Trimethylamine, a gut bacteria metabolite and air pollutant, increases blood pressure and markers of kidney damage including proteinuria and KIM-1 in rats

Abstract

Background Trimethylamine oxide (TMAO) is a biomarker in cardiovascular and renal diseases. TMAO originates from the oxidation of trimethylamine (TMA), a product of gut microbiota and manufacturing industries-derived pollutant, by flavin monooxygenases (FMOs). The effect of chronic exposure to TMA on cardiovascular and renal systems is undetermined. Methods Metabolic, hemodynamic, echocardiographic, biochemical and histopathological evaluations were performed in 12-week-old male SPRD rats receiving water (controls) or TMA (200 or 500 µM/day) in water for 18 weeks. TMA and TMAO levels, the expression of FMOs and renin-angiotensin system (RAS) genes were evaluated in various tissues. Results In comparison to controls, rats receiving high dose of TMA had significantly increased arterial systolic blood pressure (126.3 ± 11.4 vs 151.2 ± 19.9 mmHg; P = 0.01), urine protein to creatinine ratio (1.6 (1.5; 2.8) vs 3.4 (3.3; 4.2); P = 0.01), urine KIM-1 levels (2338.3 ± 732.0 vs. 3519.0 ± 953.0 pg/mL; P = 0.01), and hypertrophy of the tunica media of arteries and arterioles (36.61 ± 0.15 vs 45.05 ± 2.90 µm, P = 0.001 and 18.44 ± 0.62 vs 23.79 ± 2.60 µm, P = 0.006; respectively). Mild degeneration of renal bodies with glomerulosclerosis was also observed. There was no significant difference between the three groups in body weight, water-electrolyte balance, echocardiographic parameters and RAS expression. TMA groups had marginally increased 24 h TMA urine excretion, whereas serum levels and 24 h TMAO urine excretion were increased up to 24-fold, and significantly increased TMAO levels in the liver, kidneys and heart. TMA groups had lower FMOs expression in the kidneys. Conclusions Chronic exposure to TMA increases blood pressure and increases markers of kidney damage, including proteinuria and KIM-1. TMA is rapidly oxidized to TMAO in rats, which may limit the toxic effects of TMA on other organs.

Causal Effects of Specific Gut Microbiota on Chronic Kidney Diseases and Renal Function—A Two-Sample Mendelian Randomization Study

“…and accumulating in the blood circulation. These toxins and inflammatory mediators have been shown to be involved in the activation of the RAAS system [ 37 ], changes in the tissue microenvironment [ 38 ], and other pathways, which ultimately lead to the burden and damage of the kidney [ 39 ]. It is important to note that this buildup of toxins should result in various organ damage, not just the kidney.…”

Mice, rats, and guinea pigs differ in FMOs expression and tissue concentration of TMAO, a gut bacteria-derived biomarker of cardiovascular and metabolic diseases

“…Analyte concentrations were evaluated using Waters Acquity Ultra Performance Liquid Chromatography (Waters, Milford, Massachusetts, USA) coupled with Waters TQ-S triple-quadrupole mass spectrometer (Waters, Manchester, UK). Tissue preparation and the exact determination of metabolites in tissue homogenates have been previously described [ 52 ]. The metabolite concentrations in tissues were measured in dry tissue mass.…”

Does the Composition of Gut Microbiota Affect Hypertension? Molecular Mechanisms Involved in Increasing Blood Pressure

“…Although the direct role of TMA and TMAO in the development of hypertension remains uncertain [ 50 ], studies have reported that TMAO might show the ability to prolong the hypertensive effect of angiotensin II [ 51 , 52 ]. It has been noticed in the literature that patients with chronic kidney disease (CKD) demonstrated higher plasma levels of TMAO [ 53 , 54 ].…”

“…The recent animal-based study has found that rats receiving TMA solution presented increased arterial blood pressure (especially systolic). Moreover, rats administered a higher dose of TMA showed increased systemic vascular resistance, which might suggest the vasoconstrictive mechanism of observed phenomenon [ 50 , 56 ]. Although TMA and TMAO levels might not play a main role in the pathogenesis of arterial hypertension, they might contribute to the development and progression of the disease [ 57 ].…”