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Amelioration of TMAO through probiotics and its potential role in atherosclerosis. Din Ahmad Ud,Hassan Adil,Zhu Yuan,Yin Tieying,Gregersen Hans,Wang Guixue Applied microbiology and biotechnology Atherosclerosis is a major cause of mortalities and morbidities worldwide. It is associated with hyperlipidemia and inflammation, and become chronic by triggering metabolites in different metabolic pathways. Disturbance in the human gut microbiota is now considered a critical factor in the atherosclerosis. Trimethylamine-N-oxide (TMAO) attracts attention and is regarded as a vital contributor in the development of atherosclerosis. TMAO is generated from its dietary precursors choline, carnitine, and phosphatidylcholine by gut microbiota into an intermediate compound known as trimethylamine (TMA), which is then oxidized into TMAO by hepatic flavin monooxygenases. The present review focus on advances in TMAO preventing strategies through probiotics, including, modulation of gut microbiome, metabolomics profile, miRNA, or probiotic antagonistic abilities. Furthermore, possible recommendations based on relevant literature have been presented, which could be applied in probiotics and atherosclerosis-preventing strategies. 10.1007/s00253-019-10142-4
Cholesterol, cholesterol lowering, and endothelial function. Vogel R A,Corretti M C,Gellman J Progress in cardiovascular diseases A strong relationship between hypercholesterolemia and atherosclerosis has been established through epidemiological, experimental, and clinical trial data. Traditional theories on the pathophysiology of this relationship involve the deposition, modification, and cellular uptake of cholesterol, and the release of inflammatory and growth factors resulting in smooth muscle cell proliferation and collagen matrix production. The vasculature has recently been found to be an active and complex organ, with the endothelium playing a controlling role in vascular tone, lipid breakdown, thrombogenesis, inflammation, and vessel growth. In the presence of risk factors such as hypercholesterolemia, the endothelium promotes vasoconstriction, monocyte and platelet adhesion, thrombogenesis, and growth factor release. A high-fat diet also directly impairs endothelial function and increases coagulation factors. Endothelial dysfunction is associated with decreased availability of the predominant vasodilator nitric oxide, possibly by increased destruction by oxygen free radicals. This dysfunctional state appears before the earliest anatomic evidence of atherosclerosis and may represent an important initial step in its development. Several studies have shown improvements in endothelial function with cholesterol lowering in both normal individuals and those with coronary heart disease. Short-term improvements in endothelial-dependent vasodilation and adhesion molecule expression have also been reported with antioxidant therapy. These observations suggest that atherosclerosis is at least in part caused by endothelial dysfunction that favors cellular proliferation. This new understanding helps to explain the early and substantial reductions in major cardiovascular events associated with cholesterol lowering.
Consumption of Probiotic Lactobacillus fermentum MTCC: 5898-Fermented Milk Attenuates Dyslipidemia, Oxidative Stress, and Inflammation in Male Rats Fed on Cholesterol-Enriched Diet. Yadav Radha,Khan Suhail Hakeem,Mada Sanusi Bello,Meena Sunita,Kapila Rajeev,Kapila Suman Probiotics and antimicrobial proteins There is a growing and alarming prevalence that increased serum cholesterol is closely related to increased cardiovascular disease risk. Probiotic consumption could be a safe and natural strategy to combat. Therefore, we sought to examine the cholesterol-lowering potential of co-supplementation of probiotic bacteria Lactobacillus fermentum MTCC: 5898-fermented buffalo milk (2.5% fat) in rats fed cholesterol-enriched diet. Male Wistar rats were divided into three groups on the basis of feed, viz. group 1, fed standard diet (SD); group 2, fed cholesterol-enriched diet (CED); and group 3, fed cholesterol-enriched diet along with L. fermentum MTCC: 5898-fermented milk (CED+LF) for 90 days. At the endpoint, significantly higher levels of serum total cholesterol, low-density lipoprotein cholesterol, triacylglycerols, very low density lipoprotein cholesterol, atherogenic index, coronary artery risk index, hepatic lipids, lipid peroxidation, and mRNA expression of inflammatory cytokines (TNF-α and IL-6) in the liver while significantly lower levels of serum high-density lipoprotein cholesterol and anti-oxidative enzyme activities, catalase, superoxide dismutase, and glutathione peroxidase in the liver and kidney were observed in the CED group compared to the SD group. Compared to the CED group, these adverse physiological alterations were found significantly improved in the CED+LF group. Hence, this study proposes that L. fermentum MTCC: 5898 is a potential probiotic bacteria that can be consumed to tackle hypercholesterolemia. Graphical Abstract ᅟ. 10.1007/s12602-018-9429-4
Importance of microbial defence systems to bile salts and mechanisms of serum cholesterol reduction. Horáčková Šárka,Plocková Milada,Demnerová Kateřina Biotechnology advances An important feature of the intestinal microbiota, particularly in the case of administered probiotic microorganisms, is their resistance to conditions in the gastrointestinal tract, particularly tolerance to and growth in the presence of bile salts. Bacteria can use several defence mechanisms against bile, including special transport mechanisms, the synthesis of various types of surface proteins and fatty acids or the production of exopolysaccharides. The ability to enzymatically hydrolyse bile salts occurs in a variety of bacteria. Choloylglycine hydrolase (EC 3.5.1.24), a bile salt hydrolase, is a constitutive intracellular enzyme responsible for the hydrolysis of an amide bond between glycine or taurine and the steroid nucleus of bile acids. Its presence was demonstrated in specific microorganisms from several bacterial genera (Lactobacillus spp., Bifidobacterium spp., Clostridium spp., Bacteroides spp.). Occurrence and gene arrangement encoding this enzyme are highly variable in probiotic microorganisms. Bile salt hydrolase activity may provide the possibility to use the released amino acids by bacteria as sources of carbon and nitrogen, to facilitate detoxification of bile or to support the incorporation of cholesterol into the cell wall. Deconjugation of bile salts may be directly related to a lowering of serum cholesterol levels, from which conjugated bile salts are synthesized de novo. Furthermore, the ability of microorganisms to assimilate or to bind ingested cholesterol to the cell wall or to eliminate it by co-precipitation with released cholic acid was also documented. Some intestinal microflora produce cholesterol reductase that catalyses the conversion of cholesterol to insoluble coprostanol, which is subsequently excreted in faeces, thereby also reducing the amount of exogenous cholesterol. 10.1016/j.biotechadv.2017.12.005
Cholesterol-lowering efficacy of Lactobacillus plantarum CECT 7527, 7528 and 7529 in hypercholesterolaemic adults. Fuentes Mari C,Lajo Teresa,Carrión Juan M,Cuñé Jordi The British journal of nutrition Previous studies have indicated that supplementation with probiotic bacteria may improve lipid metabolism. The present study was aimed at investigating the effects of a mixture of three strains of Lactobacillus plantarum (CECT 7527, CECT 7528 and CECT 7529) on cholesterol-lowering efficacy in hypercholesterolaemic patients. A total of sixty volunteers (thirty participants in the placebo group and thirty counterparts in the L. plantarum group), aged 18–65 years old, participated in a controlled, randomised, double-blind trial. The study group received one capsule daily containing 1·2 × 10(9) colony-forming units of Lactobacillus strains in a unique dose; the placebo group consumed the same product without bacteria for 12 weeks. A significant reduction of 13·6 % in plasma total cholesterol (TC) levels was observed after 12 weeks of consumption in the L. plantarum group when compared with the placebo group. The lipidic outcomes were also analysed based on TC values at baseline: low initial values (LIV, 2000-2500 mg/l) v. high initial values (HIV, 2510–3000 mg/l). In the HIV group, the L. plantarum treatment showed a reduction after 12 weeks of consumption compared with the placebo group in TC, LDL-cholesterol (LDL-C) and oxidised LDL-C (17·4, 17·6 and 15·6 %, respectively). In the LIV, the L. plantarum treatment only showed a reduction after 12 weeks of consumption when compared with the placebo group in TC (9·4 %). The present results showed that the biofunctionality of L. plantarum (CECT 7527, CECT 7528 and CECT 7529) is proportional to the cardiovascular risk of the patient, having a better effect in patients with higher levels of cholesterol. 10.1017/S000711451200373X
Effect of potential probiotic Leuconostoc mesenteroides FB111 in prevention of cholesterol absorption by modulating NPC1L1/PPARα/SREBP-2 pathways in epithelial Caco-2 cells. Le Bao,Yang Seung-Hwan International microbiology : the official journal of the Spanish Society for Microbiology Mustard kimchi consumption reduces cholesterol levels in rats. To identify lactic acid bacteria (LAB) in kimchi which exert this effect, 20 LAB isolates were evaluated for cholesterol reduction in an in vitro screen. The FB111 strain showed the highest cholesterol-lowering activity and was identified as Leuconostoc mesenteroides. This strain was characterized as a potential probiotic through sequential analyses for resistance to gastrointestinal digestion and bile salts, and adhesion to Caco-2 cells. The Caco-2 cells treated with L. mesenteroides FB111 (6-8 log CFU/mL) showed toxicological effect. The reduction of cholesterol uptake in these cells was inhibited by 48.6% compared to the control and significantly higher than that of the Lactobacillus rhamnosus GG (LGG) strain-treated group after 2-h incubation. The levels of NPC1L1, ABCG5, ABCG8, SREBP-1, SREBP-2, and PPARα gene expression were determined by reverse transcription-quantitative polymerase chain reaction analysis. The L. mesenteroides FB111 and LGG inhibited the mRNA expression of NPC1L1 (P < 0.05), whereas the expression of PPARα was increased. Moreover, the FB111 strain also inhibited the expression of SREBP-2 mRNA. Overall, we found that L. mesenteroides FB111 has efficient cholesterol-lowering effects and might be useful as a probiotic in the food industry. 10.1007/s10123-018-00047-z
Effect of supplementation of probiotics and phytosterols alone or in combination on serum and hepatic lipid profiles and thyroid hormones of hypercholesterolemic rats. Awaisheh S S,Khalifeh M S,Al-Ruwaili M A,Khalil O M,Al-Ameri O H,Al-Groom R Journal of dairy science Probiotic bacteria and phytosterols are natural hypocholesterolemic agents with potential cardiovascular benefits. Accordingly, the present study was conducted to evaluate the effect of supplementation of probiotics and phytosterols alone or in combination on serum and hepatic lipid profiles and thyroid hormones of hypercholesterolemic rats. Mixed probiotics treatment consisted of 8 probiotic strains: 2 strains of each of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus gasseri, and Lactobacillus reuteri. The rats were fed for 8 wk with the given treatments in addition to a high-fat-high-cholesterol basal diet to induce hypercholesterolemia. Results showed that supplementation significantly reduced serum total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol, and triglycerides compared with the controls. The symbiotic treatment was more effective in lowering LDL-C, whereas mixed probiotics treatment more effectively lowered serum total cholesterol and LDL-C than the phytosterol-containing treatment. The phytosterol-containing treatments induced the increased activity of thyroid glands, as evident by elevated levels of serum total thyroxine, total triiodothyronine, and free triiodothyronine. In conclusion, the lipid profile can effectively be reduced to lower the incidence of cardiovascular disease using combinations of Lactobacillus-based probiotics and phytosterols in functional foods. 10.3168/jds.2012-5442
Cholesterol lowering with bile salt hydrolase-active probiotic bacteria, mechanism of action, clinical evidence, and future direction for heart health applications. Jones Mitchell L,Tomaro-Duchesneau Catherine,Martoni Christopher J,Prakash Satya Expert opinion on biological therapy INTRODUCTION:Cardiovascular diseases (CVD) are the leading cause of global mortality and morbidity. Current CVD treatment methods include dietary intervention, statins, fibrates, niacin, cholesterol absorption inhibitors, and bile acid sequestrants. These formulations have limitations and, thus, additional treatment modalities are needed. Probiotic bacteria, especially bile salt hydrolase (BSH)-active probiotic bacteria, have demonstrated cholesterol-lowering efficacy in randomized controlled trials. AREAS COVERED:This review describes the current treatments for CVD and the need for additional therapeutics. Gut microbiota etiology of CVD, cholesterol metabolism, and the role of probiotic formulations as therapeutics for the treatment and prevention of CVD are described. Specifically, we review studies using BSH-active bacteria as cholesterol-lowering agents with emphasis on their cholesterol-lowering mechanisms of action. Potential limitations and future directions are also highlighted. EXPERT OPINION:Numerous clinical studies have concluded that BSH-active probiotic bacteria, or products containing them, are efficient in lowering total and low-density lipoprotein cholesterol. However, the mechanisms of action of BSH-active probiotic bacteria need to be further supported. There is also the need for a meta-analysis to provide better information regarding the therapeutic use of BSH-active probiotic bacteria. The future of BSH-active probiotic bacteria most likely lies as a combination therapy with already existing treatment options. 10.1517/14712598.2013.758706
Effects of probiotics consumption on lowering lipids and CVD risk factors: a systematic review and meta-analysis of randomized controlled trials. Sun Jing,Buys Nicholas Annals of medicine This meta-analysis examined the effect of probiotics on the reduction of lipid components and coexisting risk factors associated with cardiovascular disease. All randomized controlled trials published in English on PubMed and Scopus from 2000 to 2014 were systematically searched. Using the PEDro scale to assess the quality of studies, a total of 15 studies with 788 subjects were selected for inclusion in the analysis. The mean difference and effect size with a 95% confidence interval (CI) were extracted from individual studies. Statistically significant pooled effects of probiotics were found on reduction of total cholesterol, low-density lipoprotein (LDL), body mass index (BMI), waist circumference, and inflammatory markers. Subgroup analysis revealed statistically significant effects of probiotics on total cholesterol and LDL when the medium was fermented milk or yogurt (P < 0.001) compared to capsule form, consumption was at least 8 weeks in duration (P < 0.001), and the probiotics consisted of multiple strains (P < 0.001) rather than a single strain. A significant reduction was found in LDL in trials which contained Lactobacillus Acidophilus strain (P < 0.001) compared to other types of strains. Our findings suggest that probiotic supplementation use is effective in lowering the lipid level and coexisting factors associated with cardiovascular disease. 10.3109/07853890.2015.1071872
Effects of probiotics supplement in patients with type 2 diabetes mellitus: A meta-analysis of randomized trials. Hu Yi-Meng,Zhou Feng,Yuan Yin,Xu Yan-Cheng Medicina clinica BACKGROUND AND OBJECTIVE:To objectively evaluate the effects of probiotics supplement on glycemic control and lipid metabolism in patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS:The randomized controlled trials (RCTs) with regard to the probiotics or synbiotics for the treatment of T2DM were collected through retrieving 5 databases from their establishment to March 2016. After study selection, quality assessment and data extraction were performed by 2 authors independently; and STATA software was used for statistical analysis. The level of evidence was evaluated by applying the GRADE system. RESULTS:Twelve RCTs involving 770 participants were enrolled. The results of the meta-analysis showed that probiotics could significantly reduce fasting blood glucose by -11.27mg/dL (95% CI -21.76 to -0.79; P<.001) and serum insulin concentration by -2.36μU/mL (95% CI -4.01 to -0.72; P=.005), but with no significant reduction on HbA (-0.19%; 95% CI -0.49 to 0.12; P=.23). Probiotics could significantly reduce HOMA-IR of T2DM patients (-1.05; 95% CI -1.52 to -0.59; P<.001). Nevertheless, the effect on QUICKI was negligible (0.00; 95% CI -0.00 to 0.01; P=.27). Results also confirmed the significant lowering effect of probiotics on total cholesterol (-8.49mg/dL; 95% CI -15.24 to -1.73; P=.014) and triglycerides (TG; -23.66mg/dL; 95% CI -40.26 to -7.05; P<.001), as well as the elevating effect on HDL-c (3.92mg/dL; 95% CI 2.14 to5.7; P<.01). However, there was no significant change on LDL-c (-0.84mg/dL; 95% CI -5.84 to 4.17; P=.75). Subgroup analysis was conducted for 2 outcomes, that is, serum insulin concentration and TG, whose heterogeneity was too high. The results showed multiple species of probiotics had stronger reduction effect on serum insulin concentration (-3.32μU/mL; 95% CI -5.89 to-0.75; P=.001) and TG (-25.94mg/dL; 95% CI -65.33 to 13.44; P<.001). In addition, it also suggested that only the duration of treatment for≥8 weeks could significantly reduce TG by -24.47mg/dL (95% CI -40.15 to -8.78; P=.001). The duration of treatment for<8 weeks didn't result in significant reduction on TG (-4.31mg/dL; 95% CI -37.69 to 29.06; P=.8). Finally, all the evidences were at moderate and low levels according to the GRADE system. CONCLUSION:As a kind of the potential biotherapeutics in the management of T2DM, probiotics can improve glucose control and lipid metabolism. 10.1016/j.medcli.2016.11.036
Probiotics--interactions with bile acids and impact on cholesterol metabolism. Pavlović Nebojša,Stankov Karmen,Mikov Momir Applied biochemistry and biotechnology The use of probiotics, alone or in interaction with bile acids, is a modern strategy in the prevention and treatment of hypercholesterolemia. Numerous mechanisms for hypocholesterolemic effect of probiotics have been hypothesized, based mostly on in vitro evidence. Interaction with bile acids through reaction of deconjugation catalyzed by bile salt hydrolase enzymes (BSH) is considered as the main mechanism of cholesterol-lowering effects of probiotic bacteria, but it has been reported that microbial BSH activity could be potentially detrimental to the human host. There are several approaches for prevention of possible side effects associated with BSH activity, which at the same time increase the viability of probiotics in the intestines and also in food matrices. The aim of our study was to summarize present knowledge of probiotics-bile acids interactions, with special reference to cholesterol-lowering mechanisms of probiotics, and to report novel biotechnological approaches for increasing the pharmacological benefits of probiotics. 10.1007/s12010-012-9904-4
Mechanisms of cholesterol-lowering effects of lactobacilli and bifidobacteria strains as potential probiotics with their bsh gene analysis. Öner Özer,Aslim Belma,Aydaş Selcen Babaoğlu Journal of molecular microbiology and biotechnology The bile salt hydrolase (BSH) enzyme activities of human-derived lactic acid bacteria and bifidobacteria were evaluated. The highest enzyme activity was identified as 1.76 ± 0.23 U/mg protein for Bifidobacterium breve A26 and 1.42 ± 0.11 U/mg protein for Lactobacillus plantarum LA3. The bile salt deconjugation ability of the 6 isolates representing the highest BSH enzyme activity was calculated as the release of cholic acid and was between the range of 2.03 ± 0.22 and 1.05 ± 0.25 mM. The strains with high BSH enzyme activity also showed high deconjugation ability (p < 0.01). The effect of increasing bile concentrations on the growth of bacteria and their cholesterol removal abilities based on cholesterol precipitation were determined. Cholesterol removal in control medium was between 22.6 ± 0.4 and 26.5 ± 0.4%. The highest value was recorded at a 0.2% bile concentration. As the biliary concentration increased, a decrease in cholesterol removal and viability of the bacteria was noted in all strains. The percent of similarity of the bsh gene region between different genes was specified. The results may throw some light on proving the ability of these probiotics either as a novel alternative or as adjuvants to chemical drugs in treating hypercholesterolemia. 10.1159/000354316
Probiotics and the BSH-related cholesterol lowering mechanism: a Jekyll and Hyde scenario. Choi Sy-Bing,Lew Lee-Ching,Yeo Siok-Koon,Nair Parvathy Seema,Liong Min-Tze Critical reviews in biotechnology Probiotic microorganisms have been documented over the past two decades to play a role in cholesterol-lowering properties via various clinical trials. Several mechanisms have also been proposed and the ability of these microorganisms to deconjugate bile via production of bile salt hydrolase (BSH) has been widely associated with their cholesterol lowering potentials in prevention of hypercholesterolemia. Deconjugated bile salts are more hydrophobic than their conjugated counterparts, thus are less reabsorbed through the intestines resulting in higher excretion into the feces. Replacement of new bile salts from cholesterol as a precursor subsequently leads to decreased serum cholesterol levels. However, some controversies have risen attributed to the activities of deconjugated bile acids that repress the synthesis of bile acids from cholesterol. Deconjugated bile acids have higher binding affinity towards some orphan nuclear receptors namely the farsenoid X receptor (FXR), leading to a suppressed transcription of the enzyme cholesterol 7-alpha hydroxylase (7AH), which is responsible in bile acid synthesis from cholesterol. This notion was further corroborated by our current docking data, which indicated that deconjugated bile acids have higher propensities to bind with the FXR receptor as compared to conjugated bile acids. Bile acids-activated FXR also induces transcription of the IBABP gene, leading to enhanced recycling of bile acids from the intestine back to the liver, which subsequently reduces the need for new bile formation from cholesterol. Possible detrimental effects due to increased deconjugation of bile salts such as malabsorption of lipids, colon carcinogenesis, gallstones formation and altered gut microbial populations, which contribute to other varying gut diseases, were also included in this review. Our current findings and review substantiate the need to look beyond BSH deconjugation as a single factor/mechanism in strain selection for hypercholesterolemia, and/or as a sole mean to justify a cholesterol-lowering property of probiotic strains. 10.3109/07388551.2014.889077
The perspective on cholesterol-lowering mechanisms of probiotics. Ishimwe Nestor,Daliri Eric B,Lee Byong H,Fang Fang,Du Guocheng Molecular nutrition & food research The use of probiotics as food components combats not only cardiovascular diseases but also many gastrointestinal tract disorders. Their health benefits along with their increased global market have interested scientists for better formulation and appropriate administration to the consumers. However, the lack of clear elucidation of their cholesterol-lowering mechanisms has complicated their proper dosage and administration to the beneficiaries. In this review, proposed mechanisms of cholesterol reduction such as deconjugation of bile via bile salt hydrolase activity, binding of cholesterol to probiotic cellular surface and incorporation into their cell membrane, production of SCFAs from oligosaccharides, coprecipitation of cholesterol with deconjugated bile, and cholesterol conversion to coprostanol have been discussed. Also, hypocholesterolemic effects on human- and animal-trial results, commonly used probiotics and synbiotics with effect on serum cholesterol regulation, types of bile salt hydrolase genes, and substrate specificities have been discussed. 10.1002/mnfr.201400548
Screening for Cholesterol-Lowering Probiotics from Lactic Acid Bacteria Isolated from Corn Silage Based on Three Hypothesized Pathways. Ma Changlu,Zhang Shuwen,Lu Jing,Zhang Cai,Pang Xiaoyang,Lv Jiaping International journal of molecular sciences A total of 85 strains of lactic acid bacteria were isolated from corn silage in this study and analyzed for their cholesterol removal, NPC1L1 protein down-regulation and bile salt deconjugation ability, respectively. Nineteen strains were selected for further analysis for their probiotic potential. Finally, 3 strains showing better probiotic potential were evaluated for their cholesterol-lowering activity in hamsters. The strains showing the greater cholesterol removal and NPC1L1 protein down-regulation activity had no significant effects on serum and hepatic cholesterol levels in hamsters ( > 0.05). However, CAAS 18008 (1 × 10 CFU/d) showing the greater bile salt deconjugation ability significantly reduced serum low-density lipoprotein cholesterol, total cholesterol, and hepatic total cholesterol levels by 28.8%, 21.7%, and 30.9%, respectively ( < 0.05). The cholesterol-lowering mechanism was attributed to its bile salt hydrolase activity, which enhanced daily fecal bile acid excretion levels and thereby accelerated new bile acid synthesis from cholesterol in liver. This study demonstrated that the strains showing greater cholesterol removal and NPC1L1 protein down-regulation activity hardly reveal cholesterol-lowering activity , whereas the strains showing greater bile salt deconjugation ability has large potential to decrease serum cholesterol levels . 10.3390/ijms20092073