitol wipes, which specifically targets the cariogenic bacteria S. mutans is associated with reduced BSI in pediatric patients, lead us to investigate dental caries as a risk factor for BSI. Methods. A total of 41 pediatric patients admitted for allogenic or autologous HCT, age 8 months to 25 years, were enrolled. Subjects with high dental caries risk were identified as those who had dental restorations completed within 2 months of admission for transplant, or who had untreated decay. Fisher’s exact test was used to determine if there was a significant association between caries risk and BSI. Dental plaque and saliva were collected on a cotton swab from a subset of 4 high caries risk (HCR) and 4 low caries risk (LCR) children following pretransplant conditioning. 16SrRNA sequencing was used to compare the microbiome of HCR and LCR subjects and to identify microbes that were significantly different between the 2 groups. Results. There was a statistically significant association between caries risk and BSI (p<0.035) (Fisher’s exact test). Multivariate logistic regression analysis showed children in the high dental caries risk group were 21.39 times more likely to have BSI, with no significant effect of age or mucositis severity. HCR subjects showed significantly reduced microbial alpha diversity as compared to LCR subjects. LEfse metagenomic analyses, showed the oral microbiome in HCR children enriched in order Lactobacillales. This order includes Streptococcus and Lactobacillus, both which contain bacteria primarily associated with dental caries. Discussion. These findings support the possibility that the cariogenic microbiome can enhance the risk of BSI in pediatric populations. Future metagenomic analyses to measure microbial differences at, before, and after conditioning related to caries risk, may further unravel the complex relationship between the oral microbiome, and whether it affects health outcomes such as BSI.

Project description:Purpose: Dental caries is characterized by a dysbiotic shift at the biofilm-tooth surface interface, yet comprehensive biochemical characterizations of the biofilm are scant. We used metabolomics to identify biochemical features of the supragingival biofilm associated with early childhood caries (ECC) prevalence and severity. Methods: The study’s analytical sample comprised 289 children ages 3-5 (51% with ECC) who attended public preschools in North Carolina and were enrolled in a community-based cross-sectional study of early childhood oral health. Clinical examinations were conducted by calibrated examiners in community locations using ICDAS criteria. Supragingival plaque collected from the facial/buccal surfaces of all primary teeth in the upper-left quadrant were analyzed using Ultra Performance Liquid Chromatography-tandem Mass Spectrometry. Associations between individual metabolites and 18 clinical traits (based on different ECC definitions and sets of tooth surfaces) were quantified using Brownian distance correlations (dCor) and linear regression modeling of log2-transformed values, applying a False Discovery Rate multiple testing correction. A tree-based pipeline optimization tool (TPOT)-machine learning process was used to identify the best-fitting ECC classification metabolite model. Results: There were 503 named metabolites identified, including microbial, host and exogenous biochemicals. Most significant ECC-metabolite associations were positive (i.e., upregulations/enrichments). The localized ECC case definition (ICDAS≥1 caries experience within the surfaces from which plaque was collected) had the strongest correlation with the metabolome (dCor p=8x10-3). Sixteen metabolites were significantly associated with ECC after multiple testing correction, including: fucose (p=3.0x10-6) and N-acetylneuraminate (p=6.8x10-6) with higher ECC prevalence; catechin (p=4.7x10-6) and epicatechin (p=2.9x10-6) with lower. Catechin, epicatechin, imidazole propionate, fucose, 9,10-DiHOME, and N-acetylneuraminate were among the top 15 metabolites in terms of ECC classification importance in the automated TPOT model. Conclusion: These supragingival biofilm metabolite findings provide novel insights in ECC biology and can serve as the basis for the development of measures of disease activity or risk assessment.

Project description:Metabolites are important determinants of disease progression. In this study, we conducted a case-control study to explore permanent teeth caries-related differences in salivary metabolite profiles and related changes in the composition of the oral microbiota in 200 subjects including 100 caries-free individuals and 100 with moderate-to-severe caries with good homogeneity through widely targeted metabolomics and 16S rRNA deep sequencing technologies. We found that: 1) 822 metabolites were detectable in salivary samples from these participants, of which 4-acetamidobutyric acid and adipic acid were respectively enriched in healthy individuals and individuals with caries, exhibited the greatest area under the curve (AUC) values of > 0.970; 2) less diversity was observed in individuals with dental caries relative to caries-free individuals, and significant differences in the dominant taxa were evident between the two groups. For example, the healthy oral microbiome is enriched for Rothia aeria and Neisseria perflava, whereas Prevotella melaninogenica, Streptococcus salivarius, Streptococcus parasanguinis and Prevotella histicola, and Streptococcus mutans were enriched in individuals with caries; 3) Prevotella histicola, Oribacterium asaccharolyticum and Rothia aeria were the top 3 species being required to differentiate caries from caries free population; 4) adipic acid and 4-acetamidobutyric acid derived from microbiota and host-microbiota co-metabolism, respectively. A negative correlation was observed between the microbes enriched in caries individuals (such as Prevotella histicola) and 4-acetamidobutyric acid. Moreover, the upstream regulatory factor ALDH of 4-acetamidobutyric acid is expressed throughout the entire process of tooth development including the differentiation of tooth bud, ameloblasts and odontoblasts. Together, these results suggest that 4-acetamidobutyric acid and adipic acid are important targets for future caries-focused research, offering insight into cariogenic activity or risk assessment in moderate or severe cases.

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Bacterial mixed DNA library

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