Gut microbiome-wide association study of depression

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

10.1101/557124 ◽

2019 ◽

Author(s):

Petar Scepanovic ◽

Flavia Hodel ◽

Stanislas Mondot ◽

Valentin Partula ◽

Allyson Byrd ◽

...

Keyword(s):

Environmental Factors ◽

Gut Microbiome ◽

Genetic Factors ◽

European Ancestry ◽

Healthy Individuals ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Microbiome Diversity ◽

Α Diversity ◽

Host Genetic

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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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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Lessons on dietary biomarkers from twin studies

Proceedings of The Nutrition Society ◽

10.1017/s0029665116002810 ◽

2017 ◽

Vol 76 (3) ◽

pp. 303-307 ◽

Cited By ~ 1

Author(s):

Cristina Menni

Keyword(s):

Gut Microbiome ◽

Twin Studies ◽

Dietary Interventions ◽

Twin Design ◽

Dietary Biomarkers ◽

Microbiome Composition ◽

Twin Model ◽

Nutrition Research ◽

Gene Environment ◽

Microbiome Diversity

Metabolomic and microbiome profiling are promising tools to identify biomarkers of food intake and health status. The individual's genetic makeup plays a significant role on health, metabolism, gut microbes and diet and twin studies provide unique opportunities to untangle gene–environment effects on complex phenotypes. This brief review discusses the value of twin studies in nutrition research with a particular focus on metabolomics and the gut microbiome. Although, the twin model is a powerful tool to segregate the genetic component, to date, very few studies combine the twin design and metabolomics/microbiome in nutritional sciences. Moreover, since the individual's diet has a strong influence on the microbiome composition and the gut microbiome is modifiable (60 % of microbiome diversity is due to the environment), future studies should target the microbiome via dietary interventions.

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Genetics of human gut microbiome composition

10.1101/2020.06.26.173724 ◽

2020 ◽

Cited By ~ 3

Author(s):

Alexander Kurilshikov ◽

Carolina Medina-Gomez ◽

Rodrigo Bacigalupe ◽

Djawad Radjabzadeh ◽

Jun Wang ◽

...

Keyword(s):

Association Study ◽

Gut Microbiome ◽

Genome Wide Association Study ◽

Food Preferences ◽

Microbial Composition ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Genome Wide ◽

A Genome ◽

Gwas Signal

AbstractTo study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed whole-genome genotypes and 16S fecal microbiome data from 18,473 individuals (25 cohorts). Microbial composition showed high variability across cohorts: we detected only 9 out of 410 genera in more than 95% of the samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 30 loci affecting microbome taxa at a genome-wide significant (P<5×10-8) threshold. Just one locus, the lactase (LCT) gene region, reached study-wide significance (GWAS signal P=8.6×10−21); it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.94×10−10<P<5×10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization analyses identified enrichment of microbiome trait loci SNPs in the metabolic, nutrition and environment domains and indicated food preferences and diseases as mediators of genetic effects.

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Quantifying the impact of Human Leukocyte Antigen on the human gut microbiome

10.1101/2020.01.14.907196 ◽

2020 ◽

Cited By ~ 2

Author(s):

Stijn P. Andeweg ◽

Can Keşmir ◽

Bas E. Dutilh

Keyword(s):

Immune System ◽

Gut Microbiome ◽

Human Leukocyte ◽

Human Gut ◽

Microbiome Composition ◽

Leukocyte Antigen ◽

Human Gut Microbiome ◽

Microbiome Diversity ◽

Human Immune ◽

Hla Molecules

AbstractObjectiveThe gut microbiome is affected by a number of factors, including the innate and adaptive immune system. The major histocompatibility complex (MHC), or the human leukocyte antigen (HLA) in humans, performs an essential role in vertebrate immunity, and is very polymorphic in different populations. HLA determines the specificity of T lymphocyte and natural killer (NK) cell responses, including against the commensal bacteria present in the human gut. Thus, it is likely that our HLA molecules and thereby the adaptive immune response, can shape the composition of our microbiome. Here, we investigated the effect of HLA haplotype on the microbiome composition.ResultsWe performed HLA typing and microbiota composition analyses on 3,002 public human gut microbiome datasets. We found that (i) individuals with functionally similar HLA molecules (i.e. presenting similar peptides) are also similar in their microbiota, and (ii) HLA homozygosity correlated with microbiome diversity, suggesting that diverse immune responses limit microbiome diversity.ConclusionOur results show a statistical association between host HLA haplotype and gut microbiome composition. Because the HLA haplotype is a readily measurable parameter of the human immune system, these results open the door to incorporating the immune system into predictive microbiome models.IMPORTANCEThe microorganisms that live in the digestive tracts of humans, known as the gut microbiome, are essential for hosts survival as they support crucial functions. For example, they support the host in facilitating the uptake of nutrients and give colonization resistance against pathogens. The composition of the gut microbiome varies among humans. Studies have proposed multiple factors driving the observed variation, including; diet, lifestyle, and health condition. Another major influence on the microbiome is the host’s genetic background. We hypothesized the immune system to be one of the most important genetic factors driving the differences observed between gut microbiomes. Therefore, we are interested in linking the polymorphic molecules that play a role in human immune responses to the composition of the microbiome. HLA molecules are the most polymorphic molecules in our genome and therefore makes an excellent candidate to test such an association/link. To our knowledge for the first time, our results indicate a significant impact of the HLA on the human gut microbiome composition.

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Differences in Gut Microbiome Composition Between Sympatric Wild and Allopatric Laboratory Populations of Omnivorous Cockroaches

Frontiers in Microbiology ◽

10.3389/fmicb.2021.703785 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kara A. Tinker ◽

Elizabeth A. Ottesen

Keyword(s):

Microbial Community ◽

Gut Microbiome ◽

Periplaneta Americana ◽

Laboratory Environment ◽

Microbiome Composition ◽

Relative Contribution ◽

Microbiome Diversity ◽

Before And After ◽

Laboratory Populations ◽

Gut Microbial Community

Gut microbiome composition is determined by a complex interplay of host genetics, founder’s effects, and host environment. We are using omnivorous cockroaches as a model to disentangle the relative contribution of these factors. Cockroaches are a useful model for host–gut microbiome interactions due to their rich hindgut microbial community, omnivorous diet, and gregarious lifestyle. In this study, we used 16S rRNA sequencing to compare the gut microbial community of allopatric laboratory populations of Periplaneta americana as well as sympatric, wild-caught populations of P. americana and Periplaneta fuliginosa, before and after a 14 day period of acclimatization to a common laboratory environment. Our results showed that the gut microbiome of cockroaches differed by both species and rearing environment. The gut microbiome from the sympatric population of wild-captured cockroaches showed strong separation based on host species. Laboratory-reared and wild-captured cockroaches from the same species also exhibited distinct gut microbiome profiles. Each group of cockroaches had a unique signature of differentially abundant uncharacterized taxa still present after laboratory cultivation. Transition to the laboratory environment resulted in decreased microbiome diversity for both species of wild-caught insects. Interestingly, although laboratory cultivation resulted in similar losses of microbial diversity for both species, it did not cause the gut microbiome of those species to become substantially more similar. These results demonstrate how competing factors impact the gut microbiome and highlight the need for a greater understanding of host–microbiome interactions.

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