Several studies have suggested negative effects of trimethylamine oxide (TMAO) on the circulatory system. However, a number of studies have shown protective functions of TMAO, a piezolyte and osmolyte, in animals exposed to high hydrostatic and/or osmotic stress. We evaluated the effects of TMAO treatment on the development of hypertension and its complications in male spontaneously hypertensive rats (SHRs) maintained on water (SHR-Water) and SHRs drinking TMAO water solution from weaning (SHR-TMAO). Wistar-Kyoto (WKY) rats were used as normotensive controls to discriminate between age-dependent and hypertension-dependent changes. Telemetry measurements of blood pressure were performed in rats between the 7th and 16th weeks of life. Anesthetized rats underwent echocardiographic, electrocardiographic, and direct left ventricular end-diastolic pressure (LVEDP) measurements. Hematoxylin and eosin as well as van Gieson staining for histopathological evaluation were performed. Plasma TMAO measured by chromatography coupled with mass spectrometry was significantly higher in the SHR-Water group compared with the WKY group (~20%). TMAO treatment increased plasma TMAO by four- to fivefold and did not affect the development of hypertension in SHRs. Sixteen-week-old rats in the SHR-Water and SHR-TMAO groups (12-wk TMAO treatment) showed similar blood pressures, angiopathy, and cardiac hypertrophy. However, the SHR-TMAO group had lower plasma NH2-terminal pro-B-type natriuretic peptide, LVEDP, and cardiac fibrosis. In contrast to age-matched WKY rats, 60-wk-old SHRs showed hypertensive angiopathy and heart failure with preserved ejection fraction. Compared with the SHR-Water group, the SHR-TMAO group (56-wk TMAO treatment) showed significantly lower plasma NH2-terminal pro-B-type natriuretic peptide and vasopressin, significantly lower LVEDP, and cardiac fibrosis. In conclusion, a four- to fivefold increase in plasma TMAO does not exert negative effects on the circulatory system. In contrast, increased dietary TMAO seems to reduce diastolic dysfunction in pressure-overloaded hearts in rats. NEW & NOTEWORTHY Chronic, low-dose trimethylamine oxide (TMAO) treatment that increases plasma TMAO by four- to fivefold reduces plasma NH2-terminal pro-B-type natriuretic peptide and vasopressin, left ventricular end-diastolic pressure, and cardiac fibrosis in pressure-overloaded hearts in hypertensive rats. Our study provides evidence that a moderate increase in plasma TMAO does not have a negative effect on the circulatory system. In contrast, increased dietary TMAO seems to reduce diastolic dysfunction in the pressure-overloaded heart.
The gut-blood barrier (GBB) controls the passage of nutrients, bacterial metabolites and drugs from intestinal lumen to the bloodstream. The GBB integrity is disturbed in gastrointestinal, cardiovascular and metabolic diseases, which may result in easier access of biologically active compounds, such as gut bacterial metabolites, to the bloodstream. Thus, the permeability of the GBB may be a marker of both intestinal and extraintestinal diseases. Furthermore, the increased penetration of bacterial metabolites may affect the functioning of the entire organism. Commonly used methods for studying the GBB permeability are performed ex vivo. The accuracy of those methods is limited, because the functioning of the GBB depends on intestinal blood flow. On the other hand, commonly used in vivo methods may be biased by liver and kidney performance, as those methods are based on evaluation of urine or/and peripheral blood concentrations of exogenous markers. Here, we present a direct measurement of GBB permeability in rats using an in vivo method based on portal blood sampling, which preserves intestinal blood flow and is virtually not affected by the liver and kidney function. Polyurethane catheters are inserted into the portal vein and inferior vena cava just above the hepatic veins confluence. Blood is sampled at baseline and after administration of a selected marker into a desired part of the gastrointestinal tract. Here, we present several applications of the method including (1) evaluation of the colon permeability to TMA, a gut bacterial metabolite, (2) evaluation of liver clearance of TMA, and (3) evaluation of a gut-portal blood-liver-peripheral blood pathway of gut bacteria-derived short-chain fatty acids. Furthermore, the protocol may also be used for tracking intestinal absorption and liver metabolism of drugs or for measurements of portal blood pressure.
Tryptophan is an essential amino acid. Paradoxically, both tryptophan‐low and tryptophan‐rich diets have been found to decrease weight gain in rats, however, the mechanisms are not clear.Energy and water‐electrolyte balance were evaluated in 12‐week‐old, male, Sprague Dawley rats maintained on either control diet (TC) or tryptophan‐high (TH) or tryptophan‐low (TL) or control diet with neomycin, an antibiotic (TCA), for 10 days. Feces and blood levels of tryptophan and its bacterial metabolites were evaluated using chromatography coupled with mass spectrometry.TL rats showed reduction in body weight. TH showed body weight gain, however, it was significantly lower than in TC and TCA rats. TL rats showed significantly lower blood level of tryptophan and its bacterial derivatives including indoxyl sulfate and indole‐3‐propionic acid (I‐3‐P). TH rats had significantly higher blood tryptophan level comparing to TL rats. I‐3‐P in feces and in portal blood of TH rats was significantly higher comparing to TC, TL and TCA rats. In a separate series of experiments rats treated daily i.p. with I‐3‐P showed significantly smaller weight gain than rats treated with the vehicle.Our study suggests that tryptophan‐rich diet has a negative effect on energy balance via I‐3‐P, a gut bacteria metabolite of tryptophan. In contrast, tryptophan‐deficient diet may reduce weight due to the deficiency of the essential amino acid and decreased anabolism.Support or Funding InformationSupported by the Ministry of Science and Higher Education Republic of Poland, Diamond grant DI2016 007346This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Butyric acid (BA) is one of several short‐chain fatty acids (SCFAs) produced by gut microbiota. The aim of the study was to evaluate if BA may exert hemodynamic effects via an afferent gut‐nervous system signalling. Hemodynamics were recorded in male, 14‐week‐old, anesthetized, Wistar rats. A vehicle (0.9% NaCl), BA, or 3‐hydroxybutyrate, an antagonist of SCFA receptors GPR41/43 (ANT) were administered into the colon (IC) or intravenously (IV). Reactivity of mesenteric (MA) and gracilis muscle (GMA) arteries was tested in vitro. SCFAs concentration was measured using ultra performance liquid chromatograph with mass spectrometer. Physiological BA concentration in the colon content (stools) was ≈ 9mM but 1000‐fold lower in systemic venous blood. The vehicle and ANT did not affect arterial blood pressure (BP) and heart rate (HR). BA administered IC produced 2–3‐fold increase in BA colon content and a prolonged decrease in BP and HR, with no significant changes in QTc, a marker of cardiotoxicity. Intestinal blood flow was not affected. Subphrenic vagotomy and IC pretreatment with ANT significantly reduced the hypotensive effect of IC BA. The hypotensive effect was also reduced by IV administered hexamethonium but not by atropine. BA administered IV produced shorter decrease in BP than BA administered IC, and did not affect HR. The ANT reduced, whereas L‐NAME, a nitric oxide synthase inhibitor, did not affect the hypotensive effect of IV BA. In vitro, BA dilated MA and GMA at concentrations 10–20‐fold higher than physiological concentration of BA in systemic blood. In conclusion, at physiological concentration the colon appears the most likely site of BA action. An increase in colonic BA lowers BP. This seems to be mediated by vagal signaling and GPR41/43.Support or Funding InformationSupported by the National Science Centre, Poland grant no. UMO‐2016/22/E/NZ5/00647This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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