The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.
Reperfusion is mandatory after ischemia but also triggers ischemia-reperfusion (I/R) injury. Ischemic preconditioning (IPC) can limit endothelial I/R injury. Nonetheless, translation of IPC to the clinical arena is often disappointing. Since application of IPC typically relates to older patients, efficacy of IPC may be attenuated with aging. Our objective was to examine the impact of advanced age on the ability of IPC to protect against endothelial dysfunction due to I/R injury. We included 15 healthy young (20-25 yr) and 15 older (68-77 yr) men. We examined brachial artery endothelial function using flow-mediated dilation (FMD) before and after arm I/R (induced by inflation of an upper-arm blood pressure cuff for 20 min and 15 min of reperfusion). In a randomized order, I/R was preceded by IPC or a control intervention consisting of three cycles of 5 min upper-arm cuff inflation to 220 or 20 mmHg, respectively. As a result, in young men, FMD decreased significantly after I/R (6.4 ± 2.7 to 4.4 ± 2.5%). This decrease was not present when I/R was preceded by IPC (5.9 ± 2.3 to 5.6 ± 2.5%). IPC-induced protection appeared to be significantly reduced in the elderly patients (P = 0.04). Although FMD decreased after I/R in older men (3.5 ± 1.7 to 2.5 ± 1.0%), IPC could not prevent this (3.7 ± 2.1 to 2.2 ± 1.1%). In conclusion, this study is the first to observe in humans in vivo that older age is associated with an abolished effect of IPC to protect against endothelial dysfunction after I/R in the brachial artery. This provides a possible explanation for the problematic translation of strategies that reduce I/R injury from preclinical work to the clinical arena.
Carotid artery intima-medial thickness (cIMT) represents a popular measure of atherosclerosis and is predictive of future cardiovascular and cerebrovascular events. Although older age is associated with a higher cIMT, little is known about whether this increase in cIMT follows a linear relationship with age or it is affected under influence of cardiovascular diseases (CVD) or CVD risk factors. We hypothesize that the relationship between cIMT and age is nonlinear and is affected by CVD or risk factors. A systematic review of studies that examined cIMT in the general population and human populations free from CVD/risk factors was undertaken. The literature search was conducted in PubMed, Scopus, and Web of Science. Seventeen studies with 32 unique study populations, involving 10,124 healthy individuals free from CVD risk factors, were included. Furthermore, 58 studies with 115 unique study populations were included, involving 65,774 individuals from the general population (with and without CVD risk factors). A strong positive association was evident between age and cIMT in the healthy population, demonstrating a gradual, linear increase in cIMT that did not differ between age decades (r = 0.91, P < 0.001). Although populations with individuals with CVD demonstrated a higher cIMT compared to populations free of CVD, a linear relation between age and cIMT was also present in this population. Our data suggest that cIMT is strongly and linearly related to age. This linear relationship was not affected by CVD or risk factors.
Summary Bile acids (BAs) facilitate intestinal fat absorption and act as important signaling molecules in host□gut microbiota crosstalk. BA-metabolizing pathways in the microbial community have been identified, but how the highly variable genomes of gut bacteria interact with host BA metabolism remains largely unknown. We characterized 8,282 structural variants (SVs) of 55 bacterial species in the gut microbiomes of 1,437 individuals from two Dutch cohorts and performed a systematic association study with 39 plasma BA parameters. Both variations in SV-based continuous genetic makeup and discrete subspecies showed correlations with BA metabolism. Metagenome-wide association analysis identified 797 replicable associations between bacterial SVs and BAs and SV regulators that mediate the effects of lifestyle factors on BA metabolism. This is the first large-scale microbial genetic association analysis to demonstrate the impact of bacterial SVs on human BA composition, and highlights the potential of targeting gut microbiota to regulate BA metabolism through lifestyle intervention.
Abstract Context Atherosclerosis is a dominant cause of cardiovascular disease (CVD), including myocardial infarction and stroke. Objective To investigate metabolic states that are associated with the development of atherosclerosis. Methods Cross-sectional cohort study at a university hospital in the Netherlands. A total of 302 adult subjects with a body mass index (BMI) ≥ 27 kg/m2 were included. We integrated plasma metabolomics with clinical metadata to quantify the “atherogenic state” of each individual, providing a continuous spectrum of atherogenic states that ranges between nonatherogenic states to highly atherogenic states. Results Analysis of groups of individuals with different clinical conditions—such as metabolically healthy individuals with obesity, and individuals with metabolic syndrome—confirmed the generalizability of this spectrum; revealed a wide variation of atherogenic states within each condition; and allowed identification of metabolites that are associated with the atherogenic state regardless of the particular condition, such as gamma-glutamyl-glutamic acid and homovanillic acid sulfate. The analysis further highlighted metabolic pathways such as catabolism of phenylalanine and tyrosine and biosynthesis of estrogens and phenylpropanoids. Using validation cohorts, we confirmed variation in atherogenic states in healthy subjects (before atherosclerosis plaques become visible), and showed that metabolites associated with the atherogenic state were also associated with future CVD. Conclusion Our results provide a global view of atherosclerosis risk states using plasma metabolomics.
Abstract Background Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids that are associated with an increased risk of cardiometabolic diseases (CMD). However, there are still only limited insights into potential direct associations between BCAAs and a wide range of CMD parameters, especially those remaining after correcting for covariates and underlying causal relationships. Methods To shed light on these relationships, we systematically characterized the associations between plasma BCAA concentrations and a large panel of 537 CMD parameters (including atherosclerosis-related parameters, fat distribution, plasma cytokine concentrations and cell counts, circulating concentrations of cardiovascular-related proteins and plasma metabolites) in 1400 individuals from the Dutch population cohort LifeLines DEEP and 294 overweight individuals from the 300OB cohort. After correcting for age, sex, and BMI, we assessed associations between individual BCAAs and CMD parameters. We further assessed the underlying causality using Mendelian randomization. Results A total of 838 significant associations were detected for 409 CMD parameters. BCAAs showed both common and specific associations, with the most specific associations being detected for isoleucine. Further, we found that obesity status substantially affected the strength and direction of associations for valine, which cannot be corrected for using BMI as a covariate. Subsequent univariable Mendelian randomization (UVMR), after removing BMI-associated SNPs, identified seven significant causal relationships from four CMD traits to BCAA levels, mostly for diabetes-related parameters. However, no causal effects of BCAAs on CMD parameters were supported. Conclusions Our cross-sectional association study reports a large number of associations between BCAAs and CMD parameters. Our results highlight some specific associations for isoleucine, as well as obesity-specific effects for valine. MR-based causality analysis suggests that altered BCAA levels can be a consequence of diabetes and alteration in lipid metabolism. We found no MR evidence to support a causal role for BCAAs in CMD. These findings provide evidence to (re)evaluate the clinical importance of individual BCAAs in CMD diagnosis, prevention, and treatment.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)