A Comprehensive Assessment of Demographic, Environmental and Host Genetic Associations with Gut Microbiome Diversity in Healthy Individuals

ABSTRACTBackgroundThe 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 1,000 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.ResultsAmong 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.ConclusionIn 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.

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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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Gut Microbiota of Great Spotted Cuckoo Nestlings is a Mixture of Those of Their Foster Magpie Siblings and of Cuckoo Adults

Genes ◽

10.3390/genes9080381 ◽

2018 ◽

Vol 9 (8) ◽

pp. 381 ◽

Cited By ~ 6

Author(s):

Magdalena Ruiz-Rodríguez ◽

Manuel Martín-Vivaldi ◽

Manuel Martínez-Bueno ◽

Juan José Soler

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Natural Populations ◽

Microbiome Composition ◽

Operational Taxonomic Units ◽

Sequencing Technologies ◽

Genetic Components ◽

Α Diversity ◽

Host Genetic ◽

Diversity Estimates

Diet and host genetic or evolutionary history are considered the two main factors determining gut microbiota of animals, although studies are scarce in natural populations. The system of great spotted cuckoos (Clamator glandarius) parasitizing magpies (Pica pica) is ideal to study both effects since magpie adults feed cuckoo and magpie nestlings with the same diet and, consequently, differences in gut microbiota of nestlings of these two species will mainly reflect the importance of genetic components. Moreover, the diet of adults and of nestling cuckoos drastically differ from each other and, thus, differences and similarities in their microbiotas would respectively reflect the effect of environmental and genetic factors. We used next-generation sequencing technologies to analyze the gut microbiota of cuckoo adults and nestlings and of magpie nestlings. The highest α-diversity estimates appeared in nestling cuckoos and the lowest in nestling magpies. Moreover, despite the greatest differences in the microbiome composition of magpies and cuckoos of both ages, cuckoo nestlings harbored a mixture of the Operational Taxonomic Units (OTUs) present in adult cuckoos and nestling magpies. We identified the bacterial taxa responsible for such results. These results suggest important phylogenetic components determining gut microbiome of nestlings, and that diet might be responsible for similarities between gut microbiome of cuckoo and magpie nestlings that allow cuckoos to digest food provided by magpie adults.

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Understanding the development of the gut microbiome in pigs: an overview

10.19103/as.2021.0089.07 ◽

2022 ◽

pp. 179-202

Author(s):

Marion Borey ◽

◽

Jordi Estelle ◽

Claire Rogel-Gaillard ◽

◽

...

Keyword(s):

Environmental Factors ◽

Microbial Communities ◽

Gut Microbiome ◽

Environmental Changes ◽

Feed Additives ◽

Fecal Microbiome ◽

Host Genetics ◽

Microbiome Composition ◽

Living Organisms ◽

Host Development

Living organisms continuously and intimately interact with commensal microbial communities referred to as microbiota and microbiomes. These complex ecosystems provide their hosts with vital services. The gut microbiome develops and diversifies after birth in pigs, as in all mammals. The diversification dynamics follows the host development early in life, reaches an initial level of richness and stabilization before 60 days of age, and continues to mature but at a much lower rate while ageing and adapting to environmental changes. There is a wide variation in microbiome composition at individual and group levels, due to a combination of many factors including host genetics, environmental factors, feed and feed additives, and farm practices. Although the gut microbiome displays region-specific composition along the digestive tract, with likely sequential, complementary biological functionalities, the fecal microbiome is often considered as a good surrogate and provides many of the associations identified with host phenotypes.

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Gut microbiome-wide association study of depression

10.21203/rs.3.rs-570388/v1 ◽

2021 ◽

Author(s):

Djawad Radjabzadeh ◽

Jos Bosch ◽

André Uitterlinden ◽

Koos Zwinderman ◽

M. Arfan Ikram ◽

...

Keyword(s):

Gut Microbiome ◽

Study Cohort ◽

Learning Approaches ◽

Biological Mechanisms ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Amino Butyric Acid ◽

Area Of Interest ◽

Microbiome Diversity ◽

Novel Bacteria

Abstract Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying depression and the gut microbiome is a novel area of interest. In this study we investigated the relation of fecal microbiome diversity and composition with depression in 1,054 from the Rotterdam Study cohort and validated these findings in the Amsterdam HELIUS cohort in 1,539 subjects. Using supervised and unsupervised machine learning approaches, we identified and replicated the association of several microbial genera. We confirm the association of genus Eggerthella, Subdoligranulum, Coprococcus and family Ruminococcaceae and identify novel bacteria including Sellimonas, Lachnoclostridium, Hungatella, Ruminococcaceae (UCG002,UCG003 and UCG005), LachnospiraceaeUCG001, Eubacterium ventriosum and Ruminococcusgauvreauiigroup associated with depression. These bacteria are known to be involved in the synthesis of glutamate, butyrate, serotonin and gamma amino butyric acid (GABA), which are key neurotransmitters for depression. Our study suggests the gut microbiome composition may play a key role in depression.

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Vaginal microbiome Lactobacillus crispatus is heritable among European American women

Communications Biology ◽

10.1038/s42003-021-02394-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Michelle L. Wright ◽

Jennifer M. Fettweis ◽

Lindon J. Eaves ◽

Judy L. Silberg ◽

Michael C. Neale ◽

...

Keyword(s):

Genetic Factors ◽

European Ancestry ◽

P Value ◽

European American ◽

Extrinsic Factors ◽

American Women ◽

Lactobacillus Crispatus ◽

Host Genetic ◽

Host Genetic Factors ◽

European American Women

AbstractThe diversity and dominant bacterial taxa in the vagina are reported to be influenced by multiple intrinsic and extrinsic factors, including but not limited to pregnancy, contraceptive use, pathogenic states, socioeconomic status, and ancestry. However, the extent to which host genetic factors influence variation in the vaginal microbiota is unclear. We used a biometrical genetic approach to determine whether host genetic factors contribute to inter-individual differences in taxa from a sample of 332 twins who self-identified as being of African (44 pairs) or European ancestry (122 pairs). Lactobacillus crispatus, a major determinant of vaginal health, was identified as heritable among European American women (narrow-sense heritability = 34.7%, P-value = 0.018). Heritability of L. crispatus is consistent with the reduced prevalence of adverse reproductive disorders, including bacterial vaginosis and preterm birth, among women of European ancestry.

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Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans

Leukemia ◽

10.1038/s41375-021-01344-9 ◽

2021 ◽

Author(s):

Geffen Kleinstern ◽

J. Brice Weinberg ◽

Sameer A. Parikh ◽

Esteban Braggio ◽

Sara J. Achenbach ◽

...

Keyword(s):

Environmental Factors ◽

B Cell ◽

Risk Score ◽

Genetic Factors ◽

Strong Predictor ◽

Lymphocytic Leukemia ◽

European Ancestry ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

C Statistic

AbstractMonoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10−29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10−63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10−5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

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Basal Diet Determined Long-Term Composition of the Gut Microbiome and Mouse Phenotype to a Greater Extent than Fecal Microbiome Transfer from Lean or Obese Human Donors

Nutrients ◽

10.3390/nu11071630 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1630 ◽

Cited By ~ 6

Author(s):

Daphne M. Rodriguez ◽

Abby D. Benninghoff ◽

Niklas D.J. Aardema ◽

Sumira Phatak ◽

Korry J. Hintze

Keyword(s):

Gut Microbiome ◽

Basal Diet ◽

Body Type ◽

Human Donor ◽

Final Body Weight ◽

Linear Discriminant ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Diet Induced Obesity ◽

Obese Human

The Western dietary pattern can alter the gut microbiome and cause obesity and metabolic disorders. To examine the interactions between diet, the microbiome, and obesity, we transplanted gut microbiota from lean or obese human donors into mice fed one of three diets for 22 weeks: (1) a control AIN93G diet; (2) the total Western diet (TWD), which mimics the American diet; or (3) a 45% high-fat diet-induced obesity (DIO) diet. We hypothesized that a fecal microbiome transfer (FMT) from obese donors would lead to an obese phenotype and aberrant glucose metabolism in recipient mice that would be exacerbated by consumption of the TWD or DIO diets. Prior to the FMT, the native microbiome was depleted using an established broad-spectrum antibiotic protocol. Interestingly, the human donor body type microbiome did not significantly affect final body weight or body composition in mice fed any of the experimental diets. Beta diversity analysis and linear discriminant analysis with effect size (LEfSe) showed that mice that received an FMT from obese donors had a significantly different microbiome compared to mice that received an FMT from lean donors. However, after 22 weeks, diet influenced the microbiome composition irrespective of donor body type, suggesting that diet is a key variable in the shaping of the gut microbiome after FMT.

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Almond Snacking for 8 wk Increases Alpha-Diversity of the Gastrointestinal Microbiome and Decreases Bacteroides fragilis Abundance Compared with an Isocaloric Snack in College Freshmen

Current Developments in Nutrition ◽

10.1093/cdn/nzz079 ◽

2019 ◽

Vol 3 (8) ◽

Cited By ~ 7

Author(s):

Jaapna Dhillon ◽

Zhaoping Li ◽

Rudy M Ortiz

Keyword(s):

Gut Microbiome ◽

College Freshmen ◽

Bacteroides Fragilis ◽

Alpha Diversity ◽

Control Group ◽

Dietary Regimen ◽

Unifrac Distance ◽

Fecal Microbiome ◽

Microbiome Diversity ◽

Cardiometabolic Disorders

ABSTRACT Background Changes in gut microbiota are associated with cardiometabolic disorders and are influenced by diet. Almonds are a rich source of fiber, unsaturated fats, and polyphenols, all nutrients that can favorably alter the gut microbiome. Objectives The aim of this study was to examine the effects of 8 wk of almond snacking on the gut (fecal) microbiome diversity and abundance compared with an isocaloric snack of graham crackers in college freshmen. Methods A randomized, controlled, parallel-arm, 8-wk intervention in 73 college freshmen (age: 18–19 y; 41 women and 32 men; BMI: 18–41 kg/m2) with no cardiometabolic disorders was conducted. Participants were randomly allocated to either an almond snack group (56.7 g/d; 364 kcal; n = 38) or graham cracker control group (77.5 g/d; 338 kcal/d; n = 35). Stool samples were collected at baseline and 8 wk after the intervention to assess primary microbiome outcomes, that is, gut microbiome diversity and abundance. Results Almond snacking resulted in 3% greater quantitative alpha-diversity (Shannon index) and 8% greater qualitative alpha-diversity (Chao1 index) than the cracker group after the intervention (P < 0.05). Moreover, almond snacking for 8 wk decreased the abundance of the pathogenic bacterium Bacteroides fragilis by 48% (overall relative abundance, P < 0.05). Permutational multivariate ANOVA showed significant time effects for the unweighted UniFrac distance and Bray–Curtis beta-diversity methods (P < 0.05; R2 ≤ 3.1%). The dietary and clinical variables that best correlated with the underlying bacterial community structure at week 8 of the intervention included dietary carbohydrate (percentage energy), dietary fiber (g), and fasting total and HDL cholesterol (model Spearman rho = 0.16; P = 0.01). Conclusions Almond snacking for 8 wk improved alpha-diversity compared with cracker snacking. Incorporating a morning snack in the dietary regimen of predominantly breakfast-skipping college freshmen improved the diversity and composition of the gut microbiome. This trial was registered at clinicaltrials.gov as NCT03084003.

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0135 Self-Reported Sleep and Gut Microbiome Composition and Diversity: Associations in Well-Functioning Older Adults

SLEEP ◽

10.1093/sleep/zsaa056.133 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A53-A53

Author(s):

C Holingue ◽

N T Mueller ◽

T Tanaka ◽

M K Differding ◽

C W Chia ◽

...

Keyword(s):

Older Adults ◽

Sleep Duration ◽

Relative Abundance ◽

Gut Microbiome ◽

Rating Scale ◽

Self Report ◽

Microbiome Composition ◽

Microbiome Diversity ◽

Falling Asleep ◽

Insomnia Symptoms

Abstract Introduction The gut microbiome is believed to play an important role in health and disease, yet little is known about the link between sleep and the gut microbiome in humans. We investigated the association of self-reported sleep with gut microbiome composition and diversity in a cohort of well-functioning older adults. Methods We studied 791 participants (mean age = 71.5±12.0 years, 55% women) in the Baltimore Longitudinal Study of Aging with self-report sleep measures and whole-genome DNA sequencing of stool samples. Predictors (modeled as continuous variables) included insomnia symptoms from the Women’s Health Initiative Insomnia Rating Scale (WHIIRS), sleep duration (<5, 5–6, 6–7, >7 hours), and frequency of excessive daytime sleepiness (EDS). We tested their association with gut microbiome diversity (Shannon index) and relative abundance of individual taxa using Kendall Tau Correlation. Next, we assessed whether these sleep variables were associated with overall microbiome structure (Bray-Curtis), adjusting for age, sex, race, education, BMI, depressive symptoms, and number of comorbidities. Results Sleep duration was associated with overall microbiome composition (p<0.01), with longer sleep duration associated with lower biodiversity of microbes in the gut (p<0.05). In phylum-level analyses, higher WHIIRS total (i.e., more severe insomnia) was associated with lower relative abundance of Actinobacteria, while more frequent EDS was associated with lower relative abundance of Fusobacteria. More frequent trouble falling asleep, staying asleep, early waking, poorer sleep quality and higher WHIIRS total were associated with lower abundance of Synergistetes (all p<0.05). Conclusion In well-functioning older adults, self-reported sleep duration, symptoms of insomnia, and EDS were associated with microbiome diversity and composition. The phylum Synergistetes, which has been associated with protective humoral immune response in prior literature, may be an important correlate of insomnia symptoms in older adults. Future investigations are needed to examine the gut microbiome as a driver or mediator of sleep-health associations. Support This study was supported in part by National Institute on Aging (NIA) grant R01AG050507, the NIA Intramural Research Program (IRP), and Research and Development Contract HHSN-260-2004-00012C.

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Persistence of Supplemented Bifidobacterium longum subsp. infantis EVC001 in Breastfed Infants

mSphere ◽

10.1128/msphere.00501-17 ◽

2017 ◽

Vol 2 (6) ◽

Cited By ~ 49

Author(s):

Steven A. Frese ◽

Andra A. Hutton ◽

Lindsey N. Contreras ◽

Claire A. Shaw ◽

Michelle C. Palumbo ◽

...

Keyword(s):

Human Milk ◽

Gut Microbiome ◽

Bifidobacterium Longum ◽

Specific Substrate ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Breastfed Infants ◽

Gut Function ◽

First Time

ABSTRACT The gut microbiome in early life plays an important role for long-term health and is shaped in large part by diet. Probiotics may contribute to improvements in health, but they have not been shown to alter the community composition of the gut microbiome. Here, we found that breastfed infants could be stably colonized at high levels by provision of B. infantis EVC001, with significant changes to the overall microbiome composition persisting more than a month later, whether the infants were born vaginally or by caesarean section. This observation is consistent with previous studies demonstrating the capacity of this subspecies to utilize human milk glycans as a nutrient and underscores the importance of pairing a probiotic organism with a specific substrate. Colonization by B. infantis EVC001 resulted in significant changes to fecal microbiome composition and was associated with improvements in fecal biochemistry. The combination of human milk and an infant-associated Bifidobacterium sp. shows, for the first time, that durable changes to the human gut microbiome are possible and are associated with improved gut function. Attempts to alter intestinal dysbiosis via administration of probiotics have consistently shown that colonization with the administered microbes is transient. This study sought to determine whether provision of an initial course of Bifidobacterium longum subsp. infantis (B. infantis) would lead to persistent colonization of the probiotic organism in breastfed infants. Mothers intending to breastfeed were recruited and provided with lactation support. One group of mothers fed B. infantis EVC001 to their infants from day 7 to day 28 of life (n = 34), and the second group did not administer any probiotic (n = 32). Fecal samples were collected during the first 60 postnatal days in both groups. Fecal samples were assessed by 16S rRNA gene sequencing, quantitative PCR, mass spectrometry, and endotoxin measurement. B. infantis-fed infants had significantly higher populations of fecal Bifidobacteriaceae, in particular B. infantis, while EVC001 was fed, and this difference persisted more than 30 days after EVC001 supplementation ceased. Fecal milk oligosaccharides were significantly lower in B. infantis EVC001-fed infants, demonstrating higher consumption of human milk oligosaccharides by B. infantis EVC001. Concentrations of acetate and lactate were significantly higher and fecal pH was significantly lower in infants fed EVC001, demonstrating alterations in intestinal fermentation. Infants colonized by Bifidobacteriaceae at high levels had 4-fold-lower fecal endotoxin levels, consistent with observed lower levels of Gram-negative Proteobacteria and Bacteroidetes. IMPORTANCE The gut microbiome in early life plays an important role for long-term health and is shaped in large part by diet. Probiotics may contribute to improvements in health, but they have not been shown to alter the community composition of the gut microbiome. Here, we found that breastfed infants could be stably colonized at high levels by provision of B. infantis EVC001, with significant changes to the overall microbiome composition persisting more than a month later, whether the infants were born vaginally or by caesarean section. This observation is consistent with previous studies demonstrating the capacity of this subspecies to utilize human milk glycans as a nutrient and underscores the importance of pairing a probiotic organism with a specific substrate. Colonization by B. infantis EVC001 resulted in significant changes to fecal microbiome composition and was associated with improvements in fecal biochemistry. The combination of human milk and an infant-associated Bifidobacterium sp. shows, for the first time, that durable changes to the human gut microbiome are possible and are associated with improved gut function.

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