NEW YORK — By characterizing the plasma metabolome of individuals from two biobank cohorts in the Netherlands, a Dutch team has begun to tease out how genetics, diet, and the gut microbiome all influence the metabolome.
The metabolome reflects the metabolic activity of all organs and tissues of the body, and various metabolites have been linked to risk of developing conditions like cardiovascular disease and diabetes. But a number of factors are thought to affect someone's metabolome.
To examine how genetics, diet, and the gut microbiome contribute to variation in the plasma metabolome, researchers from University Medical Center Groningen assessed the levels of nearly 1,200 plasma metabolites in individuals from the Lifelines DEEP and Genome of the Netherlands cohorts. As they reported in Nature Medicine on Monday, the researchers found that an individual's genetics, diet, and gut microbiome in combination with intrinsic factors like age and sex explain about a quarter of the variance in the plasma metabolome. They further uncovered likely causative relationships between diet or the gut microbiome and metabolites.
Better understanding these relationships could aid in the design of approaches to foster a healthy metabolome, the researchers said. "[T]he dietary, genetic, and microbial associations with plasma metabolites and the causal and mediation linkages that we report here provide a comprehensive resource that can guide follow-up studies aimed at designing preventive and therapeutic strategies for human metabolic health," senior author Jingyuan Fu, a researcher at UMCG, and colleagues wrote in their paper.
For their analysis, the researchers studied the fasting plasma metabolomes of 1,368 individuals from the two cohorts using flow-injection time-of-flight mass spectrometry, yielding plasma levels of 1,183 metabolites spanning a range of types from lipids to benzenoids. They combined those results with data on dietary habits, genetic data, and the gut microbiome abundance that had been already collected from those individuals.
Based on this, genetics could account for 3.3 percent of the inter-individual variation in the plasma metabolome, while dietary factors could explain 9.3 percent of the variation and the gut microbiome 12.8 percent. When combined with intrinsic factors, they together accounted for 25.1 percent of the variation in the plasma metabolome.
In pairwise analyses between various metabolites, dietary variables, genetic variants, and gut microbial taxa, the researchers uncovered thousands of interactions. Among them were 2,854 associations with dietary habits, 48 associations with 40 different genetic variants, 1,373 associations with gut microbial taxa, and 2,839 associations with bacterial metabolic pathways.
These and other analyses suggested that diet and the gut microbiome have a greater influence on inter-individual variability in the metabolome than genetic factors.
In a series of Mendelian randomization studies, the researchers further examined which factors might have causal effects.
They noted a strong association between 5-acetylamino-6-formylamino-3-methyluracil (AFMU), a caffeine metabolite, and a SNP near the N-acetyltransferase 2 (NAT2) gene. AFMU is a product of NAT2 activity and has been tied to bladder cancer risk. Further, the researchers noted an association with which SNP genotype individuals had — those with the AA genotype who had similar coffee intake as GG and GA genotype individuals had a lower correlation between their coffee intake and AFMU levels.
The researchers additionally found a negative correlation between plasma hydrogen sulfite levels and the common gut microbe Eubacterium rectale, which has previously been found to promote gut health by producing butyrate and other short-chain fatty acids. As a toxin, hydrogen sulfite has also been known to affect the nervous system, the cardiovascular system, and more, leading the researchers to suspect they have identified a potential new benefit of E. rectale.
Characterizing factors of variation in the plasma metabolome could help develop ways to alter someone's diet or gut microbiome to influence a healthy metabolome, the researchers concluded. They noted, though, that their findings need to be replicated in an independent cohort, especially as their study was underpowered.