Faculty Bibliography

RATIONALE/BACKGROUND:Many studies have linked short-term exposure to ozone (O3) with morbidity and mortality, but epidemiological evidence of associations between long-term ozone exposure and mortality is more limited. OBJECTIVES/OBJECTIVE:We investigated associations of long-term (annual or warm season average) O3 exposure with all-cause and cause-specific mortality in the NIH-AARP Diet and Health Study, a large prospective cohort of U.S. adults with 17 years of follow-up from 1995 to 2011. METHODS:The cohort (N=548,780) was linked to census tract-level estimates for O3. Associations between long-term O3 exposure (averaged values from 2002-2010) and multiple causes of death were evaluated using multivariate Cox proportional hazards models, adjusted for both individual- and census tract-level covariates, as well as potentially confounding co-pollutants and temperature. MEASUREMENTS AND MAIN RESULTS/RESULTS:Long-term annual average exposure to O3 was significantly associated with deaths due to cardiovascular disease (per 10 ppb, HR=1.03; 95% CI: 1.01-1.06), ischemic heart disease (HR=1.06; 95% CI: 1.02-1.09), respiratory disease (HR=1.04; 95% CI: 1.00-1.09), and chronic obstructive pulmonary disease (HR=1.09; 95% CI: 1.03-1.15) in single-pollutant models. The results were robust to alternative models and adjustment for co-pollutants (fine particulate matter and nitrogen dioxide), although some evidence of confounding by temperature was observed. Significantly elevated respiratory disease mortality risk associated with long-term O3 exposure was found among those living in locations with high temperature (p-interaction<0.05). CONCLUSIONS:This study found that long-term exposure to O3 is associated with increased risk for multiple causes of mortality, suggesting that establishment of annual and/or seasonal federal O3 standard(s) are needed to more adequately protect public health from ambient O3 exposures.

BACKGROUND:Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community. METHODS:In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression. RESULTS:Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up (p = 0.002). Among the species selected in regression, abundance of Bacteroides ovatus, Bacteroides dorei, Bacteroides massiliensis, Ruminococcus gnavus, and Blautia producta were related to shorter PFS, and Faecalibacterium prausnitzii, Coprococcus eutactus, Prevotella stercorea, Streptococcus sanguinis, Streptococcus anginosus, and Lachnospiraceae bacterium 3 1 46FAA to longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways of L-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis. CONCLUSIONS:This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.

Little is known about the dietary patterns of Chinese Americans. Understanding their dietary patterns can provide insights for addressing cardiovascular disease (CVD) risk among Chinese American immigrants. The objective of this study was to identify dietary patterns among Chinese American immigrants living in New York City (NYC) and to describe associations with demographic and CVD risk factors. A validated Food Frequency Questionnaire assessed usual dietary intake in Chinese American immigrants living in NYC as part of the Chinese American Cardiovascular Health Assessment (CHA CHA) in 2010-2011 (n = 1973, age range 21-89 years). Principal components analysis with varimax rotation retaining three factors with eigenvalues > 1.5 identified dietary patterns. Multivariable linear regression models tested associations between CVD risk factors and dietary pattern scores. In multivariable analyses, each unit of increase in the Sweets factor was associated with 0.76 ± 0.33 (mean ± SD) mg/dL higher HDL cholesterol and a 6.2 ± 2.7% increase in HOMA-IR. In contrast, each unit increase in the Fried Noodles factor was associated with a 0.27 ± 0.11 inch greater waist circumference, - 0.89 ± 0.40 mg/dL lower HDL cholesterol, and also a 6.9 ± 2.6% increase in HOMA-IR. Each unit increase in the Vegetables factor was associated with a - 1.40 ± 0.43 mmHg and - 0.95 ± 0.27 mm Hg decrease in systolic and diastolic blood pressure, respectively. Dietary patterns are significantly associated with CVD risk factors among Chinese American immigrants in NYC. Future work will inform how dietary patterns relate to level of acculturation in order to guide the development of dietary interventions to reduce CVD risk.

Incense burning is common worldwide and produces environmental toxicants that may influence health; however, biologic effects have been little studied. In 303 Emirati adults, we tested the hypothesis that incense use is linked to compositional changes in the oral microbiota that can be potentially significant for health. The oral microbiota was assessed by amplification of the bacterial 16S rRNA gene from mouthwash samples. Frequency of incense use was ascertained through a questionnaire and examined in relation to overall oral microbiota composition (PERMANOVA analysis), and to specific taxon abundances, by negative binomial generalized linear models. We found that exposure to incense burning was associated with higher microbial diversity (p < 0.013) and overall microbial compositional changes (PERMANOVA, p = 0.003). Our study also revealed that incense use was associated with significant changes in bacterial abundances (i.e. depletion of the dominant taxon Streptococcus), even in occasional users (once/week or less) implying that incense use impacts the oral microbiota even at low exposure levels. In summary, this first study suggests that incense burning alters the oral microbiota, potentially serving as an early biomarker of incense-related toxicities and related health consequences. Although a common indoor air pollutant, guidelines for control of incense use have yet to be developed.

BACKGROUND:Recent experimental evidence suggests that nutritional supplementation can blunt adverse cardiopulmonary effects induced by acute air pollution exposure. However, whether usual individual dietary patterns can modify the association between long-term air pollution exposure and health outcomes have not been previously investigated. We assessed, in a large cohort with detailed diet information at the individual level, whether a Mediterranean diet modifies the association between long-term exposure to ambient air pollution and cardiovascular disease mortality risk. METHODS:air pollution at the residential census-tract level. The alternative Mediterranean Diet Index (aMED), which uses a 9-point scale to assess conformity with a Mediterranean-style diet, was constructed for each participant from information in cohort baseline dietary questionnaires. We evaluated mortality risks for cardiovascular disease (CVD), ischemic heart disease (IHD), cerebrovascular disease (CER), or cardiac arrest (CAR) associated with long-term air pollution exposure. Effect modification of the associations between exposure and the mortality outcomes by aMED was examined via interaction terms. RESULTS:, we found significant associations with CVD (HR=1.06; 95% CI: 1.04-1.08), and IHD (HR=1.08; 95% CI: 1.05-1.11). Analyses indicated that Mediterranean diet modified these relationships, as those with a higher aMED score had significantly lower rates of air pollution related mortality ( p interaction<0.05). CONCLUSIONS:Mediterranean diet reduced cardiovascular disease mortality risk related to longterm exposure to air pollutants in a large prospective U.S cohort. Increased consumption of foods rich in antioxidant compounds may aid in reducing the considerable disease burden associated with ambient air pollution.

BACKGROUND:Human microbiota have many functions that could contribute to cancer initiation and/or progression at local sites, yet the relation of the lung microbiota to lung cancer prognosis has not been studied. METHODS:In a pilot study, 16S rRNA gene sequencing was performed on paired lung tumor and remote normal samples from the same lobe/segment in 19 non-small cell lung cancer patients. We explored associations of tumor or normal tissue microbiome diversity and composition with recurrence-free and disease-free survival, and compared microbiome diversity and composition between paired tumor and normal samples. RESULTS:Higher richness and diversity in normal tissue were associated with reduced recurrence-free survival (richness p=0.08, Shannon index p=0.03) and disease-free survival (richness p=0.03, Shannon index p=0.02), as was normal tissue overall microbiome composition (Bray-Curtis p=0.09 for recurrence-free and p=0.02 for disease-free survival). In normal tissue, greater abundance of family Koribacteraceae was associated with increased recurrence-free and disease-free survival, while greater abundance of families Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae were associated with reduced recurrence-free or disease-free survival (p<0.05). Tumor tissue diversity and overall composition were not associated with recurrence-free or disease-free survival. Tumor tissue had lower richness and diversity (p≤0.0001) than paired normal tissue, though overall microbiome composition did not differ between paired samples. CONCLUSIONS:We demonstrate, for the first time, a potential relationship between the normal lung microbiota and lung cancer prognosis, which requires confirmation in a larger study. IMPACT/CONCLUSIONS:Definition of bacterial biomarkers of prognosis may lead to improved survival outcomes for lung cancer patients.

Increasing evidence indicates that gut microbiota may influence colorectal cancer risk. Diet, particularly fibre intake, may modify gut microbiota composition, which may affect cancer risk. We investigated the relationship between dietary fibre intake and gut microbiota in adults. Using 16S rRNA gene sequencing, we assessed gut microbiota in faecal samples from 151 adults in two independent study populations: National Cancer Institute (NCI), n 75, and New York University (NYU), n 76. We calculated energy-adjusted fibre intake based on FFQ. For each study population with adjustment for age, sex, race, BMI and smoking, we evaluated the relationship between fibre intake and gut microbiota community composition and taxon abundance. Total fibre intake was significantly associated with overall microbial community composition in NYU (P=0·008) but not in NCI (P=0·81). In a meta-analysis of both study populations, higher fibre intake tended to be associated with genera of class Clostridia, including higher abundance of SMB53 (fold change (FC)=1·04, P=0·04), Lachnospira (FC=1·03, P=0·05) and Faecalibacterium (FC=1·03, P=0·06), and lower abundance of Actinomyces (FC=0·95, P=0·002), Odoribacter (FC=0·95, P=0·03) and Oscillospira (FC=0·96, P=0·06). A species-level meta-analysis showed that higher fibre intake was marginally associated with greater abundance of Faecalibacterium prausnitzii (FC=1·03, P=0·07) and lower abundance of Eubacterium dolichum (FC=0·96, P=0·04) and Bacteroides uniformis (FC=0·97, P=0·05). Thus, dietary fibre intake may impact gut microbiota composition, particularly class Clostridia, and may favour putatively beneficial bacteria such as F. prausnitzii. These findings warrant further understanding of diet-microbiota relationships for future development of colorectal cancer prevention strategies.

OBJECTIVE:Recent mechanistic and epidemiological evidence implicates air pollution as a potential risk factor for diabetes; however, mortality risks have not been evaluated in a large US cohort assessing exposures to multiple pollutants with detailed consideration of personal risk factors for diabetes. RESEARCH DESIGN AND METHODS/METHODS:. Associations between the air pollutants and the risk of diabetes mortality (N = 3598) were evaluated using multivariate Cox proportional hazards models adjusted for both individual-level and census-level contextual covariates. RESULTS:(HR = 1.09; 95% CI: 1.01-1.18 per 10 ppb). The strength of the relationship was robust to alternate exposure assessments and model specifications. We also observed significant effect modification, with elevated mortality risks observed among those with higher BMI and lower levels of fruit consumption. CONCLUSIONS:, is related to increased risk of diabetes mortality in the U.S, with attenuation of adverse effects by lower BMI and higher fruit consumption, suggesting that air pollution is involved in the etiology and/or control of diabetes.

Cigarette smoking alters the oral microbiome; however, the effect of alternative tobacco products remains unclear. Middle Eastern tobacco products like dokha and shisha, are becoming globally widespread. We tested for the first time in a Middle Eastern population the hypothesis that different tobacco products impact the oral microbiome. The oral microbiome of 330 subjects from the United Arab Emirates Healthy Future Study was assessed by amplifying the bacterial 16S rRNA gene from mouthwash samples. Tobacco consumption was assessed using a structured questionnaire and further validated by urine cotinine levels. Oral microbiome overall structure and specific taxon abundances were compared, using PERMANOVA and DESeq analyses respectively. Our results show that overall microbial composition differs between smokers and nonsmokers (p = 0.0001). Use of cigarettes (p = 0.001) and dokha (p = 0.042) were associated with overall microbiome structure, while shisha use was not (p = 0.62). The abundance of multiple genera were significantly altered (enriched/depleted) in cigarette smokers; however, only Actinobacillus, Porphyromonas, Lautropia and Bifidobacterium abundances were significantly changed in dokha users whereas no genera were significantly altered in shisha smokers. For the first time, we show that smoking dokha is associated to oral microbiome dysbiosis, suggesting that it could have similar effects as smoking cigarettes on oral health.

Background: The oral microbiota play a central role in oral health, and possibly in carcinogenesis. Research suggests that coffee and tea consumption may have beneficial health effects. We examined the associations of these common beverages with the oral ecosystem in a large cross-sectional study.Methods: We assessed oral microbiota in mouthwash samples from 938 participants in two U.S. cohorts using 16S rRNA gene sequencing. Coffee and tea intake were assessed from food frequency questionnaires. We examined associations of coffee and tea intake with overall oral microbiota diversity and composition using linear regression and permutational MANOVA, respectively, and with taxon abundance using negative binomial generalized linear models; all models adjusted for age, sex, cohort, body mass index, smoking, ethanol intake, and energy intake.Results: Higher tea intake was associated with greater oral microbiota richness (P = 0.05) and diversity (P = 0.006), and shifts in overall community composition (P = 0.002); coffee was not associated with these microbiome parameters. Tea intake was associated with altered abundance of several oral taxa; these included Fusobacteriales, Clostridiales, and Shuttleworthia satelles (higher with increasing tea) and Bifidobacteriaceae, Bergeyella, Lactobacillales, and Kingella oralis (lower with increasing tea). Higher coffee intake was only associated with greater abundance of Granulicatella and Synergistetes.Conclusions: In the largest study to date of tea and coffee consumption in relation to the oral microbiota, the microbiota of tea drinkers differed in several ways from nondrinkers.Impact: Tea-driven changes to the oral microbiome may contribute to previously observed associations between tea and oral and systemic diseases, including cancers. Cancer Epidemiol Biomarkers Prev; 27(7); 814-21. ©2018 AACR.