The Human Salivary Microbiome Is Shaped by Shared Environment Rather than Genetics: Evidence from a Large Family of Closely Related Individuals

ABSTRACT The human microbiome is affected by multiple factors, including the environment and host genetics. In this study, we analyzed the salivary microbiomes of an extended family of Ashkenazi Jewish individuals living in several cities and investigated associations with both shared household and host genetic similarities. We found that environmental effects dominated over genetic effects. While there was weak evidence of geographical structuring at the level of cities, we observed a large and significant effect of shared household on microbiome composition, supporting the role of the immediate shared environment in dictating the presence or absence of taxa. This effect was also seen when including adults who had grown up in the same household but moved out prior to the time of sampling, suggesting that the establishment of the salivary microbiome earlier in life may affect its long-term composition. We found weak associations between host genetic relatedness and microbiome dissimilarity when using family pedigrees as proxies for genetic similarity. However, this association disappeared when using more-accurate measures of kinship based on genome-wide genetic markers, indicating that the environment rather than host genetics is the dominant factor affecting the composition of the salivary microbiome in closely related individuals. Our results support the concept that there is a consistent core microbiome conserved across global scales but that small-scale effects due to a shared living environment significantly affect microbial community composition. IMPORTANCE Previous research shows that the salivary microbiomes of relatives are more similar than those of nonrelatives, but it remains difficult to distinguish the effects of relatedness and shared household environment. Furthermore, pedigree measures may not accurately measure host genetic similarity. In this study, we include genetic relatedness based on genome-wide single nucleotide polymorphisms (SNPs) (rather than pedigree measures) and shared environment in the same analysis. We quantify the relative importance of these factors by studying the salivary microbiomes in members of a large extended Ashkenazi Jewish family living in different locations. We find that host genetics plays no significant role and that the dominant factor is the shared environment at the household level. We also find that this effect appears to persist in individuals who have moved out of the parental household, suggesting that aspects of salivary microbiome composition established during upbringing can persist over a time scale of years. IMPORTANCE Previous research shows that the salivary microbiomes of relatives are more similar than those of nonrelatives, but it remains difficult to distinguish the effects of relatedness and shared household environment. Furthermore, pedigree measures may not accurately measure host genetic similarity. In this study, we include genetic relatedness based on genome-wide single nucleotide polymorphisms (SNPs) (rather than pedigree measures) and shared environment in the same analysis. We quantify the relative importance of these factors by studying the salivary microbiomes in members of a large extended Ashkenazi Jewish family living in different locations. We find that host genetics plays no significant role and that the dominant factor is the shared environment at the household level. We also find that this effect appears to persist in individuals who have moved out of the parental household, suggesting that aspects of salivary microbiome composition established during upbringing can persist over a time scale of years.

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The human oral microbiome is shaped by shared environment rather than genetics: evidence from a large family of closely-related individuals

10.1101/131086 ◽

2017 ◽

Cited By ~ 1

Author(s):

Liam Shaw ◽

Andre L. R. Ribeiro ◽

Adam P. Levine ◽

Nikolas Pontikos ◽

Francois Balloux ◽

...

Keyword(s):

Genetic Relatedness ◽

Oral Microbiome ◽

Dominant Factor ◽

Shared Environment ◽

Host Genetics ◽

Microbiome Composition ◽

Genome Wide ◽

Host Genetic ◽

Related Individuals

AbstractThe human microbiome is affected by multiple factors, including the environment and host genetics. In this study, we analyzed the oral microbiome of an extended family of Ashkenazi Jewish individuals living in several cities and investigated associations with both shared household and host genetic similarities. We found that environmental effects dominated over genetic ones. While there was weak evidence of geographic structuring at the level of cities, we observed a large and significant effect of shared household on microbiome composition, supporting the role of immediate shared environment in dictating the presence or absence of taxa. This effect was also seen when including adults who had grown up in the same household but moved out prior to the time of sampling, suggesting that the establishment of the oral microbiome earlier in life may affect its long-term composition. We found weak associations between host genetic relatedness and microbiome dissimilarity when using family pedigrees as proxies for genetic similarity. However this association disappeared when using more accurate measures of kinship based on genome-wide genetic markers, indicating that environment rather than host genetics is the dominant factor affecting the composition of the oral microbiome in closely-related individuals. Our results support the concept that there is a consistent core microbiome conserved across global scales, but that small-scale effects due to shared living environment significantly affect microbial community composition.IMPORTANCEPrevious research shows that relatives have a more similar oral microbiome composition than non-relatives, but it remains difficult to distinguish the effects of relatedness and shared household environment. Furthermore, pedigree measures may not accurately measure host genetic similarity. In this study, we include genetic relatedness based on genome-wide SNPs (rather than pedigree measures) and shared environment in the same analysis. We quantify the relative importance of these factors by studying the oral microbiome in members of a large extended Ashkenazi Jewish family who share a similar diet and lifestyle despite living in different locations. We find that host genetics plays no significant role and that the dominant factor is shared environment at the household level. We also find that this effect appears to persist in individuals who have moved out of the parental household, suggesting that the oral microbiome established earlier in life persists long-term.

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Host Genetic Factors Associated with Vaginal Microbiome Composition in Kenyan Women

mSystems ◽

10.1128/msystems.00502-20 ◽

2020 ◽

Vol 5 (4) ◽

Cited By ~ 2

Author(s):

Supriya D. Mehta ◽

Drew R. Nannini ◽

Fredrick Otieno ◽

Stefan J. Green ◽

Walter Agingu ◽

...

Keyword(s):

Racial Differences ◽

Genome Wide Association Study ◽

Vaginal Microbiome ◽

Content Type ◽

Microbiome Composition ◽

Genome Wide ◽

A Genome ◽

Kenyan Women ◽

Host Genetic ◽

Women Of African Descent

ABSTRACT Bacterial vaginosis (BV) affects 20% of women worldwide and is associated with adverse reproductive health outcomes and increased risk for HIV. Typically, BV represents a shift in the vaginal microbiome from one that is dominated by Lactobacillus to one that is diverse. Persistent racial differences in BV and diverse vaginal microbiome composition overlap with racial disparities in risks for HIV and sexually transmitted infection, especially among women of African descent. Risk factors for BV and nonoptimal vaginal microbiome include sexual practices, yet racial differences persist when adjusted for behavioral factors, suggesting a host genetic component. Here, we perform a genome-wide association study on vaginal microbiome traits in Kenyan women. Linear regression and logistic regression were performed, adjusting for age and principal components of genetic ancestry, to evaluate the association between Lactobacillus crispatus, Lactobacillus iners, Gardnerella vaginalis, Shannon diversity index, and community state type (CST) with host genetic single nucleotide polymorphisms (SNPs). We identified novel genomic loci associated with the vaginal microbiome traits, though no SNP reached genome-wide significance. During pathway enrichment analysis, Toll-like receptors (TLRs), cytokine production, and other components of innate immune response were associated with L. crispatus, L. iners, and CST. Multiple previously reported genomic loci were replicated, including IL-8 (Shannon, CST), TIRAP (L. iners, Shannon), TLR2 (Shannon, CST), MBL2 (L. iners, G. vaginalis, CST), and MYD88 (L. iners, Shannon). These genetic associations suggest a role for the innate immune system and cell signaling in vaginal microbiome composition and susceptibility to nonoptimal vaginal microbiome. IMPORTANCE Globally, bacterial vaginosis (BV) is a common condition in women. BV is associated with poorer reproductive health outcomes and HIV risk. Typically, BV represents a shift in the vaginal microbiome from one that is dominated by Lactobacillus to one that is diverse. Despite many women having similar exposures, the prevalence of BV and nonoptimal vaginal microbiome is increased for women of African descent, suggesting a possible role for host genetics. We conducted a genome-wide association study of important vaginal microbiome traits in Kenyan women. We identified novel genetic loci and biological pathways related to mucosal immunity, cell signaling, and infection that were associated with vaginal microbiome traits; we replicated previously reported loci associated with mucosal immune response. These results provide insight into potential host genetic influences on vaginal microbiome composition and can guide larger longitudinal studies, with genetic and functional comparison across microbiome sites within individuals and across populations.

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Acquisition of Oral Microbiota is Driven by Environment, Not Host Genetics

10.21203/rs.3.rs-17146/v3 ◽

2020 ◽

Author(s):

Chiranjit Mukherjee ◽

Christina O. Moyer ◽

Heidi M. Steinkamp ◽

Shahr B. Hashmi ◽

Xiaohan Guo ◽

...

Keyword(s):

Genetic Relatedness ◽

Bacterial Species ◽

Oral Microbiome ◽

Individual Species ◽

Shared Environment ◽

Oral Microbiota ◽

Host Genetics ◽

Early Effects ◽

The Many

Abstract Background: The oral microbiota is acquired very early, but the factors shaping its acquisition are not well understood. Previous studies comparing monozygotic (MZ) and dizygotic (DZ) twins have suggested that host genetics plays a role. However, all twins share an equal portion of their parent’s genome, so this model is not informative for studying parent-to-child transmission. We used a novel study design that allowed us to directly examine the genetics of transmission by comparing the oral microbiota of biological versus adoptive mother-child dyads. Results: No difference was observed in how closely oral bacterial community profiles matched for adoptive versus biological mother-child pairs, indicating little if any effect of host genetics on the fidelity of transmission. Both adopted and biologic children more closely resembled their own mother as compared to unrelated women, supporting the role of contact and environment. Mother-child strain similarity increased with the age of the child, ruling out early effects of host genetic influence that are lost over time. No effect on the fidelity of mother-child strain sharing from vaginal birth or breast feeding was seen. Analysis of extended families showed that fathers and mothers were equally similar to their children, and that cohabitating couples showed even greater strain similarity than mother-child pairs. These findings support the role of contact and shared environment, and age, but not genetics, as determinants of microbial transmission, and were consistent at both species and strain level resolutions, and across multiple oral habitats. In addition, analysis of individual species all showed similar results. Conclusions: The host is clearly active in shaping the composition of the oral microbiome, since only a few of the many bacterial species in the larger environment are capable of colonizing the human oral cavity. Our findings suggest that these host mechanisms are universally shared among humans, since no effect of genetic relatedness on fidelity of microbial transmission could be detected. Instead our findings point towards contact and shared environment being the driving factors of microbial transmission, with a unique combination of these factors ultimately shaping the highly personalized human oral microbiome.

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The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for human complex diseases

10.1101/2019.12.26.888313 ◽

2019 ◽

Author(s):

Fengzhe Xu ◽

Yuanqing Fu ◽

Ting-yu Sun ◽

Zengliang Jiang ◽

Zelei Miao ◽

...

Keyword(s):

Renal Function ◽

Gut Microbiome ◽

Genome Wide Association Study ◽

Causal Effect ◽

Complex Diseases ◽

Disease Etiology ◽

Host Genetics ◽

Genome Wide ◽

Host Genetic ◽

Human Complex

AbstractThere is increasing interest about the interplay between host genetics and gut microbiome on human complex diseases, with prior evidence mainly derived from animal models. In addition, the shared and distinct microbiome features among human complex diseases remain largely unclear. We performed a microbiome genome-wide association study to identify host genetic variants associated with gut microbiome in a Chinese population with 1475 participants. We then conducted bi-directional Mendelian randomization analyses to examine the potential causal associations between gut microbiome and human complex diseases. We found that Saccharibacteria (also known as TM7 phylum) could potentially improve renal function by affecting renal function biomarkers (i.e., creatinine and estimated glomerular filtration rate). In contrast, atrial fibrillation, chronic kidney disease and prostate cancer, as predicted by the host genetics, had potential causal effect on gut microbiome. Further disease-microbiome feature analysis suggested that gut microbiome features revealed novel relationship among human complex diseases. These results suggest that different human complex diseases share common and distinct gut microbiome features, which may help re-shape our understanding about the disease etiology in humans.

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Acquisition of Oral Microbiota is Driven by Environment, Not Host Genetics

10.1101/2020.01.06.896126 ◽

2020 ◽

Author(s):

Chiranjit Mukherjee ◽

Christina O. Moyer ◽

Heidi M. Steinkamp ◽

Shahr B. Hashmi ◽

Xiaohan Guo ◽

...

Keyword(s):

Environmental Factors ◽

Genetic Relatedness ◽

Oral Microbiome ◽

Shared Environment ◽

Rrna Gene ◽

Oral Microbiota ◽

Host Genetics ◽

Intergenic Spacer Region ◽

Behavioral Similarity ◽

Mz Twins

ABSTRACTThe human oral microbiota is acquired early in an organized pattern, but the factors driving this acquisition are not well understood. Microbial “heritability” could have far-reaching consequences for health, yet no studies have specifically examined the fidelity with which the oral microbiota are passed from parents to offspring. Some previous studies comparing monozygotic (MZ) and dizygotic (DZ) twins had suggested that host genetics has a role in shaping oral microbial communities, and also identified so called “heritable” taxa. However, these findings are likely to be confounded by shared environmental factors resulting from the well-established greater behavioral similarity among MZ twins. In addition, MZ and DZ twins share an equal portion of their parent’s genome, and so this model is not informative for studying direct parent to offspring transmission.To specifically examine the contribution of genetics to the fidelity of transmission of bacteria from parents to offspring, we used a novel study design comparing fraction of shared species and strains between our genetically related group consisting of children and their biological mothers, with that of children and their adoptive mothers, constituting our genetically unrelated group. Fifty-five biological and 50 adoptive mother-child pairs were recruited along with 23 biological fathers and 16 siblings. Subjects were carefully selected to ensure the two groups were matched on child’s age. Three distinct habitats within the oral cavity: the saliva/soft tissue surface, supragingival biofilm, and subgingival biofilm, were sampled to comprehensively profile the oral microbiome. Our recently developed strategy for subspecies level characterization of bacterial communities by targeted sequencing of the ribosomal 16-23S intergenic spacer region (ISR) was utilized in the present study to track strain sharing between subjects, in addition to 16S rRNA gene sequencing for species analysis.Results showed that oral bacterial community profiles of adoptive and biological mother-child pairs were equally similar, indicating no effect of host genetics on the fidelity of transmission. This was consistent at both species and strain level resolutions, and across all three habitats sampled. We also found that all children more closely resembled their own mother as compared to unrelated women, suggesting that contact and shared environment were the major factors shaping the oral microbiota. Individual analysis of the most abundant species also did not detect any effect of host genetics on strain sharing between mother and child. Mother-child strain similarity increased with the age of the child, ruling out early effects that are lost over time. No effect on the fidelity of mother-child strain sharing from vaginal birth or breast feeding was seen. Analysis of extended families showed that fathers and mothers were equally similar to their children. Cohabitating couples showed even greater strain similarity than mother-child pairs, further supporting the role of age, contact and shared environment as determinants of microbial similarity.Based on these findings we suggest that the genetic effects on oral microbial acquisition observed in twin studies are more likely the result of confounding environmental factors based on greater behavioral similarity among MZ twins. Our findings suggest that these host mechanisms are universal to humans, since no effect of genetic relatedness on fidelity of microbial transmission could be detected. Instead, our findings point toward contact and shared environment being the driving factors of microbial transmission, with a unique combination of these factors ultimately shaping a highly personalized human oral microbiome.

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The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for complex human diseases

10.21203/rs.3.rs-40335/v2 ◽

2020 ◽

Author(s):

Fengzhe Xu ◽

Yuanqing Fu ◽

Tingyu Sun ◽

Zengliang Jiang ◽

Zelei Miao ◽

...

Keyword(s):

Atrial Fibrillation ◽

Lupus Erythematosus ◽

Gut Microbiome ◽

Genome Wide Association Study ◽

Human Diseases ◽

Host Genetics ◽

Genome Wide ◽

Disease Aetiology ◽

Significant Heritability ◽

Host Genetic

Abstract Background Interest in the interplay between host genetics and the gut microbiome in complex human diseases is increasing, with prior evidence mainly being derived from animal models. In addition, the shared and distinct microbiome features among complex human diseases remain largely unclear.Results This analysis was based on a Chinese population with 1,475 participants. We estimated the SNP-based heritability, which suggested that Desulfovibrionaceae and Odoribacter had significant heritability estimates (0.456 and 0.476, respectively). We performed a microbiome genome-wide association study to identify host genetic variants associated with the gut microbiome. We then conducted bidirectional Mendelian randomization analyses to examine the potential causal associations between the gut microbiome and complex human diseases. We found that Saccharibacteria could potentially decrease the concentration of serum creatinine and increase the estimated glomerular filtration rate. On the other hand, atrial fibrillation, chronic kidney disease and prostate cancer, as predicted by host genetics, had potential causal effects on the abundance of some specific gut microbiota. For example, atrial fibrillation increased the abundance of Burkholderiales and Alcaligenaceae and decreased the abundance of Lachnobacterium, Bacteroides coprophilus, Barnesiellaceae, undefined genus in family Veillonellaceae and Mitsuokella. Further disease-microbiome feature analysis suggested that systemic lupus erythematosus and chronic myeloid leukaemia shared common gut microbiome features.Conclusions These results suggest that different complex human diseases share common and distinct gut microbiome features, which may help reshape our understanding of disease aetiology in humans.

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Host genetic effects upon the early gut microbiota in a bovine model with graduated spectrum of genetic variation

The ISME Journal ◽

10.1038/s41396-019-0529-2 ◽

2019 ◽

Vol 14 (1) ◽

pp. 302-317 ◽

Cited By ~ 7

Author(s):

Peixin Fan ◽

Beilei Bian ◽

Lin Teng ◽

Corwin D. Nelson ◽

J. Driver ◽

...

Keyword(s):

Genetic Variation ◽

Gut Microbiota ◽

Bos Taurus ◽

Bos Indicus ◽

Nucleotide Polymorphisms ◽

Paternal Genome ◽

Host Genetics ◽

Microbe Interactions ◽

Host Genetic

Abstract Multiple synergistic factors affect the development and composition of mammalian gut microbiota, but effects of host genetics remain unclear. To illuminate the role of host genetics on gut microbiota, we employed animals with a graduated spectrum of genetic variation with minimal environmental influences. We bred 228 calves with linearly varying breed composition from 100% Angus (Bos taurus) to 100% Brahman (Bos indicus), as a proxy for genetic variation, and then raised the offspring in the same environment with identical diets. We hypothesized each breed would harbor distinct gut microbiota due to genetic influence. We found that the gut microbiota of preweaning calves at 3 months old is significantly affected by host genetics, profoundly by paternal genome. We also demonstrate that single nucleotide polymorphisms in host mucin-encoding genes, critical for gut mucosal health, are significantly correlated with both breed composition and mucin-degrading gut bacteria. We further demonstrate host genetics indirectly changes gut microbiota composition via microbe–microbe interactions. These findings indicate a strong contribution by host genetics in shaping the gut microbiota during early life stages, shedding light on impact of animal breeding on gut microbiota, which is associated with animal growth and health.

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Host genetic control of gut microbiome composition

Mammalian Genome ◽

10.1007/s00335-021-09884-2 ◽

2021 ◽

Author(s):

Jason A. Bubier ◽

Elissa J. Chesler ◽

George M. Weinstock

Keyword(s):

Genetic Control ◽

Gut Microbiome ◽

Genetic Variant ◽

Association Studies ◽

Genome Wide Association Studies ◽

Disease Phenotype ◽

Microbial Composition ◽

Host Genetics ◽

Microbiome Composition ◽

Host Genetic

AbstractThe gut microbiome plays a significant role in health and disease, and there is mounting evidence indicating that the microbial composition is regulated in part by host genetics. Heritability estimates for microbial abundance in mice and humans range from (0.05–0.45), indicating that 5–45% of inter-individual variation can be explained by genetics. Through twin studies, genetic association studies, systems genetics, and genome-wide association studies (GWAS), hundreds of specific host genetic loci have been shown to associate with the abundance of discrete gut microbes. Using genetically engineered knock-out mice, at least 30 specific genes have now been validated as having specific effects on the microbiome. The relationships among of host genetics, microbiome composition, and abundance, and disease is now beginning to be unraveled through experiments designed to test causality. The genetic control of disease and its relationship to the microbiome can manifest in multiple ways. First, a genetic variant may directly cause the disease phenotype, resulting in an altered microbiome as a consequence of the disease phenotype. Second, a genetic variant may alter gene expression in the host, which in turn alters the microbiome, producing the disease phenotype. Finally, the genetic variant may alter the microbiome directly, which can result in the disease phenotype. In order to understand the processes that underlie the onset and progression of certain diseases, future research must take into account the relationship among host genetics, microbiome, and disease phenotype, and the resources needed to study these relationships.

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Environmental factors dominate over host genetics in shaping human gut microbiota composition

10.1101/150540 ◽

2017 ◽

Cited By ~ 10

Author(s):

Daphna Rothschild ◽

Omer Weissbrod ◽

Elad Barkan ◽

Tal Korem ◽

David Zeevi ◽

...

Keyword(s):

Environmental Factors ◽

Human Genetics ◽

Human Microbiome ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Nucleotide Polymorphisms ◽

Human Gut ◽

Extrinsic Factors ◽

Host Genetics ◽

Microbiome Composition

AbstractHuman gut microbiome composition is shaped by multiple host intrinsic and extrinsic factors, but the relative contribution of host genetic compared to environmental factors remains elusive. Here, we genotyped a cohort of 696 healthy individuals from several distinct ancestral origins and a relatively common environment, and demonstrate that there is no statistically significant association between microbiome composition and ethnicity, single nucleotide polymorphisms (SNPs), or overall genetic similarity, and that only 5 of 211 (2.4%) previously reported microbiome-SNP associations replicate in our cohort. In contrast, we find similarities in the microbiome composition of genetically unrelated individuals who share a household. We define the termbiome-explainabilityas the variance of a host phenotype explained by the microbiome after accounting for the contribution of human genetics. Consistent with our finding that microbiome and host genetics are largely independent, we find significant biome-explainability levels of 16-33% for body mass index (BMI), fasting glucose, high-density lipoprotein (HDL) cholesterol, waist circumference, waist-hip ratio (WHR), and lactose consumption. We further show that several human phenotypes can be predicted substantially more accurately when adding microbiome data to host genetics data, and that the contribution of both data sources to prediction accuracy is largely additive. Overall, our results suggest that human microbiome composition is dominated by environmental factors rather than by host genetics.

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A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals

Microbiome ◽

10.1186/s40168-019-0747-x ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 20

Author(s):

Petar Scepanovic ◽

◽

Flavia Hodel ◽

Stanislas Mondot ◽

Valentin Partula ◽

...

Keyword(s):

Environmental Factors ◽

Gut Microbiome ◽

Genetic Factors ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Healthy Individuals ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Microbiome Diversity ◽

Host Genetic

Abstract Background The gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20–69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. Results Among 110 demographic, clinical, and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity, or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between > 5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. Conclusion In a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals. Trial registration ClinicalTrials.gov identifier NCT01699893

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