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Environmental Influences on the Human Microbiome and Implications for Noncommunicable Disease

Ahn, Jiyoung; Hayes, Richard B
The human microbiome contributes metabolic functions, protects against pathogens, educates the immune system, and through these basic functions, directly or indirectly, affects most of our physiologic functions. Here, we consider the human microbiome and its relationship to several major noncommunicable human conditions, including orodigestive tract cancers, neurologic diseases, diabetes, and obesity. We also highlight the scope of contextual macroenvironmental factors (toxicological and chemical environment, built environment, and socioeconomic environment) and individual microenvironmental factors (smoking, alcohol, and diet) that may push the microbiota toward less healthy or more healthy conditions, influencing the development of these diseases. Last, we highlight current uncertainties and challenges in the study of environmental influences on the human microbiome and implications for understanding noncommunicable disease, suggesting a research agenda to strengthen the scientific evidence base.
PMID: 33798404
ISSN: 1545-2093
CID: 4862382

US nativity and dietary acculturation impact the gut microbiome in a diverse US population

Peters, Brandilyn A; Yi, Stella S; Beasley, Jeannette M; Cobbs, Emilia N; Choi, Hee Sun; Beggs, Dia B; Hayes, Richard B; Ahn, Jiyoung
Little is known regarding the impact of immigrant acculturation on the gut microbiome. We characterized differences in the gut microbiome between racially/ethnically diverse US immigrant and US-born groups, and determined the impact of dietary acculturation on the microbiome. Stool samples were collected from 863 US residents, including US-born (315 White, 93 Black, 40 Hispanic) and foreign-born (105 Hispanic, 264 Korean) groups. We determined dietary acculturation from dissimilarities based on food frequency questionnaires, and used 16S rRNA gene sequencing to characterize the microbiome. Gut microbiome composition differed across study groups, with the largest difference between foreign-born Koreans and US-born Whites, and significant differences also observed between foreign-born and US-born Hispanics. Differences in sub-operational taxonomic unit (s-OTU) abundance between foreign-born and US-born groups tended to be distinct from differences between US-born groups. Bacteroides plebeius, a seaweed-degrading bacterium, was strongly enriched in foreign-born Koreans, while Prevotella copri and Bifidobacterium adolescentis were strongly enriched in foreign-born Koreans and Hispanics, compared with US-born Whites. Dietary acculturation in foreign-born participants was associated with specific s-OTUs, resembling abundance in US-born Whites; e.g., a Bacteroides plebeius s-OTU was depleted in highly diet-acculturated Koreans. In summary, we observed that US nativity is a determinant of the gut microbiome in a US resident population. Dietary acculturation may result in loss of native species in immigrants, though further research is necessary to explore whether acculturation-related microbiome alterations have consequences for immigrant health.
PMID: 32210364
ISSN: 1751-7370
CID: 4358512

Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients

Peters, Brandilyn A; Wilson, Melissa; Moran, Una; Pavlick, Anna; Izsak, Allison; Wechter, Todd; Weber, Jeffrey S; Osman, Iman; Ahn, Jiyoung
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.
PMID: 31597568
ISSN: 1756-994x
CID: 4130672

Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study

Fan, Xiaozhou; Alekseyenko, Alexander V; Wu, Jing; Peters, Brandilyn A; Jacobs, Eric J; Gapstur, Susan M; Purdue, Mark P; Abnet, Christian C; Stolzenberg-Solomon, Rachael; Miller, George; Ravel, Jacques; Hayes, Richard B; Ahn, Jiyoung
OBJECTIVE: A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case-control study. DESIGN: We selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression. RESULTS: Carriage of oral pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). Phylum Fusobacteria and its genus Leptotrichia were associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study. CONCLUSIONS: This study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer.
PMID: 27742762
ISSN: 1468-3288
CID: 2278642

Association of Oral Microbiome With Risk for Incident Head and Neck Squamous Cell Cancer

Hayes, Richard B; Ahn, Jiyoung; Fan, Xiaozhou; Peters, Brandilyn A; Ma, Yingfei; Yang, Liying; Agalliu, Ilir; Burk, Robert D; Ganly, Ian; Purdue, Mark P; Freedman, Neal D; Gapstur, Susan M; Pei, Zhiheng
Importance/UNASSIGNED:Case-control studies show a possible relationship between oral bacteria and head and neck squamous cell cancer (HNSCC). Prospective studies are needed to examine the temporal relationship between oral microbiome and subsequent risk of HNSCC. Objective/UNASSIGNED:To prospectively examine associations between the oral microbiome and incident HNSCC. Design, Setting, and Participants/UNASSIGNED:This nested case-control study was carried out in 2 prospective cohort studies: the American Cancer Society Cancer Prevention Study II Nutrition Cohort (CPS-II) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Among 122 004 participants, 129 incident patient cases of HNSCC were identified during an average 3.9 years of follow-up. Two controls per patient case (n = 254) were selected through incidence density sampling, matched on age, sex, race/ethnicity, and time since mouthwash collection. All participants provided mouthwash samples and were cancer-free at baseline. Exposures/UNASSIGNED:Oral microbiome composition and specific bacterial abundances were determined through bacterial 16S rRNA gene sequencing. Overall oral microbiome composition and specific taxa abundances were compared for the case group and the control group, using PERMANOVA and negative binomial generalized linear models, respectively, controlling for age, sex, race, cohort, smoking, alcohol, and oral human papillomavirus-16 status. Taxa with a 2-sided false discovery rate (FDR)-adjusted P-value (q-value) <.10 were considered significant. Main Outcomes and Measures/UNASSIGNED:Incident HNSCC. Results/UNASSIGNED:The study included 58 patient cases from CPS-II (mean [SD] age, 71.0 [6.4] years; 16 [27.6%] women) and 71 patient cases from PLCO (mean [SD] age, 62.7 [4.8] years; 13 [18.3%] women). Two controls per patient case (n = 254) were selected through incidence density sampling, matched on age, sex, race/ethnicity, and time since mouthwash collection. Head and neck squamous cell cancer cases and controls were similar with respect to age, sex, and race. Patients in the case group were more often current tobacco smokers, tended to have greater alcohol consumption (among drinkers), and to be positive for oral carriage of papillomavirus-16. Overall microbiome composition was not associated with risk of HNSCC. Greater abundance of genera Corynebacterium (fold change [FC], 0.58; 95% confidence interval [CI], 0.41-0.80; q = .06) and Kingella (FC, 0.63; 95% CI, 0.46-0.86; q = .08) were associated with decreased risk of HNSCC, potentially owing to carcinogen metabolism capacity. These findings were consistent for both cohorts and by cohort follow-up time. The observed relationships tended to be stronger for larynx cancer and for individuals with a history of tobacco use. Conclusions and Relevance/UNASSIGNED:This study demonstrates that greater oral abundance of commensal Corynebacterium and Kingella is associated with decreased risk of HNSCC, with potential implications for cancer prevention.
PMID: 29327043
ISSN: 2374-2445
CID: 2906342

Human gut microbiome and risk for colorectal cancer

Ahn, Jiyoung; Sinha, Rashmi; Pei, Zhiheng; Dominianni, Christine; Wu, Jing; Shi, Jianxin; Goedert, James J; Hayes, Richard B; Yang, Liying
We tested the hypothesis that an altered community of gut microbes is associated with risk of colorectal cancer (CRC) in a study of 47 CRC case subjects and 94 control subjects. 16S rRNA genes in fecal bacterial DNA were amplified by universal primers, sequenced by 454 FLX technology, and aligned for taxonomic classification to microbial genomes using the QIIME pipeline. Taxonomic differences were confirmed with quantitative polymerase chain reaction and adjusted for false discovery rate. All statistical tests were two-sided. From 794217 16S rRNA gene sequences, we found that CRC case subjects had decreased overall microbial community diversity (P = .02). In taxonomy-based analyses, lower relative abundance of Clostridia (68.6% vs 77.8%) and increased carriage of Fusobacterium (multivariable odds ratio [OR] = 4.11; 95% confidence interval [CI] = 1.62 to 10.47) and Porphyromonas (OR = 5.17; 95% CI = 1.75 to 15.25) were found in case subjects compared with control subjects. Because of the potentially modifiable nature of the gut bacteria, our findings may have implications for CRC prevention.
PMID: 24316595
ISSN: 0027-8874
CID: 737232

Cigarette smoking and the oral microbiome in a large study of American adults

Wu, Jing; Peters, Brandilyn A; Dominianni, Christine; Zhang, Yilong; Pei, Zhiheng; Yang, Liying; Ma, Yingfei; Purdue, Mark P; Jacobs, Eric J; Gapstur, Susan M; Li, Huilin; Alekseyenko, Alexander V; Hayes, Richard B; Ahn, Jiyoung
Oral microbiome dysbiosis is associated with oral disease and potentially with systemic diseases; however, the determinants of these microbial imbalances are largely unknown. In a study of 1204 US adults, we assessed the relationship of cigarette smoking with the oral microbiome. 16S rRNA gene sequencing was performed on DNA from oral wash samples, sequences were clustered into operational taxonomic units (OTUs) using QIIME and metagenomic content was inferred using PICRUSt. Overall oral microbiome composition differed between current and non-current (former and never) smokers (P<0.001). Current smokers had lower relative abundance of the phylum Proteobacteria (4.6%) compared with never smokers (11.7%) (false discovery rate q=5.2 x 10-7), with no difference between former and never smokers; the depletion of Proteobacteria in current smokers was also observed at class, genus and OTU levels. Taxa not belonging to Proteobacteria were also associated with smoking: the genera Capnocytophaga, Peptostreptococcus and Leptotrichia were depleted, while Atopobium and Streptococcus were enriched, in current compared with never smokers. Functional analysis from inferred metagenomes showed that bacterial genera depleted by smoking were related to carbohydrate and energy metabolism, and to xenobiotic metabolism. Our findings demonstrate that smoking alters the oral microbiome, potentially leading to shifts in functional pathways with implications for smoking-related diseases.The ISME Journal advance online publication, 25 March 2016; doi:10.1038/ismej.2016.37.
PMID: 27015003
ISSN: 1751-7370
CID: 2052252

Altered salivary microbiota associated with high-sugar beverage consumption

Fan, Xiaozhou; Monson, Kelsey R; Peters, Brandilyn A; Whittington, Jennifer M; Um, Caroline Y; Oberstein, Paul E; McCullough, Marjorie L; Freedman, Neal D; Huang, Wen-Yi; Ahn, Jiyoung; Hayes, Richard B
The human oral microbiome may alter oral and systemic disease risk. Consuming high sugar content beverages (HSB) can lead to caries development by altering the microbial composition in dental plaque, but little is known regarding HSB-specific oral microbial alterations. Therefore, we conducted a large, population-based study to examine associations of HSB intake with oral microbiome diversity and composition. Using mouthwash samples of 989 individuals in two nationwide U.S. cohorts, bacterial 16S rRNA genes were amplified, sequenced, and assigned to bacterial taxa. HSB intake was quantified from food frequency questionnaires as low (< 1 serving/week), medium (1-3 servings/week), or high (> 3 servings/week). We assessed overall bacterial diversity and presence of specific taxa with respect to HSB intake in each cohort separately and combined in a meta-analysis. Consistently in the two cohorts, we found lower species richness in high HSB consumers (> 3 cans/week) (p = 0.027), and that overall bacterial community profiles differed from those of non-consumers (PERMANOVA p = 0.040). Specifically, presence of a network of commensal bacteria (Lachnospiraceae, Peptostreptococcaceae, and Alloprevotella rava) was less common in high compared to non-consumers, as were other species including Campylobacter showae, Prevotella oulorum, and Mycoplasma faucium. Presence of acidogenic bacteria Bifodobacteriaceae and Lactobacillus rhamnosus was more common in high consumers. Abundance of Fusobacteriales and its genus Leptotrichia, Lachnoanaerobaculum sp., and Campylobacter were lower with higher HSB consumption, and their abundances were correlated. No significant interaction was found for these associations with diabetic status or with microbial markers for caries (S. mutans) and periodontitis (P. gingivalis). Our results suggest that soft drink intake may alter the salivary microbiota, with consistent results across two independent cohorts. The observed perturbations of overrepresented acidogenic bacteria and underrepresented commensal bacteria in high HSB consumers may have implications for oral and systemic disease risk.
PMID: 38862651
ISSN: 2045-2322
CID: 5669042

Sociobiome - Individual and neighborhood socioeconomic status influence the gut microbiome in a multi-ethnic population in the US

Kwak, Soyoung; Usyk, Mykhaylo; Beggs, Dia; Choi, Heesun; Ahdoot, Dariush; Wu, Feng; Maceda, Lorraine; Li, Huilin; Im, Eun-Ok; Han, Hae-Ra; Lee, Eunjung; Wu, Anna H; Hayes, Richard B; Ahn, Jiyoung
Lower socioeconomic status (SES) is related to increased incidence and mortality due to chronic diseases in adults. Association between SES variables and gut microbiome variation has been observed in adults at the population level, suggesting that biological mechanisms may underlie the SES associations; however, there is a need for larger studies that consider individual- and neighborhood-level measures of SES in racially diverse populations. In 825 participants from a multi-ethnic cohort, we investigated how SES shapes the gut microbiome. We determined the relationship of a range of individual- and neighborhood-level SES indicators with the gut microbiome. Individual education level and occupation were self-reported by questionnaire. Geocoding was applied to link participants' addresses with neighborhood census tract socioeconomic indicators, including average income and social deprivation in the census tract. Gut microbiome was measured using 16SV4 region rRNA gene sequencing of stool samples. We compared α-diversity, β-diversity, and taxonomic and functional pathway abundance by SES. Lower SES was significantly associated with greater α-diversity and compositional differences among groups, as measured by β-diversity. Several taxa related to low SES were identified, especially an increasing abundance of Prevotella copri and Catenibacterium sp000437715, and decreasing abundance of Dysosmobacter welbionis in terms of their high log-fold change differences. In addition, nativity and race/ethnicity have emerged as ecosocial factors that also influence the gut microbiota. Together, these results showed that lower SES was strongly associated with compositional and taxonomic measures of the gut microbiome, and may contribute to shaping the gut microbiota.
PMID: 38467678
ISSN: 2055-5008
CID: 5645682

A microbial causal mediation analytic tool for health disparity and applications in body mass index

Wang, Chan; Ahn, Jiyoung; Tarpey, Thaddeus; Yi, Stella S; Hayes, Richard B; Li, Huilin
BACKGROUND:Emerging evidence suggests the potential mediating role of microbiome in health disparities. However, no analytic framework can be directly used to analyze microbiome as a mediator between health disparity and clinical outcome, due to the non-manipulable nature of the exposure and the unique structure of microbiome data, including high dimensionality, sparsity, and compositionality. METHODS:Considering the modifiable and quantitative features of the microbiome, we propose a microbial causal mediation model framework, SparseMCMM_HD, to uncover the mediating role of microbiome in health disparities, by depicting a plausible path from a non-manipulable exposure (e.g., ethnicity or region) to the outcome through the microbiome. The proposed SparseMCMM_HD rigorously defines and quantifies the manipulable disparity measure that would be eliminated by equalizing microbiome profiles between comparison and reference groups and innovatively and successfully extends the existing microbial mediation methods, which are originally proposed under potential outcome or counterfactual outcome study design, to address health disparities. RESULTS:Through three body mass index (BMI) studies selected from the curatedMetagenomicData 3.4.2 package and the American gut project: China vs. USA, China vs. UK, and Asian or Pacific Islander (API) vs. Caucasian, we exhibit the utility of the proposed SparseMCMM_HD framework for investigating the microbiome's contributions in health disparities. Specifically, BMI exhibits disparities and microbial community diversities are significantly distinctive between reference and comparison groups in all three applications. By employing SparseMCMM_HD, we illustrate that microbiome plays a crucial role in explaining the disparities in BMI between ethnicities or regions. 20.63%, 33.09%, and 25.71% of the overall disparity in BMI in China-USA, China-UK, and API-Caucasian comparisons, respectively, would be eliminated if the between-group microbiome profiles were equalized; and 15, 18, and 16 species are identified to play the mediating role respectively. CONCLUSIONS:The proposed SparseMCMM_HD is an effective and validated tool to elucidate the mediating role of microbiome in health disparity. Three BMI applications shed light on the utility of microbiome in reducing BMI disparity by manipulating microbial profiles. Video Abstract.
PMID: 37496080
ISSN: 2049-2618
CID: 5592392