Human genetics shape the gut microbiome.

Host genetics and the gut microbiome can both influence metabolic phenotypes. However, whether host genetic variation shapes the gut microbiome and interacts with it to affect host phenotype is unclear. Here, we compared microbiotas across >1,000 fecal samples obtained from the TwinsUK population, including 416 twin pairs. We identified many microbial taxa whose abundances were influenced by host genetics. The most heritable taxon, the family Christensenellaceae, formed a co-occurrence network with other heritable Bacteria and with methanogenic Archaea. Furthermore, Christensenellaceae and its partners were enriched in individuals with low body mass index (BMI). An obese-associated microbiome was amended with Christensenella minuta, a cultured member of the Christensenellaceae, and transplanted to germ-free mice. C. minuta amendment reduced weight gain and altered the microbiome of recipient mice. Our findings indicate that host genetics influence the composition of the human gut microbiome and can do so in ways that impact host metabolism.

Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases.

The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD.

Heritable components of the human fecal microbiome are associated with visceral fat.

Obesity and its associated diseases are one of the major causes of death worldwide. The gut microbiota has been identified to have essential regulatory effects on human metabolism and obesity in particular. In a recent study we provided some insights into the link between the gut microbiota (GM) and adiposity, as well as host genetic modulation of these processes. Our results identify novel evidence of association between 6 adiposity phenotypes and faecal microbial operational taxonomic units (OTUs). Accumulation of visceral fat, a key risk factor for cardio-metabolic disease, has the strongest and most pervasive signature on the gut microbiota of the factors we examined. Furthermore, we observe that the adiposity-associated OTUs were classified as heritable and in some cases were also associated with host genetic variation at obesity-associated human candidate genes FHIT, TDRG1 and ELAVL4. This addendum confirms our previously published results in the TwinsUK cohort using a different approach to OTU clustering and multivariate analysis, and discusses further the importance of considering the GM as a complex ecosystem.

An Investigation Into Physical Frailty as a Link Between the Gut Microbiome and Cognitive Health.

The preservation of cognitive abilities with aging is a priority both for individuals and nations given the aging populations of many countries. Recently the gut microbiome has been identified as a new territory to explore in relation to cognition. Experiments using rodents have identified a link between the gut microbiome and cognitive function, particularly that low microbial diversity leads to poor cognition function. Similar studies in humans could identify novel targets to encourage healthy cognition in an aging population. Here, we investigate the association of gut microbiota and cognitive function in a human cohort considering the influence of physical frailty. We analyzed 16S rRNA gene sequence data, derived from fecal samples obtained from 1,551 individuals over the age of 40. Cognitive data was collected using four cognitive tests: verbal fluency (n = 1,368), Deary-Liewald Reaction Time Test (DLRT; n = 873), Mini Mental State Examination (recall; n = 1,374) and Paired Associates Learning from the Cambridge Neuropsychological Test Automated Battery (CANTAB-PAL; n = 405). We use mixed effects models to identify associations with alpha diversity, operational taxonomic units (OTUs) and taxa and performed further analyses adjusting for physical frailty. We then repeated the analyses in a subset of individuals with dietary data, also excluding those using medications shown to influence gut microbiome composition. DLRT and verbal fluency were negatively associated with alpha diversity of the gut microbiota (False-Discovery Rate, FDR, p < 0.05). However, when considering frailty as a covariate, only associations between the DLRT and diversity measures remained. Repeating analyses excluding Proton pump inhibitor (PPI) and antibiotic users and accounting for diet, we similarly observe significant negative associations between the DLRT and alpha diversity measures and a further negative association between DLRT and the abundance of the order Burkholderiales that remains significant after adjusting for host frailty. This highlights the importance of considering concurrent differences in physical health in studies of cognitive performance and suggests that physical health has a relatively larger association with the gut microbiome. However, the frailty independent cognitive-gut microbiota associations that were observed might represent important targets for further research, with potential for use in diagnostic surveillance in cognitive aging and interventions to improve vitality.

Genetic Determinants of the Gut Microbiome in UK Twins.

Studies in mice and humans have revealed intriguing associations between host genetics and the microbiome. Here we report a 16S rRNA-based analysis of the gut microbiome in 1,126 twin pairs, a subset of which was previously reported. Tripling the sample narrowed the confidence intervals around heritability estimates and uncovered additional heritable taxa, some of which are validated in other studies. Repeat sampling of subjects showed heritable taxa to be temporally stable. A candidate gene approach uncovered associations between heritable taxa and genes related to diet, metabolism, and olfaction. We replicate an association between Bifidobacterium and the lactase (LCT) gene locus and identify an association between the host gene ALDH1L1 and the bacteria SHA-98, suggesting a link between formate production and blood pressure. Additional genes detected are involved in barrier defense and self/non-self recognition. Our results indicate that diet-sensing, metabolism, and immune defense are important drivers of human-microbiome co-evolution.

Metabolomic profiling to dissect the role of visceral fat in cardiometabolic health.

OBJECTIVE: Abdominal obesity is associated with increased risk of type 2 diabetes (T2D) and cardiovascular disease. The aim of this study was to assess whether metabolomic markers of T2D and blood pressure (BP) act on these traits via visceral fat (VF) mass. METHODS: Metabolomic profiling of 280 fasting plasma metabolites was conducted on 2,401 women from TwinsUK. The overlap was assessed between published metabolites associated with T2D, insulin resistance, or BP and those that were identified to be associated with VF (after adjustment for covariates) measured by dual-energy X-ray absorptiometry. RESULTS: In addition to glucose, six metabolites were strongly associated with both VF mass and T2D: lactate and branched-chain amino acids, all of them related to metabolism and the tricarboxylic acid cycle; on average, 38.5% of their association with insulin resistance was mediated by their association with VF mass. Five metabolites were associated with BP and VF mass including the inflammation-associated peptide HWESASXX, the steroid hormone androstenedione, lactate, and palmitate. On average, 29% of their effect on BP was mediated by their association with VF mass. CONCLUSIONS: Little overlap was found between the metabolites associated with BP and those associated with insulin resistance via VF mass.

Signatures of early frailty in the gut microbiota.

BACKGROUND: Frailty is arguably the biggest problem associated with population ageing, and associates with gut microbiome composition in elderly and care-dependent individuals. Here we characterize frailty associations with the gut microbiota in a younger community dwelling population, to identify targets for intervention to encourage healthy ageing. METHOD: We analysed 16S rRNA gene sequence data derived from faecal samples obtained from 728 female twins. Frailty was quantified using a frailty index (FI). Mixed effects models were used to identify associations with diversity, operational taxonomic units (OTUs) and taxa. OTU associations were replicated in the Eldermet cohort. Phenotypes were correlated with modules of OTUs collapsed by co-occurrence. RESULTS: Frailty negatively associated with alpha diversity of the gut microbiota. Models considering a number of covariates identified 637 OTUs associated with FI. Twenty-two OTU associations were significant independent of alpha diversity. Species more abundant with frailty included Eubacterium dolichum and Eggerthella lenta. A Faecalibacterium prausnitzii OTU was less abundant in frailer individuals, and retained significance in discordant twin analysis. Sixty OTU associations were replicated in the Eldermet cohort. OTU co-occurrence modules had mutually exclusive associations between frailty and alpha diversity. CONCLUSIONS: There was a striking negative association between frailty and gut microbiota diversity, underpinned by specific taxonomic associations. Whether these relationships are causal or consequential is unknown. Nevertheless, they represent targets for diagnostic surveillance, or for intervention studies to improve vitality in ageing.

Heritable components of the human fecal microbiome are associated with visceral fat.

BACKGROUND: Variation in the human fecal microbiota has previously been associated with body mass index (BMI). Although obesity is a global health burden, the accumulation of abdominal visceral fat is the specific cardio-metabolic disease risk factor. Here, we explore links between the fecal microbiota and abdominal adiposity using body composition as measured by dual-energy X-ray absorptiometry in a large sample of twins from the TwinsUK cohort, comparing fecal 16S rRNA diversity profiles with six adiposity measures. RESULTS: We profile six adiposity measures in 3666 twins and estimate their heritability, finding novel evidence for strong genetic effects underlying visceral fat and android/gynoid ratio. We confirm the association of lower diversity of the fecal microbiome with obesity and adiposity measures, and then compare the association between fecal microbial composition and the adiposity phenotypes in a discovery subsample of twins. We identify associations between the relative abundances of fecal microbial operational taxonomic units (OTUs) and abdominal adiposity measures. Most of these results involve visceral fat associations, with the strongest associations between visceral fat and Oscillospira members. Using BMI as a surrogate phenotype, we pursue replication in independent samples from three population-based cohorts including American Gut, Flemish Gut Flora Project and the extended TwinsUK cohort. Meta-analyses across the replication samples indicate that 8 OTUs replicate at a stringent threshold across all cohorts, while 49 OTUs achieve nominal significance in at least one replication sample. Heritability analysis of the adiposity-associated microbial OTUs prompted us to assess host genetic-microbe interactions at obesity-associated human candidate loci. We observe significant associations of adiposity-OTU abundances with host genetic variants in the FHIT, TDRG1 and ELAVL4 genes, suggesting a potential role for host genes to mediate the link between the fecal microbiome and obesity. CONCLUSIONS: Our results provide novel insights into the role of the fecal microbiota in cardio-metabolic disease with clear potential for prevention and novel therapies.

Gut-Microbiota-Metabolite Axis in Early Renal Function Decline.

INTRODUCTION: Several circulating metabolites derived from bacterial protein fermentation have been found to be inversely associated with renal function but the timing and disease severity is unclear. The aim of this study is to explore the relationship between indoxyl-sulfate, p-cresyl-sulfate, phenylacetylglutamine and gut-microbial profiles in early renal function decline. RESULTS: Indoxyl-sulfate (Beta(SE) = -2.74(0.24); P = 8.8x10-29), p-cresyl-sulfate (-1.99(0.24), P = 4.6x10-16), and phenylacetylglutamine(-2.73 (0.25), P = 1.2x10-25) were inversely associated with eGFR in a large population base cohort (TwinsUK, n = 4439) with minimal renal function decline. In a sub-sample of 855 individuals, we analysed metabolite associations with 16S gut microbiome profiles (909 profiles, QIIME 1.7.0). Three Operational Taxonomic Units (OTUs) were significantly associated with indoxyl-sulfate and 52 with phenylacetylglutamine after multiple testing; while one OTU was nominally associated with p-cresyl sulfate. All 56 microbial members belong to the order Clostridiales and are represented by anaerobic Gram-positive families Christensenellaceae, Ruminococcaceae and Lachnospiraceae. Within these, three microbes were also associated with eGFR. CONCLUSIONS: Our data suggest that indoxyl-sulfate, p-cresyl-sulfate and phenylacetylglutamine are early markers of renal function decline. Changes in the intestinal flora associated with these metabolites are detectable in early kidney disease. Future efforts should dissect this relationship to improve early diagnostics and therapeutics strategies.