Ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigates its cardiovascular and renal damage through modulating gut microbiota

Abstract

Trimethylamine N-oxide (TMAO) leads to the development of cardiovascular and chronic kidney diseases, but there are currently no potent drugs that inhibit the production or toxicity of TMAO. In this study, high-fat diet-fed ApoE-/-mice were treated with finasteride, ranitidine, and andrioe. Subsequently, the distribution and quantity of gut microbiota in the faeces of the mice in each group were analysed using 16S rRNA sequencing of the V3+V4 regions. Pathological examination confirmed that both ranitidine and finasteride reduced atherosclerosis and renal damage in mice. HPLC analysis also indicated that ranitidine and finasteride significantly reduced the synthesis of TMAO and the TMAO precursor delta-Valerobetaine in their livers. The 16S rRNA sequencing showed that all 3 drugs significantly increased the richness and diversity of gut microbiota in the model mice. Bioinformatic analysis revealed that the faeces of mice treated with ranitidine and finasteride, had significant increases in the number of microbes in the families g_Helicobacter, f_Desulfovibrionaceae, Mucispirillum_schaedleri_ASF457, and g_Blautia, whereas the relative abundances of microbes in the families Enterobacter_sp._IPC1-8 and g_Bacteroides were significantly reduced. The microbiota metabolic pathways, such as nucleotide and cofactor and vitamin metabolism were also significantly increased, whereas the activities of metabolic signalling pathways related to glycan biosynthesis and metabolism and cardiovascular diseases were significantly reduced. Therefore, our study indicates that in addition to their known pharmacological effects, ranitidine and finasteride also exhibit potential cardiovascular and renal protective effects. They inhibit the synthesis and metabolism of TMAO and delay the deposition of lipids and endotoxins through improving the composition of the gut microbiota.

The implications of histamine metabolism and signaling in renal function

“…Oral gavage, 20 mg/kg/day dissolved in 2 ml saline (Sahin et al, 2019); Orally via catheter, 20 mg/kg (Tok et al, 2012) Ameliorated glomerular and tubular histology, decreased kidney expression of caspase-1 and fraction of TUNEL-positive cells (apoptosis) and kidney expression of NLRP3 and IL-1β (inflammation) in a rat model of diabetes (Sahin et al, 2019); reduced levels of lipid peroxidation and oxidative injury products in renal tissue, improved histological appearance in a rat I/R model (Tok et al, 2012) (Hattori et al, 2016) Ranitidine Blocker 36-94 ng/ml (IC50) Fed at 1.5 mg/30 g body weight Reduced renal damage and attenuated atherosclerosis in a HFD mouse model (Liu et al, 2020) Cimetidine Antagonist 70 nM (Ki) IP injection of 150 mg/kg (Estaphan et al, 2015); 0.25-1.2 mM addition to cell-free extract (Minai-Tehrani et al, 2011) Decreased creatinine, BUN, K + , Na + , NO, blood pressure creatine kinase, increased GFR, urine volume, and renal glutathione (Estaphan et al, 2015); improved renal function when used in combination with L-carnitine in a rat model of glycerol induced acute renal failure (Minai-Tehrani et al, 2011) epithelial cells equipped with histamine synthesis machinery. Thus, antagonism of histamine receptors has been proposed for the management of cardiac damage in hypertensive diseases (Potnuri et al, 2018).…”

Bovine serum albumin aggravates macrophage M1 activation and kidney injury in heterozygous Klotho-deficient mice via the gut microbiota-immune axis

“…In BSA-treated Klotho-deficient mice, metabolic pathways associated with signal transduction, xenobiotics biodegradation and metabolism, lipid metabolism substances were significantly more active than that in the control group; the abundance of proteins involved in signal transduction mechanisms and cell motility also improved significantly. Our previous studies 9 , 48 suggest that a change in gut microbial species stimulates the intestinal mucosal barrier and mucosal immune changes, affecting the distribution of intestinal immune cells, immune cells, and peripheral blood and polarity of anomalies.…”

“…The sections were counterstained with Masson's ponceau acid fuchsin solution (Beyotime Biotechnology) for 6-10 min and then rinsed with 2% ice-cold aqueous acetic acid (Beyotime Biotechnology) for 5 s. The sections were differentiated for 3-5 min with 1% aqueous phosphomolybdic acid (Beyotime Biotechnology), stained by direct immersion in aniline blue for 5 min, and then washed with 0.2% aqueous glacial acetic acid (Beyotime Biotechnology) for several seconds. The stained sections were cleared, sealed, and photographed 9 . The quantitative statistical method of collagen area from masson staining: Collegen area fraction (%) = (MASSON stainging collegen positive area / total area) * 100%”.…”

“…In addition, bacterial 16S rDNA amplification and DNA pyrosequencing suggest that the DNA of gut microbiota is present in the plasma of CKD patients on chronic hemodialysis 7 , 8 , and the levels of bacterial DNA is correlated with increased plasma inflammatory marker levels 7 , 8 . Our previous study revealed that ranitidine and finasteride inhibit the synthesis and release of trimethylamine N-oxide and mitigate its cardiovascular and kidney damage through modulating gut microbiota 9 . Indoxyl sulfate is a typical uremic toxin that is not efficiently removed by hemodialysis; modulation of indoxyl sulfate production in the gut microbiota is a promising strategy for decreasing indoxyl sulfate concentration, thus delaying CKD progression 10 .…”

The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’s Not All Bad

“…Therefore, the beneficial diuretic effect of TMAO was attributed to the osmotic activity of TMAO which decreased the reabsorption of water [ 202 ]. In atherosclerosis model mice, TMAO inhibition protected against poor renal phenotypes and suggests that inhibiting microbiota TMA production is a potential treatment for renal damage during CVD [ 203 ]. These mixed TMAO effects possibly depend on the animal model used which highlights how careful selection of animal models is critical to investigating clinically relevant molecular effects of TMAO.…”