scholarly journals A Molecular-Level Landscape of Diet-Gut Microbiome Interactions: Toward Dietary Interventions Targeting Bacterial Genes

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Yueqiong Ni ◽  
Jun Li ◽  
Gianni Panagiotou
Keyword(s):  
Gene Expression ◽  
Human Health ◽  
Gut Microbiome ◽  
Dietary Intervention ◽  
Methodological Approach ◽  
Bacterial Species ◽  
Detailed Knowledge ◽  
Dietary Interventions ◽  
Microbial Composition ◽  
Bacterial Proteins

ABSTRACT As diet is considered the major regulator of the gut ecosystem, the overall objective of this work was to demonstrate that a detailed knowledge of the phytochemical composition of food could add to our understanding of observed changes in functionality and activity of the gut microbiota. We used metatranscriptomic data from a human dietary intervention study to develop a network that consists of >400 compounds present in the administered plant-based diet linked to 609 microbial targets in the gut. Approximately 20% of the targeted bacterial proteins showed significant changes in their gene expression levels, while functional and topology analyses revealed that proteins in metabolic networks with high centrality are the most “vulnerable” targets. This global view and the mechanistic understanding of the associations between microbial gene expression and dietary molecules could be regarded as a promising methodological approach for targeting specific bacterial proteins that impact human health. IMPORTANCE It is a general belief that microbiome-derived drugs and therapies will come to the market in coming years, either in the form of molecules that mimic a beneficial interaction between bacteria and host or molecules that disturb a harmful interaction or proteins that can modify the microbiome or bacterial species to change the balance of “good” and “bad” bacteria in the gut microbiome. However, among the numerous factors, what has proven the most influential for modulating the microbial composition of the gut is diet. In line with this, we demonstrate here that a systematic analysis of the interactions between the small molecules present in our diet and the gut bacterial proteome holds great potential for designing dietary interventions to improve human health.

scholarly journals The Gut Microbiome and Xenobiotics: Identifying Knowledge Gaps

2020 ◽  
Vol 176 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Vicki L Sutherland ◽  
Charlene A McQueen ◽  
Donna Mendrick ◽  
Donna Gulezian ◽  
Carl Cerniglia ◽  
...  
Keyword(s):  
Human Health ◽  
Gut Microbiome ◽  
Critical Role ◽  
Drug Efficacy ◽  
Model Systems ◽  
Microbial Composition ◽  
Breakout Group ◽  
Data Gaps ◽  
Critical Issues ◽  
And Function

Abstract There is an increasing awareness that the gut microbiome plays a critical role in human health and disease, but mechanistic insights are often lacking. In June 2018, the Health and Environmental Sciences Institute (HESI) held a workshop, “The Gut Microbiome: Markers of Human Health, Drug Efficacy and Xenobiotic Toxicity” (https://hesiglobal.org/event/the-gut-microbiome-workshop) to identify data gaps in determining how gut microbiome alterations may affect human health. Speakers and stakeholders from academia, government, and industry addressed multiple topics including the current science on the gut microbiome, endogenous and exogenous metabolites, biomarkers, and model systems. The workshop presentations and breakout group discussions formed the basis for identifying data gaps and research needs. Two critical issues that emerged were defining the microbial composition and function related to health and developing standards for models, methods and analysis in order to increase the ability to compare and replicate studies. A series of key recommendations were formulated to focus efforts to further understand host-microbiome interactions and the consequences of exposure to xenobiotics as well as identifying biomarkers of microbiome-associated disease and toxicity.

scholarly journals DOP22 Integrative -omic analysis reveals microbiota mediated molecular mechanisms influencing host mucosal gene expression in Crohn’s Disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S061-S062
Author(s):  
P Sudhakar ◽  
T Andrighetti ◽  
S Verstockt ◽  
C Caenepeel ◽  
M Ferrante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Molecular Mechanisms ◽  
Bacterial Species ◽  
Differentially Expressed ◽  
Mucosal Barrier ◽  
Bacterial Proteins ◽  
The Impact ◽  
Hub Proteins

Abstract Background Mechanistic evidence linking gut microbial changes and host mucosal barrier responses in patients with Crohn’s disease (CD) is lacking. In this study, we used a computational approach to integrate gut microbial and intestinal gene expression in CD patients. Methods Bacterial species, bacterial genes/transcripts with enhanced abundances/transcriptional activity in CD (t-statistic of > 2 and Q-value < 0.05), as well as mucosal (ileum/rectum) differentially expressed genes (DEGs) between CD (n =43) and non-IBD (n=22) subjects were retrieved from the Inflammatory Bowel Disease Meta -Omics Database (IBDMDB). The impact of bacterial proteins on host gene expression was inferred using MicrobioLink, a computational tool for inferring microbe-host interactions. Drug target information was retrieved from OpenTargets. Paired 16S read-outs from stool samples and gene expression data from ileal biopsies in CD patients (n=20) and non-IBD controls (n=15), cross-sectionally collected at our IBD referral center, were used for independent validation. Results Across the 8 identified bacterial species enriched in CD, 3.7% (n= 743) of the orthologous groups were identified as being able to bind to human proteins. Network diffusion analysis uncovered bacterial proteins which could cumulatively modulate the expression of 42% of the genes differentially expressed in the ileum of CD patients. Topological and pathway analysis of the inferred signaling network modulated by the microbiota revealed several key hub proteins and immune-related pathways associated with IL-4, IL-2 and IL-13 signaling, receptor tyrosine-kinases, NFkB, and toll-like receptors including TLR4. Seventy-eight percent of the DEGs in our discovery cohort were also differentially expressed in the validation cohort (R2 = 0.907). Bacterial proteins post-translationally modifying host receptors resulted in the up-regulation of several pro-inflammatory cytokines via critical hub proteins such as NFkB (Figure 1). We observed different levels of locational specificity (from 35 to 61%) for the top regulators such as SPI1, STAT1 and NFKB1in terms of genes regulated by them in ileum and rectum. 24 proteins including ITGA4 and JAK1 from the ileal and rectal signaling networks are existing targets of CD drugs such as vedolizumab and tofacitinib, filgotinib and upadacitinib respectively. Conclusion Our findings outline the potential mechanisms of microbiome-induced host responses and provide insights into designing microbiome-mediated therapies to prevent and/or treat CD.

scholarly journals Microsporidian Infection in Mosquitoes (Culicidae) Is Associated with Gut Microbiome Composition and Predicted Gut Microbiome Functional Content

2021 ◽  
Author(s):  
Artur Trzebny ◽  
Anna Slodkowicz-Kowalska ◽  
Johanna Björkroth ◽  
Miroslawa Dabert
Keyword(s):  
16S Rrna ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Bacterial Communities ◽  
Bacterial Species ◽  
Rrna Gene ◽  
Microbial Composition ◽  
Microbiome Composition ◽  
Microsporidian Infection ◽  
Functional Content

AbstractThe animal gut microbiota consist of many different microorganisms, mainly bacteria, but archaea, fungi, protozoans, and viruses may also be present. This complex and dynamic community of microorganisms may change during parasitic infection. In the present study, we investigated the effect of the presence of microsporidians on the composition of the mosquito gut microbiota and linked some microbiome taxa and functionalities to infections caused by these parasites. We characterised bacterial communities of 188 mosquito females, of which 108 were positive for microsporidian DNA. To assess how bacterial communities change during microsporidian infection, microbiome structures were identified using 16S rRNA microbial profiling. In total, we identified 46 families and four higher taxa, of which Comamonadaceae, Enterobacteriaceae, Flavobacteriaceae and Pseudomonadaceae were the most abundant mosquito-associated bacterial families. Our data suggest that the mosquito gut microbial composition varies among host species. In addition, we found a correlation between the microbiome composition and the presence of microsporidians. The prediction of metagenome functional content from the 16S rRNA gene sequencing suggests that microsporidian infection is characterised by some bacterial species capable of specific metabolic functions, especially the biosynthesis of ansamycins and vancomycin antibiotics and the pentose phosphate pathway. Moreover, we detected a positive correlation between the presence of microsporidian DNA and bacteria belonging to Spiroplasmataceae and Leuconostocaceae, each represented by a single species, Spiroplasma sp. PL03 and Weissella cf. viridescens, respectively. Additionally, W. cf. viridescens was observed only in microsporidian-infected mosquitoes. More extensive research, including intensive and varied host sampling, as well as determination of metabolic activities based on quantitative methods, should be carried out to confirm our results.

scholarly journals Metaproteomics as a tool for studying the protein landscape of human-gut bacterial species

2021 ◽  
Author(s):  
Moses Stamboulian ◽  
Jamie Canderan ◽  
Yuzhen Ye
Keyword(s):  
Human Health ◽  
Gut Microbiome ◽  
De Novo ◽  
Bacterial Species ◽  
Individual Species ◽  
Human Gut ◽  
Human Gut Microbiome ◽  
Microbial Species ◽  
Microbial Organisms

AbstractHost-microbiome interactions and the microbial community have broad impact in human health and diseases. Most microbiome based studies are performed at the genome level based on next-generation sequencing techniques, but metaproteomics is emerging as a powerful technique to study microbiome functional activity by characterizing the complex and dynamic composition of microbial proteins. We conducted a large-scale survey of human gut microbiome metaproteomic data to identify generalist species that are ubiquitously expressed across all samples and specialists that are highly expressed in a small subset of samples associated with a certain phenotype. We were able to utilize the metaproteomic mass spectrometry data to reveal the protein landscapes of these species, which enables the characterization of the expression levels of proteins of different functions and underlying regulatory mechanisms, such as operons. Finally, we were able to recover a large number of open reading frames (ORFs) with spectral support, which were missed by de novo protein-coding gene predictors. We showed that a majority of the rescued ORFs overlapped with de novo predicted proteincoding genes, but on opposite strands or on different frames. Together, these demonstrate applications of metaproteomics for the characterization of important gut bacterial species. Results are available for public access at https://omics.informatics.indiana.edu/GutBac.Author summaryMany reference genomes for studying human gut microbiome are available, but knowledge about how microbial organisms work is limited. Identification of proteins at individual species or community level provides direct insight into the functionality of microbial organisms. By analyzing more than a thousand metaproteomics datasets, we examined protein landscapes of more than two thousands of microbial species that may be important to human health and diseases. This work demonstrated new applications of metaproteomic datasets for studying individual genomes. We made the analysis results available through the GutBac website, which we believe will become a resource for studying microbial species important for human health and diseases.

scholarly journals 3185 A Randomized Controlled Trial Comparing the Nonabsorbable Antibiotic Rifaximin vs. Dietary Intervention Low in Fermentable Sugars (FODMAP) in Irritable Bowel Syndrome

2019 ◽  
Vol 3 (s1) ◽  
pp. 31-31
Author(s):  
Allen Lee ◽  
Krishna Rao ◽  
Emily Haller ◽  
Lauren Van Dam ◽  
Jason Baker ◽  
...  
Keyword(s):  
Dietary Intervention ◽  
Controlled Trial ◽  
Gastrointestinal Surgery ◽  
Fecal Microbiota ◽  
Longitudinal Analyses ◽  
Dietary Interventions ◽  
Microbial Composition ◽  
Hydrogen Breath Test ◽  
Fodmap Diet ◽  
Hydrogen Breath Tests

OBJECTIVES/SPECIFIC AIMS: Objectives and goals of this study are to (i) determine whether IBS-D patients randomized to either rifaximin or low FODMAP diet show improvement in IBS-related symptoms; and (2) identify using longitudinal analyses how SIBO status and fecal microbiota features associate with response to either rifaximin or low FODMAP dietary intervention. METHODS/STUDY POPULATION: 42 patients ≥ 18 years of age who meet Rome IV criteria for IBS-D will be randomized to receive either rifaximin or low FODMAP diet intervention. The primary outcome will be the proportion of responders to intervention which is defined as ≥ 30% reduction in mean daily abdominal pain or bloating by visual analog scale compared with baseline. Exclusion criteria will include: (a) history of microscopic colitis, inflammatory bowel disease, celiac disease, or other organic disease that could explain symptoms, (b) prior gastrointestinal surgery, other than appendectomy or cholecystectomy > 6 months prior to study initiation, (c) prior use of rifaximin or formal dietary interventions for IBS-D, (d) use of antibiotics within the past 3 months, or (e) use of probiotics within 1 month of study entry. Glucose hydrogen breath tests will be performed at the beginning and end of the trial to evaluate for SIBO. Fecal samples will be collected at 0, 2, and 6 weeks to determine changes in fecal microbial composition and structure. RESULTS/ANTICIPATED RESULTS: This study seeks to examine whether longitudinal analyses of small intestinal and colonic microbiota can subtype IBS-D subjects into clinically relevant phenotypes. A total of 18 subjects have been enrolled into the study. Clinical variables, hydrogen breath test results, and fecal microbiota data are being collected for ongoing analysis. DISCUSSION/SIGNIFICANCE OF IMPACT: Results from this study may help move treatment of IBS from a purely symptom based approach to a more individualized approach by stratifying IBS-D patients into distinct clinical phenotypes which are amenable to targeted therapeutic approaches.

scholarly journals High-Fiber, Whole-Food Dietary Intervention Alters the Human Gut Microbiome but Not Fecal Short-Chain Fatty Acids

mSystems ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Andrew Oliver ◽  
Alexander B. Chase ◽  
Claudia Weihe ◽  
Stephanie B. Orchanian ◽  
Stefan F. Riedel ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Human Health ◽  
Dietary Fiber ◽  
Gut Microbiome ◽  
Dietary Intervention ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Fiber Intake ◽  
High Fiber ◽  
Fiber Consumption

ABSTRACT Dietary shifts can have a direct impact on the gut microbiome by preferentially selecting for microbes capable of utilizing the various dietary nutrients. The intake of dietary fiber has decreased precipitously in the last century, while consumption of processed foods has increased. Fiber, or microbiota-accessible carbohydrates (MACs), persist in the digestive tract and can be metabolized by specific bacteria encoding fiber-degrading enzymes. The digestion of MACs results in the accumulation of short-chain fatty acids (SCFAs) and other metabolic by-products that are critical to human health. Here, we implemented a 2-week dietary fiber intervention aiming for 40 to 50 g of fiber per day within the context of a course-based undergraduate research experience (CURE) (n = 20). By coupling shotgun metagenomic sequencing and targeted gas chromatography-mass spectrometry (GC-MS), we found that the dietary intervention significantly altered the composition of individual gut microbiomes, accounting for 8.3% of the longitudinal variability within subjects. Notably, microbial taxa that increased in relative abundance as a result of the diet change included known MAC degraders (i.e., Bifidobacterium and Lactobacillus). We further assessed the genetic diversity within Bifidobacterium, assayed by amplification of the groEL gene. Concomitant with microbial composition changes, we show an increase in the abundance of genes involved in inositol degradation. Despite these changes in gut microbiome composition, we did not detect a consistent shift in SCFA abundance. Collectively, our results demonstrate that on a short-term timescale of 2 weeks, increased fiber intake can induce compositional changes of the gut microbiome, including an increase in MAC-degrading bacteria. IMPORTANCE A profound decrease in the consumption of dietary fiber in many parts of the world in the last century may be associated with the increasing prevalence of type II diabetes, colon cancer, and other health problems. A typical U.S. diet includes about ∼15 g of fiber per day, far less fiber than the daily recommended allowance. Changes in dietary fiber intake affect human health not only through the uptake of nutrients directly but also indirectly through changes in the microbial community and their associated metabolism. Here, we conducted a 2-week diet intervention in healthy young adults to investigate the impact of fiber consumption on the gut microbiome. Participants increased their average fiber consumption by 25 g/day on average for 2 weeks. The high-fiber diet intervention altered the gut microbiome of the study participants, including increases in known fiber-degrading microbes, such as Bifidobacterium and Lactobacillus.

scholarly journals The Effect of Dietary Interventions on Chronic Inflammatory Diseases in Relation to the Microbiome: A Systematic Review

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3208
Author(s):  
Carlijn A. Wagenaar ◽  
Marieke van de van de Put ◽  
Michelle Bisschops ◽  
Wendy Walrabenstein ◽  
Catharina S. de de Jonge ◽  
...  
Keyword(s):  
Systematic Review ◽  
Gut Microbiome ◽  
Pathogenic Bacteria ◽  
Dietary Intervention ◽  
Inflammatory Diseases ◽  
Fiber Intake ◽  
Diet Change ◽  
Dietary Interventions ◽  
Chronic Inflammatory Diseases ◽  
High Fiber

Chronic inflammation plays a central role in the pathophysiology of various non-communicable diseases. Dietary interventions can reduce inflammation, in part due to their effect on the gut microbiome. This systematic review aims to determine the effect of dietary interventions, specifically fiber intake, on chronic inflammatory diseases and the microbiome. It aims to form hypotheses on the potential mediating effects of the microbiome on disease outcomes after dietary changes. Included were clinical trials which performed a dietary intervention with a whole diet change or fiber supplement (>5 g/day) and investigated the gut microbiome in patients diagnosed with chronic inflammatory diseases such as cardiovascular disease (CVD), type 2 diabetes (T2DM), and autoimmune diseases (e.g., rheumatoid arthritis (RA), inflammatory bowel disease (IBD)). The 30 articles which met the inclusion criteria had an overall moderate to high risk of bias and were too heterogeneous to perform a meta-analysis. Dietary interventions were stratified based on fiber intake: low fiber, high fiber, and supplemental fiber. Overall, but most pronounced in patients with T2DM, high-fiber plant-based dietary interventions were consistently more effective at reducing disease-specific outcomes and pathogenic bacteria, as well as increasing microbiome alpha diversity and short-chain fatty acid (SCFA)-producing bacteria, compared to other diets and fiber supplements.

A WHOLE FOOD, ANTI-INFLAMMATORY DIET ESTABLISHES A BENEFICIAL GUT MICROBIOME IN INFLAMMATORY BOWEL DISEASE PATIENTS

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S38-S38
Author(s):  
Barbara Olednzki ◽  
Vanni Bucci ◽  
Caitlin Cawley ◽  
Ana Maldonado-Contreras
Keyword(s):  
Inflammatory Bowel Disease ◽  
Clinical Response ◽  
Bowel Disease ◽  
Gut Microbiome ◽  
Dietary Intervention ◽  
Bacterial Species ◽  
Model Complex ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
The Impact

Abstract Background and Aims The inflammatory bowel disease-anti-inflammatory diet (IBD-AID) is a whole food diet designed to favor the development of an anti-inflammatory microbiome and to assist with remission in patients suffering from inflammatory bowel disease (IBD). Herein, we evaluated the effect of the IBD-AID on the gut microbiome and defined the impact of specific foods on bacteria depleted in IBD patients, as well as the clinical response to the IBD-AID. Methods A single-arm, pre-post intervention trial was performed. After a baseline period, a dietary intervention was initiated. We collected stool and blood samples throughout the study and assessed dietary intake and disease severity. We applied advanced computational approaches to define and model complex interactions between the diet, microbiota, and response to the IBD-AID. Results A dense dataset comprising 553 dietary records and 340 stool samples was compiled from 22 subjects participating in the study. The IBD-AID favored bacteria that are normally depleted in IBD cohorts and capable of producing short-chain fatty acids (SCFAs). Consumption of non-starchy vegetables, nuts, and seeds positively correlated with increased abundance of SCFA-producing bacteria, including Roseburia hominis, Eubacterium eligens,and Faecalibacterium prausnitzii. Half of the subjects completing the intervention with high diet adherence (>60%) reported a positive clinical response to the IBD-AID, with a subset of bacterial species predicting diet-induced reduction of symptoms with 67% accuracy. After the intervention, subjects also exhibited a reduction of circulating inflammatory markers. Conclusions The IBD-AID favors the growth of SCFA-producing bacteria that are depleted during IBD dysbiosis. The microbiome signatures emerging after the IBD-AID can predict response to the diet.

scholarly journals High fiber, whole foods dietary intervention alters the human gut microbiome but not fecal short-chain fatty acids

2021 ◽  
Author(s):  
Andrew Oliver ◽  
Alexander B. Chase ◽  
Claudia Weihe ◽  
Stephanie B. Orchanian ◽  
Stefan F. Riedel ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Human Health ◽  
Dietary Fiber ◽  
Gut Microbiome ◽  
Dietary Intervention ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Fiber Intake ◽  
High Fiber ◽  
Fiber Consumption

ABSTRACTDietary shifts can have a direct impact on the gut microbiome by preferentially selecting for microbes capable of utilizing the various dietary nutrients. Intake of dietary fiber has decreased precipitously in the last century, while consumption of processed foods has increased. Fiber, or microbiota-accessible carbohydrates (MACs), persist in the digestive tract and can be metabolized by specific bacteria encoding fiber degrading enzymes. Digestion of MACs results in the accumulation of short-chain fatty acids (SCFAs) and other metabolic byproducts that are critical to human health. Here, we implemented a two-week dietary fiber intervention aiming for 40-50 grams of fiber per day within the context of a course-based undergraduate research experience (CURE) (n = 20). By coupling shotgun metagenomic sequencing and targeted gas-chromatography mass spectrometry (GC/MS), we found that the dietary intervention significantly altered the composition of individual gut microbiomes, accounting for 8.3% of the longitudinal variability within subjects. Notably, microbial taxa that increased in relative abundance as a result of the diet change included known MAC degraders (i.e., Bifidobacterium and Lactobacillus). We further assessed the genetic diversity within Bifidobacterium, assayed by amplification of the groEL gene. Concomitant with microbial composition changes, we show an increase in the abundance of genes involved in inositol degradation. Despite these changes in gut microbiome composition, we did not detect a consistent shift in SCFA abundance. Collectively, our results demonstrate that on a short-term timescale of two weeks, increased fiber intake can induce compositional changes of the gut microbiome, including an increase in MAC degrading bacteria.IMPORTANCEA profound decrease in the consumption of dietary fiber in many parts of the world in the last century may be associated with the increasing prevalence of Type II diabetes, colon cancer, and other health problems. A typical U.S. diet includes about ∼15 grams of fiber per day, far less fiber than daily recommended allowance. Changes in dietary fiber intake affect human health not only through the uptake of nutrients directly, but also indirectly through changes in the microbial community and their associated metabolism. Here we conducted a two-week diet intervention in healthy young adults to investigate the impact of fiber consumption on the gut microbiome. Participants increased their average fiber consumption by 25 grams/day on average for two weeks. The high fiber diet intervention altered the gut microbiome of the study participants, including increases in known fiber degrading microbes such as Bifidobacterium and Lactobacillus.

scholarly journals Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk

2019 ◽  
Vol 124 (12) ◽  
pp. 1808-1820 ◽  
Author(s):  
Alexander Kurilshikov ◽  
Inge C.L. van den Munckhof ◽  
Lianmin Chen ◽  
Marc J. Bonder ◽  
Kiki Schraa ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Bacterial Species ◽  
Short Chain Fatty Acids ◽  
Population Based ◽  
Liver Fat ◽  
Plasma Metabolites ◽  
Cvd Risk ◽  
Microbial Composition ◽  
Lipoprotein Subclasses ◽  
Microbial Associations

Rationale: Altered gut microbial composition has been linked to cardiovascular diseases (CVDs), but its functional links to host metabolism and immunity in relation to CVD development remain unclear. Objectives: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes, and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts. Methods and Results: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based LLD (Lifelines DEEP) cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, sex, and body mass index, the gut microbiome could explain ≤11.1% and 16.4% of the variation in plasma metabolites in the population-based and obesity cohorts, respectively. Obese-specific microbial associations were found for lipid compositions in the VLDL, IDL, and LDL lipoprotein subclasses. Bacterial L-methionine biosynthesis and a Ruminococcus species were associated to cardiovascular phenotypes in obese individuals, namely atherosclerosis and liver fat content, respectively. Integration of microbiome-diet-inflammation analysis in relation to metabolic risk score of CVD in the population cohort revealed 48 microbial pathways associated to CVD risk that were largely independent of diet and inflammation. Our data also showed that plasma levels rather than fecal levels of short-chain fatty acids were relevant to inflammation and CVD risk. Conclusions: This study presents the largest metagenome-based association study on plasma metabolism and microbiome relevance to diet, inflammation, CVD risk, and cardiometabolic phenotypes in both population-based and clinical obesity cohorts. Our findings identified novel bacterial species and pathways that associated to specific lipoprotein subclasses and revealed functional links between the gut microbiome and host health that provide a basis for developing microbiome-targeted therapy for disease prevention and treatment.

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