Molecular Identification and Selection of Probiotic Strains Able to Reduce the Serum TMAO Level in Mice Challenged with Choline

Trimethylamine oxide (TMAO) originates from trimethylamine (TMA), which is oxidized in the liver by hepatic flavin-containing monooxygenases (FMO3). TMA is produced by its dietary precursors such as choline, carnitine, and phosphatidylcholine by gut microbiota. TMAO attracts attention, identified as a novel and independent risk factor for promoting obesity, atherosclerosis and cardiovascular disease (CVD), chronic kidney disease (CKD), insulin tolerance, and colon cancer. Probiotics have been considered as live microorganisms, providing benefits to their host when they are given in sufficient quantities and administered continuously. The objective of this study is to suggest a method to select potential probiotic strains to reduce the serum concentration of TMAO in mice fed with choline. In this work, we chose three lactobacilli with strong adherence capability, and fed multistrain formula (MF) to the mice challenged with choline. On days 7, 14, and day 28, it was found that the MF-containing L. amylovorus LAM1345, Lpb. plantarum LP1145, and Lim. fermentum LF33 showed a significant reduction in serum TMAO and TMA levels. For the single strains, LP1145 reduced TMAO on days 14 and 28, and strain LAM1345 reduced TMAO significantly on days 7 and day 14. For strain LF1143 from strain LF33, it showed no significant effect on TMAO and TMA. Thus, MF showed the best effect, which may be due to the additive and synergetic effect and the contribution of strain LP1145 and LAM1345. Finally, for the LAM1345 and LP1145 strains, we used molecular identification and typing methods to assure that these two strains are unique strains. The methods used for LAM 1345 were leader peptidase A (lepA) gene analysis and phylogenetic analysis, while for strain LP 1145and other strains of Lpb. plantarum subsp. plantarum sequences were compared using the whole-genome multilocus sequence typing (wgMLST) method.

Trimethylamine oxide and its possible role in the development and progression of cardiovascular disease

Cardiovascular diseases continue to be the leading cause of death throughout the world and in Russia. Therefore, new possible risk factors for their development and progression are being studied. To date, information have been accumulated on unfavorable prognostic effect of elevated trimethylamine oxide (TMAO) levels on cardiovascular events, and the possible role of phospholipids (PLs) is being discussed. The aim of this review was to analyze the literature data on the potential relationship of TMAO and PLs with cardiovascular risk (CVR), as well as possible solutions to this problem. The search and analysis of publications was performed using Elibrary, PubMed, Medline, and Google Scholar databases in the period from their creation to 2021. It was found that high TMAO concentrations can have pro-inflammatory effects, stimulate atherogenesis and increase platelet aggregation. An increase in the blood TMAO levels increases the risk of cardiovascular events in patients with coronary artery disease, is associated with an increased risk of cardiovascular and all-cause death in patients with peripheral arterial disease and heart failure, and correlates with the extent of brain regions involved in stroke. The most important part in TMAO formation is taken by the gut microbiota, which metabolizes substrates, including PLs, to trimethylamine, which, when absorbed, is converted into TMAO in the liver. The analysis of available studies shows that the excessive intake of PLs into the gastrointestinal tract and the increased TMAO production are potentially interrelated with an increase in CVR. At the same time, PLs are currently used as drugs, in particular, as hepatoprotective agents. In view of this, large-scale randomized clinical trials are needed to study the CVR profile in patients receiving such therapy. Currently, other hepatoprotective agents are available that are devoid of such potential risks, since they do not contain PLs. One of these agents is ursodeoxycholic acid, which has proven its effectiveness and safety, including in patients with high CVR in routine clinical practice.

Trimethylamine oxide: a potential target for heart failure therapy

Heart failure (HF) is a clinical syndrome in the late stage of cardiovascular disease and is associated with high prevalence, mortality and rehospitalisation rate. The pathophysiological mechanisms of HF have experienced the initial ‘water-sodium retention’ mode to ‘abnormal hemodynamics’ mode, and subsequent to ‘abnormal activation of neuroendocrine’ mode, which has extensively promoted the reform of HF treatment and updated the treatment concept. Since the Human Microbiome Project commencement, the study on intestinal microecology has swiftly developed, providing a new direction to reveal the occurrence of diseases and the mechanisms behind drug effects. Intestinal microecology comprises the gastrointestinal lumen, epithelial secretion, food entering the intestine, intestinal flora and metabolites. Choline and L-carnitine in the diet are metabolised to trimethylamine (TMA) by the intestinal micro-organisms, with TMA being absorbed into the blood. TMA then enters the liver through the portal vein circulation and is oxidised to trimethylamine oxide (TMAO) by the hepatic flavin-containing mono-oxygenase (FMO) family, especially FMO3. The circulating TMAO levels are associated with adverse outcomes in HF (mortality and readmission), and lower TMAO levels indicate better prognosis. As HF progresses, the concentration of TMAO in patients gradually increases. Whether the circulating TMAO level can be decreased by intervening with the intestinal microflora or relevant enzymes, thereby affecting the prognosis of patients with HF, has become a research hotspot. Therefore, based on the HF intestinal hypothesis, exploring the treatment strategy for HF targeting the TMAO metabolite of the intestinal flora may update the treatment concept in HF and improve its therapeutic effect.

Possible Biochemical Processes Underlying the Positive Health Effects of Plant-Based Diets—A Narrative Review

Plant-based diets are becoming more popular for many reasons, and epidemiological as well as clinical data also suggest that a well-balanced vegan diet can be adopted for the prevention, and in some cases, in the treatment of many diseases. In this narrative review, we provide an overview of the relationships between these diets and various conditions and their potential biochemical background. As whole plant foods are very rich in food-derived antioxidants and other phytochemicals, they have many positive physiological effects on different aspects of health. In the background of the beneficial health effects, several biochemical processes could stand, including the reduced formation of trimethylamine oxide (TMAO) or decreased serum insulin-like growth factor 1 (IGF-1) levels and altered signaling pathways such as mechanistic target of rapamycin (mTOR). In addition, the composition of plant-based diets may play a role in preventing lipotoxicity, avoiding N-glycolylneuraminic acid (Neu5Gc), and reducing foodborne endotoxin intake. In this article, we attempt to draw attention to the growing knowledge about these diets and provide starting points for further research.

Development of a New Deodorization Method of Herring Milt Hydrolysate: Impacts of pH, Stirring with Nitrogen and Deaerator Treatment on the Odorous Content

Herring milt hydrolysate (HMH) presents the disadvantage of being associated with an unpleasant smell limiting its use. Thus, to develop a new effective and easy-to-use deodorization method, this research aimed to deepen the knowledge regarding the impacts of pH (pH 7 vs. pH 10), overnight stirring with nitrogen (+N vs. −N) and deaerator treatment (+D vs. −D) on the odorous content of HMH. This latter included dimethylamine (DMA), trimethylamine (TMA), trimethylamine oxide (TMAO) and the most potent odor-active compounds of HMH. Results showed that pH had a huge impact on the targeted compounds resulting in higher detected concentrations of DMA, TMA and TMAO at pH 10 than at pH 7 (p < 0.05) while the opposite trend was observed for the most potent odor-active compounds of HMH (p < 0.05). Moreover, independently of the pH condition, the overnight stirring with or without nitrogen had no impact (p > 0.05). Finally, the deaerator treatment was more effective to remove TMA and DMA at pH 10 than at pH 7 (p < 0.05) while the opposite trend was observed for the most potent odor-active compounds (p < 0.05). Sensory analysis confirmed that the application of pH 10 −N +D and pH 7 −N +D + alkalization pH 10 conditions led to the least odorous products (p < 0.05).

Metabolic Profiling in Bipolar Disorder Patients During Depressive Episodes

Bipolar disorder (BD) is a common and debilitating mental disorder. Bipolar depression is the main episode of BD. Furthermore, there are no objective biomarkers available for diagnosing the disorder. In this research, a Nuclear Magnetic Resonance (NMR) spectroscopy based on a metabonomics technique was used to analyze serum samples from 37 patients with bipolar depression and 48 healthy control participants to determine potential biomarkers for bipolar depression. In total, seven different metabolites were identified that could effectively distinguish patients from healthy controls. The metabolites indicated that disturbances of amino acid and energy metabolisms might be involved in the pathogenesis of BD. Finally, a panel consisting of four potential biomarkers (lactate, trimethylamine oxide, N-acetyl glycoprotein, and α-glucose) was identified, which showed a higher combined diagnostic ability with an area under the curve of 0.893. Our findings may contribute to the development of an objective method for diagnosing bipolar depression.

Effects of phenolic compounds from blueberry leaves on the thermal decomposition of trimethylamine oxide in squid extract

The effects of chlorogenic acid and quercetin-3-D-galactoside on the decomposition of trimethylamine oxide (TMAO) in squid extract and the main mechanism of inhibition of thermal decomposition were studied. The results indicated that chlorogenic acid and quercetin-3-D-galactoside could inhibit decomposition of TMAO in squid extract. The amount of TMAO was increased by 11.79 and 15.76% in squid extract treated with chlorogenic acid and quercetin-3-D-galactoside from 0 and 2.5 g/L, respectively. The contents of trimethylamine (TMA), dimethylamine (DMA), and formaldehyde (FA) were significantly decreased with increasing contents of chlorogenic acid and quercetin-3-D-galactoside. There were many free radicals in squid extract at high temperatures; however, the free radical signals were weakened after the addition of chlorogenic acid and quercetin-3-D-galactoside therein. This implied that chlorogenic acid and quercetin-3-D-galactoside could inhibit the thermal decomposition of TMAO in squid extract, which was associated with the scavenging of their free radicals. This result provides a theoretical basis for the development and utilization of blueberry leaf extract as an efficient FA inhibitor for aquatic products.

What connection is there between intestinal microbiota and heart disease?

Information on the correlation between intestinal microbiota and cardiovascular risk is growing. Some species of the microbiota influence the metabolism of specific food components (such as carnitine, choline, phosphatidyl-choline), synthesizing the precursor of trimethylamine oxide, a molecule with documented harmful activity on the vascular wall. Other strains, on the other hand, metabolize dietary fibre by synthesizing short-chain fatty acids, which have a significant anti-inflammatory activity, or produce secondary metabolites originating from molecules present in food (such as enterodiol, which derives from lignin), characterized by a vascular protection activity. Prebiotic effects from plant compounds (such as berberine or resveratrol) are also documented, which would induce favourable changes in the composition of the microbiota. The possibility of influencing the composition and activity of the intestinal microbiota will probably represent, in the future, an important component of cardiovascular prevention strategies.

An In Vitro Intestinal Model Captures Immunomodulatory Properties of the Microbiota in Inflammation

BackgroundThere is a growing appreciation for the significance of the gut microbiome in health and disease. Specifically, considerable effort has been put forth to understand mechanisms by which the microbiota modulates and responds to inflammation. Here, we explored whether oxidation metabolites produced by the host during inflammation, sodium nitrate and trimethylamine oxide, impact the composition of a human stool bacterial population in a gut simulator. We then assessed whether an immune-competent in vitro intestinal model responded differently to spent medium from bacteria exposed to these cues compared to spent medium from a control bacterial population. ResultsThe host-derived oxidation products were found to decrease levels of Bacteroidaceae and overall microbiota metabolic potential, while increasing levels of pro-inflammatory Enterobacteriaceae and lipopolysaccharide in bacterial cultures, reflecting shifts that occur in vivo in inflammation. Spent medium, with or without sodium nitrate and trimethylamine oxide, induced elevated intracellular mucin levels and reduced intestinal monolayer integrity as reflected in trans-epithelial electrical resistance relative to fresh medium controls. However, multiplexed cytokine analysis revealed markedly different cytokine signatures from intestinal cultures exposed to spent medium with added oxidation products relative to spent control medium, while cytokine signatures of cultures exposed to fresh media were similar regardless of addition of host-derived cues. Further, the presence of immune cells in the intestinal model was required for this differentiation of cytokine signatures. ConclusionsThis study indicates that simple in vitro immune-competent intestinal models can capture bacterial-mammalian cross-talk in response to host-derived oxidation products and supports utility of these systems for mechanistic studies of interactions between the gut microbiome and host in inflammation.

Taking the “Me” out of meat: A new demethylation pathway dismantles a toxin's precursor

Carnitine, a molecule found in red meat, is metabolized to trimethylamine (TMA) by the gut microbiota. TMA is then converted in the liver to trimethylamine oxide, a causative agent for atherosclerosis. Kountz et al. have discovered an alternative pathway for carnitine metabolism in the gut bacterium Eubacterium limosum. Instead of forming TMA, carnitine is demethylated by the newly discovered methyltransferase MtcB, sending one-carbon units into production of short-chain fatty acids. These results suggest that bacterial metabolic activities could promote cardiovascular health by preventing the buildup of toxin precursors.