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Cross-omics analysis revealed gut microbiome-related metabolic pathways underlying atherosclerosis development after antibiotics treatment.

ABSTRACT: OBJECTIVE:The metabolic influence of gut microbiota plays a pivotal role in the pathogenesis of cardiometabolic diseases. Antibiotics affect intestinal bacterial diversity, and long-term usage has been identified as an independent risk factor for atherosclerosis-driven events. The aim of this study was to explore the interaction between gut dysbiosis by antibiotics and metabolic pathways with the impact on atherosclerosis development. METHODS:We combined oral antibiotics with different diets in an Apolipoprotein E-knockout mouse model linking gut microbiota to atherosclerotic lesion development via an integrative cross-omics approach including serum metabolomics and cecal 16S rRNA targeted metagenomic sequencing. We further investigated patients with carotid atherosclerosis compared to control subjects with comparable cardiovascular risk. RESULTS:Here, we show that increased atherosclerosis by antibiotics was connected to a loss of intestinal diversity and alterations of microbial metabolic functional capacity with a major impact on the host serum metabolome. Pathways that were modulated by antibiotics and connected to atherosclerosis included diminished tryptophan and disturbed lipid metabolism. These pathways were related to the reduction of certain members of Bacteroidetes and Clostridia by antibiotics in the gut. Patients with atherosclerosis presented a similar metabolic signature as those induced by antibiotics in our mouse model. CONCLUSION:Taken together, this work provides insights into the complex interaction between intestinal microbiota and host metabolism. Our data highlight that detrimental effects of antibiotics on the gut flora are connected to a pro-atherogenic metabolic phenotype beyond classical risk factors.

SUBMITTER: Kappel BA

PROVIDER: S-EPMC7183232 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Cross-omics analysis revealed gut microbiome-related metabolic pathways underlying atherosclerosis development after antibiotics treatment.

Kappel Ben Arpad BA De Angelis Lorenzo L Heiser Michael M Ballanti Marta M Stoehr Robert R Goettsch Claudia C Mavilio Maria M Artati Anna A Paoluzi Omero A OA Adamski Jerzy J Mingrone Geltrude G Staels Bart B Burcelin Remy R Monteleone Giovanni G Menghini Rossella R Marx Nikolaus N Federici Massimo M

Molecular metabolism 20200313

<h4>Objective</h4>The metabolic influence of gut microbiota plays a pivotal role in the pathogenesis of cardiometabolic diseases. Antibiotics affect intestinal bacterial diversity, and long-term usage has been identified as an independent risk factor for atherosclerosis-driven events. The aim of this study was to explore the interaction between gut dysbiosis by antibiotics and metabolic pathways with the impact on atherosclerosis development.<h4>Methods</h4>We combined oral antibiotics with diff ...[more]

PMID: 32251665

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Project description:BackgroundThe gastrointestinal tract (GIT) microbiome of ruminants and its metabolic repercussions vastly influence host metabolism and growth. However, a complete understanding of the bidirectional interactions that occur across the host-microbiome axis remains elusive, particularly during the critical development stages at early life. Here, we present an integrative multi-omics approach that simultaneously resolved the taxonomic and functional attributes of microbiota from five GIT regions as well as the metabolic features of the liver, muscle, urine, and serum in sika deer (Cervus nippon) across three key early life stages.ResultsWithin the host, analysis of metabolites over time in serum, urine, and muscle (longissimus lumborum) showed that changes in the fatty acid profile were concurrent with gains in body weight. Additional host transcriptomic and metabolomic analysis revealed that fatty acid β-oxidation and metabolism of tryptophan and branched chain amino acids play important roles in regulating hepatic metabolism. Across the varying regions of the GIT, we demonstrated that a complex and variable community of bacteria, viruses, and archaea colonized the GIT soon after birth, whereas microbial succession was driven by the cooperative networks of hub populations. Furthermore, GIT volatile fatty acid concentrations were marked by increased microbial metabolic pathway abundances linked to mannose (rumen) and amino acids (colon) metabolism. Significant functional shifts were also revealed across varying GIT tissues, which were dominated by host fatty acid metabolism associated with reactive oxygen species in the rumen epithelium, and the intensive immune response in both small and large intestine. Finally, we reveal a possible contributing role of necroptosis and apoptosis in enhancing ileum and colon epithelium development, respectively.ConclusionsOur findings provide a comprehensive view for the involved mechanisms in the context of GIT microbiome and ruminant metabolic growth at early life. Video Abstract.

Project description:Carotid atherosclerosis (CAS) is a reflection of systemic atherosclerosis and the main pathological processes of cardiovascular disease (CVD), namely, carotid intima-media thickening, carotid plaque formation, and carotid stenosis. Accumulating evidence indicates that the gut microbiota plays an important role in CVD and gut-brain disorders, but the associations of the composition and metabolites of the gut microbiome with CAS have not been studied comprehensively. We performed a gut microbiome genome-wide association study in 31 patients with CAS and 51 healthy controls using whole-genome shotgun sequencing. We found that several risk factors (waist circumference, body mass index, diastolic blood pressure, systolic blood pressure, fasting blood glucose, glycated hemoglobin A1c, total cholesterol, triglyceride, and low-density lipoprotein cholesterol) and inflammatory markers (white blood cell count and absolute value of neutrophils) were significantly higher in the CAS group than in the control group. In addition, 21 species and 142 pathways were enriched in the CAS group, and 10 species and 1 pathway were enriched in the control group. Specifically, Bacteroides eggerthii, Escherichia coli, and Klebsiella pneumoniae were the most abundant species in the CAS group, whereas Parabacteroides unclassified, Prevotella copri, Bacteroides sp 3_1_19, and Haemophilus parainfluenzae were the most abundant species in the control group. Finally, we found that most gut microbes and microbial pathways that were enriched in the CAS group had significant positive correlations with clinical characteristics, whereas the microbes and pathways enriched in healthy controls had significant negative correlations with clinical characteristics excluding high-density lipoprotein cholesterol. In addition, the associations between gut microbes and some microbial pathways (short-chain fatty acid, lipopolysaccharide, and menaquinol biosynthesis) were identified. Our results indicate the existence of a cyclic pathway that elevates the circulating concentrations of trimethylamine-N-oxide in patients with CAS but reduces its concentrations in healthy controls.

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Cross-omics analysis revealed gut microbiome-related metabolic pathways underlying atherosclerosis development after antibiotics treatment.

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Cross-omics analysis revealed gut microbiome-related metabolic pathways underlying atherosclerosis development after antibiotics treatment.

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