TMAO, a seafood-derived molecule, produces diuresis and reduces mortality in heart failure rats

Abstract

Background. There is an ongoing debate whether trimethylamine-oxide (TMAO), a molecule present in seafood and a derivate of microbiota metabolism, is beneficial or harmful for the circulatory system. Interestingly, deep-water animals accumulate TMAO that protects proteins such as lactate dehydrogenase (LDH) against high hydrostatic pressure. We hypothesized that TMAO may benefit the circulatory system by protecting cardiac LDH exposed to hydrostatic stress (HS) produced by contracting heart.Methods and Results. Male, 6-week-old, Sprague-Dawley (SD, n=40) and Spontaneously-Hypertensive-Heart-Failure (SHHF n=18) rats were divided into either Water or TMAO oral treatment. After 56 weeks, half of Water and TMAO SD rats were given isoprenaline (ISO) to produce catecholamine stress. In vitro, LDH with or without TMAO was exposed to HS (changes in pressure 0-250mmHg x 280min -1 ) and was evaluated using fluorescence correlation spectroscopy. After 58 weeks of the treatment survival was 100% in SD-Water, SD-TMAO, ISO-TMAO and 90% in ISO-Water. In SHHF-Water survival was 66% vs 100% in SHHF-TMAO. In general, TMAO-treated rats showed higher diuresis and natriuresis. In comparison to SHHF-Water, SHHF-TMAO showed significantly lower diastolic arterial blood pressure, plasma NT-proBNP and expression of angiotensinogen and AT1 receptors in the heart. In separate experiments, intravenous TMAO but not vehicle or urea significantly increased diuresis in SD. In vitro, exposure of LDH to HS with or without TMAO did not affect the protein structure.Conclusions. TMAO reduces mortality in SHHF rats that is associated with diuretic, natriuretic and hypotensive effects. HS produced by the contracting heart is neutral for cardiac LDH structure. Study protocolSix-week-old SHHF (n=18) and SD (n=40) were randomly assigned to either Water group (rats drinking tap water) or TMAO group (rats drinking TMAO solution in tap water, TMAO -abcr GmbH -Karlsruhe, Germany, 333 mg/l). The dose of TMAO have been selected in order to increase plasma TMAO concentration by 3-5 times (to mimic possible physiological concentrations) and to avoid suprapharmacological effects of TMAO, based on our previous study [7]. Rats were housed in groups of 2-3 animals, in polypropylene cages with environmental enrichment, 12hrs light/12hrs dark cycle, temperature 22-23 o C, humidity 45-55%, fed standard laboratory diet (0.19 % Na, Labofeed B standard, Kcynia, Poland) and water ad libitum. SHHF-TMAO (n=9), SHFF-Water (n=9), SD-TMAO (n=10), SD-Water (n=10) were not subjected to any interventions except of standard animal care until the age of 58 weeks. At the age of 56 weeks ISO-Water (n=10) and ISO-TMAO (n=10) series were given (s.c.) isoprenaline at a dose of 100 mg/kg b.w. (isoprenaline hydrochloride, Sigma-Aldrich, SaintLouis, MO, USA) to produce catecholamine stress as previously described by others [19]. The experimental protocol is depicted in Fig. 1. Experimental protocol in SD and SHHF58-week-old rats were maintained in metabolism cages for 2 days to evaluate 24hr...

Relationship between Plasma Trimethylamine N-Oxide Levels and Renal Dysfunction in Patients with Hypertension

“…For example, TMAO reduced mortality in the SHHF mouse model, an effect associated with osmotic diuresis caused by the hyperosmotic state of TMAO. TMAO increased the level of vasopressin, in addition to its diuretic and natriuretic effects [28]. However, the study did not directly measure the blood pressure of mice, and the findings were contradictory to previous animal experiments, showing that TMAO upregulated the effect of AQP-2 and led to sodium and water retention by increasing plasma osmotic pressure, and amplified the boosting effect of Ang-II [11, 12], which may be related to variation in TMAO dosage and methods of intervention.…”

“…TMAO was initially thought to exist primarily in deep-sea fish and other aquatic products, functioning to maintain cell osmotic pressure and protect protein invariance. Eating these fish is thought to be good for the circulatory system [29-31], but animal experiments have shown that TMAO does not improve the prognosis of SHHF mice by affecting the structure of proteins such as lactate dehydrogenase [28].…”

Loop Diuretics Inhibit Renal Excretion of Trimethylamine N-Oxide

“…In a recent report, it was suggested that the organic osmolyte function of TMAO induced diuresis when given at supraphysiologic levels, which led to improved heart failure outcomes. The investigators reported a primary diuretic effect in TMAO-fed rats ( 42 ). Interestingly, all the TMAO-fed rats (a different animal model compared with most TMAO studies) in this study also exhibited decreased plasma sodium with increased plasma renin, which is typically seen in worsened heart failure physiology.…”

Metabolomics analysis of human plasma reveals decreased production of trimethylamine N‐oxide retards the progression of chronic kidney disease

“…TMAO has also been reported as a standby marker for some diseases, such as cardiovascular events (Guasti et al, 2021;Janeiro et al, 2018). While most studies of TMAO have focused on its role in and/or association with cardiovascular disease (Dannenberg et al, 2020;Gawrys-Kopczynska et al, 2020;Guasti et al, 2021;Janeiro et al, 2018;Mafune et al, 2016;Poll et al, 2020;Querio et al, 2019;, TMAO has also been reported to be associated with kidney disease (Gruppen et al, 2017;Rhee et al, 2013;Sun et al, 2017;Tang et al, 2015). Rhee et al reported that the baseline plasma levels of TMAO and its precursor choline are predictors of CKD in the cohort of the Framingham Heart Study who did not have CKD at baseline (Rhee et al, 2013).…”

“…In contrast, TMAO has been reported to benefit or at least not harm health. For example, Stubbs et al reported no evidence linking TMAO to clinical cardiovascular outcomes in patients with end-stage kidney disease (Stubbs et al, 2019), and TMAO reduced mortality in rats with heart failure (Gawrys-Kopczynska et al, 2020). TMAO has also been reported as a standby marker for some diseases, such as cardiovascular events (Guasti et al, 2021;Janeiro et al, 2018).…”