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Fulltext Rethinking Culture to Unlock the Potential of Medical Research

Marques FZ

Hypertension, 2024 Jan;81(1):110-113.
PMID: 37990913 DOI: 10.1161/HYPERTENSIONAHA.123.22321
Diet-related gut microbial metabolites and sensing in hypertension

R Muralitharan R, Marques FZ

J Hum Hypertens, 2021 02;35(2):162-169.
PMID: 32733062 DOI: 10.1038/s41371-020-0388-3

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.
The conundrum of the gut microbiome and blood pressure: the importance of studying sex and ethnicity

Muralitharan RR, Nakai ME, Marques FZ

Eur Heart J, 2020 11 21;41(44):4268-4270.
PMID: 33210116 DOI: 10.1093/eurheartj/ehaa760
Microbial Peer Pressure: The Role of the Gut Microbiota in Hypertension and Its Complications

Muralitharan RR, Jama HA, Xie L, Peh A, Snelson M, Marques FZ

Hypertension, 2020 12;76(6):1674-1687.
PMID: 33012206 DOI: 10.1161/HYPERTENSIONAHA.120.14473

There is increasing evidence of the influence of the gut microbiota on hypertension and its complications, such as chronic kidney disease, stroke, heart failure, and myocardial infarction. This is not surprising considering that the most common risk factors for hypertension, such as age, sex, medication, and diet, can also impact the gut microbiota. For example, sodium and fermentable fiber have been studied in relation to both hypertension and the gut microbiota. By combining second- and, now, third-generation sequencing with metabolomics approaches, metabolites, such as short-chain fatty acids and trimethylamine N-oxide, and their producers, have been identified and are now known to affect host physiology and the cardiovascular system. The receptors that bind these metabolites have also been explored with positive findings-examples include known short-chain fatty acid receptors, such as G-protein coupled receptors GPR41, GPR43, GPR109a, and OLF78 in mice. GPR41 and OLF78 have been shown to have inverse roles in blood pressure regulation, whereas GPR43 and GPR109A have to date been demonstrated to impact cardiac function. New treatment options in the form of prebiotics (eg, dietary fiber), probiotics (eg, Lactobacillus spp.), and postbiotics (eg, the short-chain fatty acids acetate, propionate, and butyrate) have all been demonstrated to be beneficial in lowering blood pressure in animal models, but the underlying mechanisms remain poorly understood and translation to hypertensive patients is still lacking. Here, we review the evidence for the role of the gut microbiota in hypertension, its risk factors, and cardiorenal complications and identify future directions for this exciting and fast-evolving field.
Guidelines for microbiome studies in renal physiology

Muralitharan RR, Snelson M, Meric G, Coughlan MT, Marques FZ

Am J Physiol Renal Physiol, 2023 Sep 01;325(3):F345-F362.
PMID: 37440367 DOI: 10.1152/ajprenal.00072.2023

Gut microbiome research has increased dramatically in the last decade, including in renal health and disease. The field is moving from experiments showing mere association to causation using both forward and reverse microbiome approaches, leveraging tools such as germ-free animals, treatment with antibiotics, and fecal microbiota transplantations. However, we are still seeing a gap between discovery and translation that needs to be addressed, so that patients can benefit from microbiome-based therapies. In this guideline paper, we discuss the key considerations that affect the gut microbiome of animals and clinical studies assessing renal function, many of which are often overlooked, resulting in false-positive results. For animal studies, these include suppliers, acclimatization, baseline microbiota and its normalization, littermates and cohort/cage effects, diet, sex differences, age, circadian differences, antibiotics and sweeteners, and models used. Clinical studies have some unique considerations, which include sampling, gut transit time, dietary records, medication, and renal phenotypes. We provide best-practice guidance on sampling, storage, DNA extraction, and methods for microbial DNA sequencing (both 16S rRNA and shotgun metagenome). Finally, we discuss follow-up analyses, including tools available, metrics, and their interpretation, and the key challenges ahead in the microbiome field. By standardizing study designs, methods, and reporting, we will accelerate the findings from discovery to translation and result in new microbiome-based therapies that may improve renal health.
Guidelines for Transparency on Gut Microbiome Studies in Essential and Experimental Hypertension

Marques FZ, Jama HA, Tsyganov K, Gill PA, Rhys-Jones D, Muralitharan RR, et al.

Hypertension, 2019 12;74(6):1279-1293.
PMID: 31679421 DOI: 10.1161/HYPERTENSIONAHA.119.13079

Hypertension is a complex and modifiable condition in which environmental factors contribute to both onset and progression. Recent evidence has accumulated for roles of diet and the gut microbiome as environmental factors in blood pressure regulation. However, this is complex because gut microbiomes are a unique feature of each individual reflecting that individual's developmental and environmental history creating caveats for both experimental models and human studies. Here, we describe guidelines for conducting gut microbiome studies in experimental and clinical hypertension. We provide a complete guide for authors on proper design, analyses, and reporting of gut microbiota/microbiome and metabolite studies and checklists that can be used by reviewers and editors to support robust reporting and interpretation. We discuss factors that modulate the gut microbiota in animal (eg, cohort, controls, diet, developmental age, housing, sex, and models used) and human studies (eg, blood pressure measurement and medication, body mass index, demographic characteristics including age, cultural identification, living structure, sex and socioeconomic environment, and exclusion criteria). We also provide best practice advice on sampling, storage of fecal/cecal samples, DNA extraction, sequencing methods (including metagenomics and 16S rRNA), and computational analyses. Finally, we discuss the measurement of short-chain fatty acids, metabolites produced by the gut microbiota, and interpretation of data. These guidelines should support better transparency, reproducibility, and translation of findings in the field of gut microbiota/microbiome in hypertension and cardiovascular disease.
Rodent models of hypertension

Jama HA, Muralitharan RR, Xu C, O'Donnell JA, Bertagnolli M, Broughton BRS, et al.

Br J Pharmacol, 2022 Mar;179(5):918-937.
PMID: 34363610 DOI: 10.1111/bph.15650

Elevated blood pressure (BP), or hypertension, is the main risk factor for cardiovascular disease. As a multifactorial and systemic disease that involves multiple organs and systems, hypertension remains a challenging disease to study. Models of hypertension are invaluable to support the discovery of the specific genetic, cellular and molecular mechanisms underlying essential hypertension, as well as to test new possible treatments to lower BP. Rodent models have proven to be an invaluable tool for advancing the field. In this review, we discuss the strengths and weaknesses of rodent models of hypertension through a systems approach. We highlight the ways how target organs and systems including the kidneys, vasculature, the sympathetic nervous system (SNS), immune system and the gut microbiota influence BP in each rodent model. We also discuss often overlooked hypertensive conditions such as pulmonary hypertension and hypertensive-pregnancy disorders, providing an important resource for researchers. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.
Fulltext Essential Hypertension Is Associated With Changes in Gut Microbial Metabolic Pathways: A Multisite Analysis of Ambulatory Blood Pressure

Nakai M, Ribeiro RV, Stevens BR, Gill P, Muralitharan RR, Yiallourou S, et al.

Hypertension, 2021 09;78(3):804-815.
PMID: 34333988 DOI: 10.1161/HYPERTENSIONAHA.121.17288

[Figure: see text].
Renal ACE2 (Angiotensin-Converting Enzyme 2) Expression Is Modulated by Dietary Fiber Intake, Gut Microbiota, and Their Metabolites

Snelson M, R Muralitharan R, Dinakis E, Nakai M, Jama HA, Shihata WA, et al.

Hypertension, 2021 06;77(6):e53-e55.
PMID: 33866801 DOI: 10.1161/HYPERTENSIONAHA.121.17039
Fulltext Influence of angiotensin II on the gut microbiome: modest effects in comparison to experimental factors

R Muralitharan R, Nakai ME, Snelson M, Zheng T, Dinakis E, Xie L, et al.

Cardiovasc Res, 2024 Sep 02;120(10):1155-1163.
PMID: 38518247 DOI: 10.1093/cvr/cvae062

AIMS: 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 randomized 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 β-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 β-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%).
CONCLUSION: 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.
Fulltext Lifestyle management of hypertension: International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension

Charchar FJ, Prestes PR, Mills C, Ching SM, Neupane D, Marques FZ, et al.

J Hypertens, 2024 Jan 01;42(1):23-49.
PMID: 37712135 DOI: 10.1097/HJH.0000000000003563

Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools.