ABSTRACT
INTRODUCTION: Animal models are regularly used to test the role of the gut microbiome in hypertension. Small-scale pre-clinical studies have investigated changes to the gut microbiome in the angiotensin II hypertensive model. However, the gut microbiome is influenced by internal and external experimental factors which are not regularly considered in the study design. Once these factors are accounted for, it is unclear if microbiome signatures are reproduceable. We aimed to determine the influence of angiotensin II treatment on the gut microbiome using a large and diverse cohort of mice and to quantify the magnitude by which other factors contribute to microbiome variations. METHODS AND RESULTS: We conducted a retrospective study to establish a diverse mouse cohort resembling large human studies. We sequenced the V4 region of the 16S rRNA gene from 538 samples across the gastrointestinal tract of 303 male and female C57BL/6J mice randomised into sham or angiotensin II treatment from different genotypes, diets, animal facilities, and age groups. Analysing over 17 million sequencing reads, we observed that angiotensin II treatment influenced α-diversity (P = 0.0137) and ß-diversity (i.e., composition of the microbiome, P < 0.001). Bacterial abundance analysis revealed patterns consistent with a reduction in short-chain fatty acid-producers, microbial metabolites that lower blood pressure. Furthermore, animal facility, genotype, diet, age, sex, intestinal sampling site, and sequencing batch had significant effects on both α- and ß-diversity (all P < 0.001). Sampling site (6.8%) and diet (6%) had the largest impact on the microbiome, while angiotensin II and sex had the smallest effect (each 0.4%). CONCLUSIONS: Our large-scale data confirmed findings from small-scale studies that angiotensin II impacted the gut microbiome. However, this effect was modest relative to most of the other factors studied. Accounting for these factors in future pre-clinical hypertensive studies will increase the likelihood that microbiome findings are replicable and translatable.
ABSTRACT
Advances in sequencing technology have increased our understanding of the composition of the gut microbiota and their contribution to health and disease states, including in cardiovascular diseases such as hypertension. The gut microbiota is heavily influenced by diet and produce metabolites such as short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO) from various food sources. SCFAs, such as acetate, propionate, and butyrate, have been shown to have blood pressure, cardiac hypertrophy, and fibrosis lowering properties, while TMAO has been associated with increased risk of major cardiovascular adverse events and mortality. Some of these metabolites have known ligands (for example, SCFA receptors such as GPR41, GPR43, GPR109a, and Olf78 in mice/OR51E2 in humans) which could potentially be manipulated as therapeutic targets for hypertension. In this review, we discuss several types of diet-related gut microbial metabolites and their sensing mechanisms that are relevant for hypertension, and the future directions for the field.
