Project description:<p>Findings from recent studies suggest that the community of microbes residing in the human body is important in disease etiology; however, it remains unclear whether personal factors modulate human microbial composition. Studies based on animal models indicate that differences in composition might be attributed to sex-mediated effects. We analyzed the relationship of sex, adiposity, and dietary fiber intake with gut microbial composition using fecal samples from human subjects. We explored the associations of these factors with metrics of community composition and specific taxon abundances. We found that men and women had significantly different microbial community composition and that women had reduced abundance of a major phylum. Adiposity was associated with gut microbiome composition and specifically in women but not in men. Fiber from fruits and vegetables and fiber from beans were each associated with increased abundance of specific bacterial taxa. These findings provide initial indications that sex, adiposity, and dietary fiber might play important roles in influencing the human gut microbiome. Better understanding of these factors may have significant implications for gastrointestinal health and disease prevention.</p>
Project description:Here we use appropriate taxon-specific models along with support from independent cohorts to show association between human host genotype and gut microbiome variation. Using fecal derived 16S rRNA gene sequences and host genotype data from the Flemish Gut Flora Project (FGFP) we identify genetic associations involving multiple microbial traits. Mendelian randomization analysis was able to estimate associations between microbial traits and disease, however in the absence of clear microbiome driven effects, caution is needed in interpretation. This work marks a growing catalog of genetic associations which will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis.
Project description:Here we exploited a Han Chinese population-based cohort with extensive host metadata established in the Pinggu (PG) district of Beijing, and investigated gut microbiota from 2,338 adults (26-76 years) by metagenomic sequencing, revealing associations of the gut microbiota with sex, sex hormones, age, and a number of clinical and metabolic parameters.
Project description:Genome-wide association studies (GWAS) have revolutionized the field of genetics, providing numerous associations between human SNPs and health traits. Likewise, metagenome-wide association studies (MWAS) between bacterial SNPs and human traits can suggest mechanistic links between the microbiota and its host. However, very few such studies have been done to date, in part due to the large number of samples required to address the variable coverage of bacteria across samples and the fact that most bacteria are present in only a subset of the population. Here, we devised an MWAS framework to detect SNPs and associate them with host phenotypes systematically. We recruited and obtained gut metagenomic samples from a cohort of 7,190 healthy individuals and discovered 1,358 statistically significant associations between a bacterial SNP and host body mass index (BMI). To address the possible effects of population structure and linkage disequilibrium, we applied a clumping procedure, and found 40 independent associations between SNPs and host BMI. We uncovered BMI-associated SNPs in the genomes of 27 bacterial species, even though the relative abundance of 12 of these species was not associated with the phenotype. We separated genome-wide sub-species variations from local associations in individual SNPs, and demonstrated how this framework can highlight specific bacterial functions of interest. Our results demonstrate the importance of considering nucleotide-level diversity in microbiome studies and pave the way toward a better understanding of interpersonal gut microbiome differences and their health implications.
Project description:Gut microbiota and the circadian clock both regulate metabolism. The circadian clock and associated feeding rhythms were shown to impact on the microbial community. However, to what extent gut microbiota reciprocally affect daily rhythms of gene expression and physiology in the host remains elusive. Here, we analyzed the transcriptomes of male and female germ-free mice. While this revealed subtle changes in circadian clock gene expression in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated to rhythmic physiology. Strikingly, absence of microbiome severely compromised liver sex-dimorphism at the transcriptome and metabolome level. Their sex-specific rhythmicity was strongly attenuated. The resulting feminization of male and masculinization of female hepatic gene expression in germ-free animals is likely caused by altered sex-dimorphism in sex and growth hormone secretion, linked to differential activation of xenobiotic receptors. This defines a novel mechanism by which the gut microbiome regulates host metabolism.
Project description:Gut microbiota and the circadian clock both regulate metabolism. The circadian clock and associated feeding rhythms were shown to impact on the microbial community. However, to what extent gut microbiota reciprocally affect daily rhythms of gene expression and physiology in the host remains elusive. Here, we analyzed the transcriptomes of male and female germ-free mice. While this revealed subtle changes in circadian clock gene expression in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated to rhythmic physiology. Strikingly, absence of microbiome severely compromised liver sex-dimorphism at the transcriptome and metabolome level. Their sex-specific rhythmicity was strongly attenuated. The resulting feminization of male and masculinization of female hepatic gene expression in germ-free animals is likely caused by altered sex-dimorphism in sex and growth hormone secretion, linked to differential activation of xenobiotic receptors. This defines a novel mechanism by which the gut microbiome regulates host metabolism.
Project description:Gut microbiota and the circadian clock both regulate metabolism. The circadian clock and associated feeding rhythms were shown to impact on the microbial community. However, to what extent gut microbiota reciprocally affect daily rhythms of gene expression and physiology in the host remains elusive. Here, we analyzed the transcriptomes of male and female germ-free mice. While this revealed subtle changes in circadian clock gene expression in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated to rhythmic physiology. Strikingly, absence of microbiome severely compromised liver sex-dimorphism at the transcriptome and metabolome level. Their sex-specific rhythmicity was strongly attenuated. The resulting feminization of male and masculinization of female hepatic gene expression in germ-free animals is likely caused by altered sex-dimorphism in sex and growth hormone secretion, linked to differential activation of xenobiotic receptors. This defines a novel mechanism by which the gut microbiome regulates host metabolism.
Project description:Gut microbiota and the circadian clock both regulate metabolism. The circadian clock and associated feeding rhythms were shown to impact on the microbial community. However, to what extent gut microbiota reciprocally affect daily rhythms of gene expression and physiology in the host remains elusive. Here, we analyzed the transcriptomes of male and female germ-free mice. While this revealed subtle changes in circadian clock gene expression in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated to rhythmic physiology. Strikingly, absence of microbiome severely compromised liver sex-dimorphism at the transcriptome and metabolome level. Their sex-specific rhythmicity was strongly attenuated. The resulting feminization of male and masculinization of female hepatic gene expression in germ-free animals is likely caused by altered sex-dimorphism in sex and growth hormone secretion, linked to differential activation of xenobiotic receptors. This defines a novel mechanism by which the gut microbiome regulates host metabolism.
Project description:Early life exposure to antibiotics alters the gut microbiome. These alterations lead to changes in metabolic homeostasis and an increase in host adiposity. We used microarrays to identify metabolic genes that may be up- or down-regulated secondary to antibiotic exposure. Low dose antibiotics have been widely used as growth promoters in the agricultural industry since the 1950’s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we hypothesized that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy (STAT) to young mice and evaluated changes in the composition and capabilities of the gut microbiome. STAT administration increased adiposity in young mice and altered hormones related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids (SCFA), increases in colonic SCFA levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early life murine metabolic homeostasis through antibiotic manipulation. C57BL6 mice were divided into low-dose penicillin or control groups. Given antibiotics via drinking water after weaning. Sacrificed and liver sections collected for RNA extraction.
Project description:Although the gut microbiome plays important roles in host physiology, health and disease, we lack understanding of the complex interplay between host genetics and early life environment on the microbial and metabolic composition of the gut. We used the genetically diverse Collaborative Cross mouse system to discover that early life history impacts the microbiome composition, whereas dietary changes have only a moderate effect. By contrast, the gut metabolome was shaped mostly by diet, with specific non-dietary metabolites explained by microbial metabolism. Quantitative trait analysis identified mouse genetic trait loci (QTL) that impact the abundances of specific microbes. Human orthologues of genes in the mouse QTL are implicated in gastrointestinal cancer. Additionally, genes located in mouse QTL for Lactobacillales abundance are implicated in arthritis, rheumatic disease and diabetes. Furthermore, Lactobacillales abundance was predictive of higher host T-helper cell counts, suggesting an important link between Lactobacillales and host adaptive immunity. Correlations between specific operational taxonomic units (OTUs) and B-cell counts, body weight and neuromuscular function (rotarod performance) were also observed. This study is the first to determine and rank the complex contributions of built environment, host genetics and diet in shaping gut microbial and metabolite composition, host fitness and behavior.