Biology subjects

Paterson, M.

Publications and source records attributed to Paterson, M..

3 recordsLinked to original sources

bioRxiv2023

Experimental Factors Influence Diversity Metrics of the Gut Microbiome in Laboratory Mice

IntroductionAnimal 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 factors 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 ResultsWe 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 -diversity (P=0.0137) and {beta}-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 - and {beta}-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%). ConclusionsOur 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.

microbiology↗

bioRxiv2023

GPR41/43 regulates blood pressure by improving gut epithelial barrier integrity to prevent TLR4 activation and renal inflammation

Fermentation of dietary fibre by the gut microbiota leads to the production of metabolites called short-chain fatty acids (SCFAs), which have emerged as potent regulators of immune, metabolic, and tissue barrier functions. More recently, a high fibre diet and SCFA supplementation were shown to lower blood pressure and be cardio-protective. SCFAs activate host signalling responses via the receptors GPR41 and GPR43, which have redundancy in their signalling pathways. Whether these receptors play a role in hypertension or mediate the cardio-protective effects of fibre remains unknown. Using an experimental model that lacks both GPR41 and GPR43, we show that lack of signalling via these receptors increases risk to high blood pressure and leads to cardiorenal fibrosis and hypertrophy. Moreover, we demonstrate that GPR41/43 signalling is essential in maintaining gut epithelial barrier, which prevents the translocation of the bacterial toxins lipopolysaccharides (LPS) from entering the peripheral circulation. In the absence of GPR41/43, this is accompanied by macrophage infiltration to the kidneys, resulting in pro-inflammatory cytokine production. Using an antagonist against the LPS receptor, TLR4, a potent pro-inflammatory signalling pathway, we were able to rescue the cardiovascular phenotype in GPR41/43 knockout mice. We also demonstrate that GPR41/43 are, at least partially, responsible for the blood pressure- lowering and cardio-protective effects of a high fibre diet; however, improvements of gut barrier integrity and macrophages in the kidney were independent of GPR41/43 signalling. Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41/43 are more prevalent in hypertensive patients. Our findings highlight that lack of SCFA-receptor signalling via both GPR41/43 increases risk of high blood pressure, suggesting these receptors could be targeted as a new treatment.

physiology↗

bioRxiv2022

Dietary fibre controls blood pressure and cardiovascular risk by lowering large intestinal pH and activating the proton-sensing receptor GPR65

High blood pressure (BP) is the most common cause of death globally, due to increasing the risk of cardiovascular diseases. Dietary fiber regulates BP through gut microbial production of acidic metabolites known as short-chain fatty acids (SCFAs). The specific mechanisms of how SCFAs regulate BP are still emerging. In a phenome-wide association study, we identified that the proton-sensing G-protein-coupled receptor GPR65 gene is associated with hypertension and its associated end-organ damage phenotypes. We hypothesized that acidic metabolites produced from the gut microbiota may activate GPR65, thus conferring BP regulating effects. We found that dietary fiber levels determined the luminal and interstitial tissue pH in the large intestine through production of SCFAs by the gut microbiota. We identified that low pH produced by high fiber intake, acting via GPR65 signaling, increased cAMP production and phosphorylation of CREB, and restricted the production of hypertension-promoting inflammatory cytokines by CD8+ T cells. Gpr65-/- mice spontaneously developed higher BP, cardiac and renal hypertrophy and fibrosis. We showed that the benefits of a diet high in fiber, which prevented hypertension and associated end-organ damage, were decreased in Gpr65-/- mice. Finally, adoptive transfers revealed that GPR65 deficiency in CD8+ T cells causally explained this phenotype. In conclusion, we showed that pH sensing by GPR65 in CD8+ T cells mediates much of the cardiovascular benefits of dietary fiber. pH sensing represents a novel gene-by-environment interaction of gut microbiota-to-host biological effects and may form the basis for new therapeutic strategies for hypertension.

molecular biology↗