Symptomatic atherosclerosis is associated with an altered gut metagenome.
ABSTRACT: Recent findings have implicated the gut microbiota as a contributor of metabolic diseases through the modulation of host metabolism and inflammation. Atherosclerosis is associated with lipid accumulation and inflammation in the arterial wall, and bacteria have been suggested as a causative agent of this disease. Here we use shotgun sequencing of the gut metagenome to demonstrate that the genus Collinsella was enriched in patients with symptomatic atherosclerosis, defined as stenotic atherosclerotic plaques in the carotid artery leading to cerebrovascular events, whereas Roseburia and Eubacterium were enriched in healthy controls. Further characterization of the functional capacity of the metagenomes revealed that patient gut metagenomes were enriched in genes encoding peptidoglycan synthesis and depleted in phytoene dehydrogenase; patients also had reduced serum levels of β-carotene. Our findings suggest that the gut metagenome is associated with the inflammatory status of the host and patients with symptomatic atherosclerosis harbor characteristic changes in the gut metagenome.
Project description:The human gut microbiota varies considerably among world populations due to a variety of factors including genetic background, diet, cultural habits and socioeconomic status. Here we characterized 110 healthy Mongolian adults gut microbiota by shotgun metagenomic sequencing and compared the intestinal microbiome among Mongolians, the Hans and European cohorts. The results showed that the taxonomic profile of intestinal microbiome among cohorts revealed the Actinobaceria and Bifidobacterium were the key microbes contributing to the differences among Mongolians, the Hans and Europeans at the phylum level and genus level, respectively. Metagenomic species analysis indicated that Faecalibacterium prausnitzii and Coprococcus comeswere enrich in Mongolian people which might contribute to gut health through anti-inflammatory properties and butyrate production, respectively. On the other hand, the enriched genus Collinsella, biomarker in symptomatic atherosclerosis patients, might be associated with the high morbidity of cardiovascular and cerebrovascular diseases in Mongolian adults. At the functional level, a unique microbial metabolic pathway profile was present in Mongolian's gut which mainly distributed in amino acid metabolism, carbohydrate metabolism, energy metabolism, lipid metabolism, glycan biosynthesis and metabolism. We can attribute the specific signatures of Mongolian gut microbiome to their unique genotype, dietary habits and living environment.
Project description:BACKGROUND:Gut microbes play a critical role in human health and disease, and researchers have begun to characterize their genomes, the so-called gut metagenome. Thus far, metagenomics studies have focused on genus- or species-level composition and microbial gene sets, while strain-level composition and single-nucleotide polymorphism (SNP) have been overlooked. The gut metagenomes of type 2 diabetes (T2D) patients have been found to be enriched with butyrate-producing bacteria and sulfate reduction functions. However, it is not known whether the gut metagenomes of T2D patients have characteristic strain patterns or SNP distributions. FINDINGS:We downloaded public gut metagenome datasets from 170 T2D patients and 174 healthy controls and performed a systematic comparative analysis of their metagenome SNPs. We found that Bacteroides coprocola, whose relative abundance did not differ between the groups, had a characteristic distribution of SNPs in the T2D patient group. We identified 65 genes, all in B. coprocola, that had remarkably different enrichment of SNPs. The first and sixth ranked genes encode glycosyl hydrolases (GenBank accession EDU99824.1 and EDV02301.1). Interestingly, alpha-glucosidase, which is also a glycosyl hydrolase located in the intestine, is an important drug target of T2D. These results suggest that different strains of B. coprocola may have different roles in human gut and a specific set of B. coprocola strains are correlated with T2D.
Project description:Atherosclerosis and its associated cardiovascular diseases (CVDs) are serious threats to human health and have been reported to be associated with the gut microbiota. Recently, the role of berberine (BBR) in atherosclerosis and gut microbiota has begun to be appreciated. The purposes of this study were to observe the effects of high or low doses of BBR on atherosclerosis and gut microbiota modulation, and to explore their correlation in ApoE-/- mice fed a high-fat diet. A significant decrease in atherosclerotic lesions was observed after treatment with BBR, with the effect of the high dose being more obvious. Both BBR treatments significantly reduced total cholesterol, APOB100, and very low-density lipoprotein cholesterol levels but levels of high/low-density lipoprotein cholesterol and lipoprotein (a) were only reduced by high-dose BBR. Decreased pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1?, IL-6 and increased anti-inflammatory IL-10 and adiponectin levels were observed in the high-dose BBR group, but no decrease in IL-6 or increase in IL-10 was evident using the low-dose of BBR. 16S rRNA sequencing showed that BBR significantly altered the community compositional structure of gut microbiota. Specifically, BBR enriched the abundance of Roseburia, Blautia, Allobaculum, Alistipes, and Turicibacter, and changed the abundance of Bilophila. These microbiota displayed good anti-inflammatory effects related to the production of short-chain fatty acids (SCFAs) and were related to glucolipid metabolism. Alistipes and Roseburia were significantly enriched in high-dose BBR group while Blautia and Allobaculum were more enriched in low-dose, and Turicibacter was enriched in both BBR doses. Metagenomic analysis further showed an elevated potential for lipid and glycan metabolism and synthesis of SCFAs, as well as reduced potential of TMAO production after BBR treatment. The findings demonstrate that both high and low-dose BBR can improve serum lipid and systemic inflammation levels, and alleviate atherosclerosis induced by high-fat diet in ApoE-/- mice. The effects are more pronounced for the high dose. This anti-atherosclerotic effect of BBR may be partly attributed to changes in composition and functions of gut microbiota which may be associated with anti-inflammatory and metabolism of glucose and lipid. Notably, gut microbiota alterations showed different sensitivity to BBR dose.
Project description:Atherosclerosis appears to have multifactorial causes - microbial component like lipopolysaccharides (LPS) and other pathogen associated molecular patterns may be plausible factors. The gut microbiota is an ample source of such stimulants, and its dependent metabolites and altered gut metagenome has been an established link to atherosclerosis. In this exploratory pilot study, we aimed to elucidate whether microbial intervention with probiotics L. rhamnosus GG (LGG) or pharmaceuticals telmisartan (TLM) could improve atherosclerosis in a gut microbiota associated manner.Atherosclerotic phenotype was established by 12 weeks feeding of high fat (HF) diet as opposed to normal chow diet (ND) in apolipoprotein E knockout (ApoE-/-) mice. LGG or TLM supplementation to HF diet was studied.Both LGG and TLM significantly reduced atherosclerotic plaque size and improved various biomarkers including endotoxin to different extents. Colonial microbiota analysis revealed that TLM restored HF diet induced increase in Firmicutes/Bacteroidetes ratio and decrease in alpha diversity; and led to a more distinct microbial clustering closer to ND in PCoA plot. Eubacteria, Anaeroplasma, Roseburia, Oscillospira and Dehalobacteria appeared to be protective against atherosclerosis and showed significant negative correlation with atherosclerotic plaque size and plasma adipocyte - fatty acid binding protein (A-FABP) and cholesterol.LGG and TLM improved atherosclerosis with TLM having a more distinct alteration in the colonic gut microbiota. Altered bacteria genera and reduced alpha diversity had significant correlations to atherosclerotic plaque size, plasma A-FABP and cholesterol. Future studies on such bacterial functional influence in lipid metabolism will be warranted.
Project description:The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted a prospective study with Crohn's disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community ?-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment.
Project description:Background: Humans with metabolic and inflammatory diseases frequently harbor lower levels of butyrate-producing bacteria in their gut. However, it is not known whether variation in the levels of these organisms is causally linked with disease development and whether diet modifies the impact of these bacteria on health. Results: We use germ-free apolipoprotein E-deficient mice colonized with synthetic microbial communities that differ in their capacity to generate butyrate to demonstrate that Roseburia intestinalis interacts with dietary components to (i) impact gene expression in the intestine, directing metabolism away from glycolysis and toward fatty acid utilization, (ii) improve intestinal barrier function, (iii) lower systemic inflammation and (iv) ameliorate atherosclerosis. Furthermore, intestinal administration of butyrate improves gut barrier function and reduces atherosclerosis development. Conclusions: Altogether, our results illustrate how modifiable diet-by-microbiota interactions impact cardiovascular disease, and suggest that interventions aimed at increasing the representation of butyrate-producing bacteria may provide protection against atherosclerosis. Overall design: Intestinal mRNA profiles of gnotobiotic ApoE KO mice colonized with "core" community or "core plus Roseburia intestinalis" were generated by deep sequencing using Illumina HiSeq.
Project description:Some Eubacterium and Roseburia species are among the most prevalent motile bacteria present in the intestinal microbiota of healthy adults. These flagellate species contribute "cell motility" category genes to the intestinal microbiome and flagellin proteins to the intestinal proteome. We reviewed and revised the annotation of motility genes in the genomes of six Eubacterium and Roseburia species that occur in the human intestinal microbiota and examined their respective locus organization by comparative genomics. Motility gene order was generally conserved across these loci. Five of these species harbored multiple genes for predicted flagellins. Flagellin proteins were isolated from R. inulinivorans strain A2-194 and from E. rectale strains A1-86 and M104/1. The amino-termini sequences of the R. inulinivorans and E. rectale A1-86 proteins were almost identical. These protein preparations stimulated secretion of interleukin-8 (IL-8) from human intestinal epithelial cell lines, suggesting that these flagellins were pro-inflammatory. Flagellins from the other four species were predicted to be pro-inflammatory on the basis of alignment to the consensus sequence of pro-inflammatory flagellins from the ?- and ?- proteobacteria. Many fliC genes were deduced to be under the control of ?(28). The relative abundance of the target Eubacterium and Roseburia species varied across shotgun metagenomes from 27 elderly individuals. Genes involved in the flagellum biogenesis pathways of these species were variably abundant in these metagenomes, suggesting that the current depth of coverage used for metagenomic sequencing (3.13-4.79 Gb total sequence in our study) insufficiently captures the functional diversity of genomes present at low (?1%) relative abundance. E. rectale and R. inulinivorans thus appear to synthesize complex flagella composed of flagellin proteins that stimulate IL-8 production. A greater depth of sequencing, improved evenness of sequencing and improved metagenome assembly from short reads will be required to facilitate in silico analyses of complete complex biochemical pathways for low-abundance target species from shotgun metagenomes.
Project description:Dietary format, and its role in pet nutrition, is of interest to pet food manufacturers and pet owners alike. The aim of the present study was to investigate the effects of pre- and post-weaning diets (kibbled or canned) on the composition and function of faecal microbiota in the domestic cat by shotgun metagenomic sequencing and gene taxonomic and functional assignment using MG-RAST. Post-weaning diet had a dramatic effect on community composition; 147 of the 195 bacterial species identified had significantly different mean relative abundances between kittens fed kibbled and canned diets. The kittens fed kibbled diets had relatively higher abundances of Lactobacillus (>100-fold), Bifidobacterium (>100-fold), and Collinsella (>9-fold) than kittens fed canned diets. There were relatively few differences in the predicted microbiome functions associated with the pre-weaning diet. Post-weaning diet affected the abundance of functional gene groups. Genes involved in vitamin biosynthesis, metabolism, and transport, were significantly enriched in the metagenomes of kittens fed the canned diet. The impact of post-weaning diet on the metagenome in terms of vitamin biosynthesis functions suggests that modulation of the microbiome function through diet may be an important avenue for improving the nutrition of companion animals.
Project description:BACKGROUND:The gastrointestinal tracts of animals are home to large, complex communities of microbes. The compositions of these communities ultimately reflect the coevolution of microorganisms with their animal host and are influenced by the living environment, diet and immune status of the host. Gut microbes have been shown to be important for human disease and health, but little research exists in the gut microbiome of the Amur tiger, which is one of the most endangered species in the world. RESULTS:In this study, we present the use of whole-metagenome shotgun sequencing to analyze the composition and functional structures of the gut microbiota in captive Amur tigers. Our results showed a high abundance of four major phyla in captive Amur tigers, including Proteobacteria, Firmicutes, Actinobacteria and Fusobacteria. Moreover, at the genus level, Escherichia, Collinsella and Fusobacterium were most abundant in the captive Amur tiger fecal metagenome. At the species level, Escherichia coli, Fusobacterium ulcerans and Fusobacterium varium were the species with highest abundances in the captive Amur tiger gut microbiota. The primary functional categories of the Amur tiger faecal metagenome were associated mainly with Carbohydrate metabolism, Membrane transport and Amino acid metabolism based on the KEGG pathway database. The comparative metagenomic analyses showed that the captive Amur tiger fecal metagenome had a lower abundance of Spirochaetes, Cyanobacteria and Ascomycota than other animals, and the primary functional categories were primarily associated with carbohydrate metabolism subsystems, clustering-based subsystems and protein metabolism. CONCLUSIONS:We presented here for the first time the use of the shotgun metagenomic sequencing approach to study the composition and functional structures of the gut microbiota in captive Amur tiger.