In a recent study published in the journal Nature Medicine, a team of researchers in China conducted a prospective analysis of metabolic multimorbidity clusters based on 21 metabolic parameters to investigate gut microbiome signatures associated with metabolism and age to better understand the relationship between metabolism, age, and the long term risk of cardiovascular disease.
Study: Divergent age-associated and metabolism-associated gut microbiome signatures modulate cardiovascular disease risk. Image Credit: Kateryna Kon / Shutterstock
Background
Cardiovascular disease is the major cause of global mortality, and metabolic perturbations and age, which are also intricately connected, are believed to contribute significantly to the risk of cardiovascular disease. Metabolic disturbances increase in complexity and prevalence with age, and older adults typically develop cardiovascular disease in a multimorbidity context.
Growing evidence on aging patterns associated with gut microbiome diversity across populations suggests that the gut microbiome interconnects immunity and metabolism, undergoes age-related changes, and could be the basis of healthy aging. Studies have found that lower diversity of Bacteroides and increased diversity of unique taxa in the gut microbiome were linked to healthy aging. However, the interaction patterns between the gut microbiome, metabolism, and age and the extent to which these interactions influence cardiovascular health remain unclear.
About the study
In the present study, the researchers began by defining multimorbidity clusters based on defined metabolic parameters and then investigated the gut microbiome signatures associated with age and these multimorbidity clusters. Subsequently, based on variations in gut microbiome signatures and 55 microbial species associated with age, they defined the concept of microbial age, which was then used to delineate roles of gut microbiome composition and microbial age in specific multimorbidity clusters.
The discovery cohorts included in this study consisted of adults between the ages of 40 and 93. Data on demographic characteristics, medical histories, metabolic variables, and lifestyle factors such as alcohol consumption, smoking behavior, and physical activity levels were collected in 2010 and 2014. Follow-up data included information on incident cardiovascular disease ascertainment. Four fecal metagenomic datasets from populations from Israel, the Netherlands, France, Germany, the United States, and the United Kingdom were used as validation cohorts
Metabolic multimorbidity clusters constructed based on 21 metabolic parameters were then linked to the risk of incident cardiovascular disease. The parameters collected to define the multimorbidity clusters included body weight, height, waist circumference, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively) levels, apolipoprotein A-1, total cholesterol, fasting insulin levels, apolipoprotein B, γ-glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, oral glucose tolerance, uric acid, triglycerides, hemoglobin A1c, and fasting plasma glucose.
Based on these parameters, five metabolic multimorbidity clusters were defined, including a healthy metabolic profile, as well as those defined by low levels of HDL-C and apolipoprotein A1, high levels of LDL-C, apolipoprotein B, and total cholesterol, insulin resistance, obesity, elevated liver enzymes, and hyperglycemia.
Stool samples were collected from all participants, and shotgun metagenome sequencing was conducted using the extracted deoxyribonucleic acid (DNA). The metagenome data was used for metagenomic profiling of the discovery cohort.
The participants were divided into two groups based on age below or above 60 years, and the hazard ratios of incident cardiovascular disease were calculated for the four unhealthy multimorbidity clusters versus the healthy metabolic profile cluster. The hazard ratios of cardiovascular disease were also calculated for the younger and older age groups.
The impact of environmental factors and host on the gut microbiome was assessed, after which the uniqueness and diversity indices for the gut microbiome were calculated. Features of the gut microbiome that were associated with age and metabolism were then examined, and the associations between metabolism, microbial age, and risk of incident cardiovascular disease were determined.
Results
The results showed that compared to the healthy metabolic profile cluster, those classified as hyperglycemia and obesity clusters had a 117% and 75% increase in the risk of 11.1-year cardiovascular disease, respectively. These findings were also replicated in the validation cohort.
Additionally, the fecal metagenomic data revealed that gut microbiome composition was correlated to both age and multimorbidity clusters. Furthermore, among individuals above the age of 60 years, an increased risk of cardiovascular disease linked to the hyperglycemia and obesity multimorbidity clusters was elevated in individuals with higher microbial age and reduced in individuals with lower microbial age, independent of factors such as sex, age, dietary factors, or lifestyles.
Younger microbial age, which was characterized by decreased abundance of Prevotella species, was found to counteract the risk of cardiovascular disease in older adults from unhealthy metabolic clusters, irrespective of medication, dietary factors, education levels, sex, age, or lifestyle.
The study revealed various age-related gut microbiome signatures, such as significant reductions in Bacteroides species and increased compositional uniqueness and richness of facultative anaerobic bacteria such as those belonging to the Enterobacteriaceae and Streptococcus genera. The related increase in pro-inflammatory pathways and these microbial aging patterns were believed to be linked to the age-associated decline in immunity, digestion, and physiological functions.
Conclusions
To conclude, the study examined the interplay between gut microbiome composition and richness, age, and metabolism and its association with the risk of cardiovascular disease. The study found that the composition of the gut microbiome was associated with age and metabolic morbidity parameters.
Furthermore, based on gut microbiome species composition, younger microbial age was found to counteract the risk of cardiovascular disease associated with metabolic dysfunction, suggesting that the gut microbiome modulated cardiovascular health in older and metabolically unhealthy individuals.
Journal reference:
- Wang, T., Shi, Z., Ren, H., Xu, M., Lu, J., Yang, F., Ye, C., Wu, K., Chen, M., Xu, X., Liu, D., Kong, L., Zheng, R., Zheng, J., Li, M., Xu, Y., Zhao, Z., Chen, Y., Yang, H., & Wang, J. (2024). Divergent age-associated and metabolism-associated gut microbiome signatures modulate cardiovascular disease risk. Nature Medicine. DOI: 10.1038/s4159102403038y, https://www.nature.com/articles/s41591-024-03038-y
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