The role of oral l-tyrosine, metabolised by the gut microbiota into p-cresol derived metabolites, in blood pressure regulation

Objective: Low fibre intake has emerged as an important risk factor for hypertension through changes in the gut microbiota, but the specific metabolites involved in this phenotype are unknown. We identified two novel secondary metabolites, p-Cresol glucuronide (PCG) and p-Cresol sulfate (PCS) that were elevated in plasma samples in mice on a low fibre diet. The precursor of PCG and PCS, p-Cresol, is a microbial metabolite derived from tyrosine fermentation by the gut microbiota. We hypothesized p-cresol-derived metabolites would trigger immune-activation to promote the development of hypertension. We aimed to assess whether oral L-tyrosine increases circulating PCG and PCS levels, leading to a worsened cardiovascular phenotype via immune-dependent mechanisms. Design and method: Male C57BL/6 mice (n = 8/group) were infused with saline or angiotensin II (Ang II, 0.5 mg/kg/day) for 4 weeks. Mice were treated with or without L-tyrosine in their drinking water accompanied by a normal chow diet for the duration of the experiment. Blood pressure (BP) was measured using tail-cuff and a targeted metabolomic approach was applied to identify the levels of PCG and PCS in the circulation. Additionally, liver enzymatic activities, immune cell activation and infiltration in the bone marrow, spleen and kidney were examined. Results: L-tyrosine treated hypertensive mice had significantly reduced systolic and diastolic BP compared to the control hypertensive mice (-16.4 and -14.2 mmHg, respectively, p < 0.01). Flow cytometric analysis revealed that L-tyrosine did not alter the numbers of the immune cells, including monocytes, neutrophils or T cells in bone marrow, spleen or kidneys in hypertensive or normotensive conditions. Furthermore, immune cell activation and production of cytokines, including TNF-alpha and IL17, did not change. Preliminary data suggests L-tyrosine increased the levels of PCS, but not PCG, in the circulation of both hypertensive and normotensive mice. The expression of the hepatic enzymes responsible for the biotransformation of p-Cresol to PCS and PCG were not differentially expressed, suggesting that conversion of p-Cresol to PCS occurs outside the liver. Conclusions: This study provides novel insights into the roles of L-tyrosine and PCS in hypertension. When delivered orally, L-tyrosine is digested by the gut microbiota, and leads to the production of PCS, lowering BP through immune-cell independent mechanisms. However, the role of PCG, a low-fibre driven-metabolite, in BP is still under investigation.