Probiotics as Regulators of Lipid Metabolism?

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heart-5The Heart-Health Benefits of Lactobacillus reuteri NCIMB 30242 By Dr Carrie Decker ND

It seems we cannot discuss any health-related topic nowadays without considering the health of the gut and the microbiota within it. Considerable data show the bacteria in our gut impact our mood and response to stress,[1],[2] the function of our immune system,[3] and even our metabolic health and the conditions associated with it.[4],[5] Intestinal permeability and a state of dysbiosis in the gut have been shown to contribute not only to a systemic inflammatory state, but also to downstream liver problems such as cholestasis and nonalcoholic fatty liver disease.[6],[7],[8] Considering that the liver aids not only in detoxification but also in cholesterol and glucose processing, microbiota-associated endotoxaemia may impact blood sugar regulation and cholesterol balance further downstream as well.[9],[10]

Our systemic health, too, is influenced by the activity of the gut microbiota. The microbes in our gut have their own metabolic processes, which are vital to their function. Byproducts of these processes include vitamins such as folate, riboflavin, and vitamins K and B12,[11] as well as short-chain fatty acids (SCFAs),[12] which are absorbed into our blood stream and cells, and support our metabolic needs.

Cholesterol metabolism is also affected by the microorganisms in our gut. Cholesterol enters the digestive tract via the diet and biliary secretions, with a combined total average of approximately 1.5 g/day.[13] Bile acids, synthesised in the liver from cholesterol, break the cholesterol down to micelles, and portions of those micelles are absorbed in the duodenum and proximal jejunum.[14],[15] Bile acids are reabsorbed or deconjugated, the latter being done primarily by the enzyme bile salt hydrolase (BSH), which is produced by certain lactobacilli or bifidobacteria in the gut.[16],[17],[18]

Deconjugation causes the bile acids to become hydrophobic, further reducing cholesterol absorption.[19] The deconjugated bile acids also become ligands of farnesoid X receptor (FXR),[20] which is highly expressed in the liver and the gut and serves to regulate cholesterol synthesis, uptake, and outflow. Eventually, about 50% of the total cholesterol that enters the digestive tract (from exogenous and endogenous sources) leaves the body through the feces.

Lactobacillus reuteri NCIMB 30242

Cholesterol effects.

BSH-producing probiotics have been clinically shown to lower total and low-density lipoprotein cholesterol (LDL-C).[21] Lactobacillus reuteri NCIMB 30242 is one probiotic strain that has been shown to produce this enzyme.[22]

The first clinical study with NCIMB 30242 was a randomised, double-blind, placebo-controlled trial (RDBPCT) with the probiotic as a yogurt formulation, provided to 114 hypercholesterolemic adult men and women not taking a statin or other cholesterol-lowering medications or supplements.22 After taking the yogurt with NCIMB 30242 twice daily for six weeks (a dosage of between 1.9 to 50 billion colony-forming units [CFUs] per yogurt), significant reductions in LDL-C (8.92%), total cholesterol (4.81%), and non-high-density lipoprotein cholesterol (non-HDL-C) (6.01%) were seen compared to placebo, as well as an absolute reduction of 0.19 mmol/L in apolipoprotein B (apoB-100), a predictor of coronary heart disease.[23]

Because data from the first study suggested the time to reach maximum effect may be longer than six weeks, a nine-week follow-up RDBPCT was performed using an encapsulated form of the probiotic. In this study, NCIMB 30242 was provided twice daily, with a potency of between 2.0 billion CFUs (endpoint) and 2.9 billion CFUs (baseline).[24]

One-hundred twenty-seven hypercholesterolemic adults, including those maintained on a stable dose of statin medications but excluding those on alternate cholesterol-reducing medications or supplements, completed this RDBPCT. At the study endpoint, significant reductions in LDL-C (11.64%), total cholesterol (9.14%), non-HDL-C (11.30%), and apoB-100 (8.41%) were seen compared to placebo.24 Significant reductions in fibrinogen (14.25%) and high-sensitivity C-reactive protein (1.05 mg/L) were also noted, indicating NCIMB 30242 may additionally reduce procoagulation tendencies and inflammation. This study, as well as a small pilot study with NCIMB 30242,[25] showed a significant increase in plasma deconjugated bile acid levels along with a reduction in plasma non-cholesterol sterol levels, suggesting the effects are at least in part due to altered bile acid metabolism and reduced cholesterol absorption.

Gastrointestinal (GI) effects.

The impact of NCIMB 30242 on gastrointestinal symptoms has also been investigated clinically. In conjunction with the second cholesterol-focused RDBPCT,24 gastrointestinal symptoms were surveyed with a 93-question self-diagnosis questionnaire for irritable bowel syndrome (IBS) in the 127 hypercholesteremic adults.[26] Much like any population, gastrointestinal symptoms of diarrhea, constipation, bloating, and burning were not uncommon, with over half of the population in the placebo group and the intervention being found to have functional bowel disorders at baseline.

After taking NCIMB 30242 or placebo twice daily for nine weeks, those receiving the intervention were found to have significant improvements in their scores related to overall GI health status and diarrhea symptoms compared to placebo. Additionally, a significantly greater percentage of responders having improved gastrointestinal health status and less diarrhea was seen in the probiotic group.

Vitamin D metabolism.

Questions concerning the effect of NCIMB 30242 on vitamin D have also been addressed. With NCIMB 30242’s effects on cholesterol absorption, concerns were raised that it may reduce levels of this fat-soluble vitamin, which, when low, is a risk factor for cardiovascular disease.[27]

Along with assessment of the gastrointestinal and cholesterol effects in the nine-week RDBPCT discussed previously,24,26 serum levels and dietary intake of vitamin A, vitamin E, beta-carotene, and 25-hydroxyvitamin D (25[OH]D) were evaluated post hoc.[28] Again, much like the standard population, levels of 25(OH)D were found to be borderline in many of the individuals in this study, with a mean of 30 ng/mL and 27.2 ng/mL in the placebo and intervention groups, respectively. Rather than finding a decrease in serum 25(OH)D, an increase of it by 25.5% (14.9 nmol/L) was seen in the NCIMB 30242 group, a significant mean change of 22.4% (17.1 nmol/L) as compared to placebo. No significant differences were observed in the levels of vitamins A, E, or beta-carotene between the baseline and final values between or within groups.

Safety.

Comprehensive labs were performed to evaluate the safety of NCIMB 30242, including assessment of a complete blood count, comprehensive metabolic panel, and serum lipase level. No biochemical changes raising concern for the safety of the intervention were seen,22,[29] and the frequency and intensity of adverse events were similar to placebo, with no serious events occurring.

Additional considerations.

In a population where hypercholesterolemia, functional digestive symptoms, and borderline low vitamin D status are prevalent, NCIMB 30242 seems to offer comprehensive support for these common issues.

References

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[2] Dinan TG, Cryan JF. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology. 2012 Sep;37(9):1369-78.

[3] Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009 May;9(5):313-23.

[4] Ley RE, et al. Microbial ecology: human gut microbes associated with obesity. Nature. 2006 Dec 21;444(7122):1022-3.

[5] Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012 Sep 13;489(7415):242-9.

[6] Chassaing B, et al. Microbiota-liver axis in hepatic disease. Hepatology. 2014 Jan;59(1):328-39.

[7] Moseley RH, et al. Effect of endotoxin on bile acid transport in rat liver: a potential model for sepsis-associated cholestasis. Am J Physiol. 1996 Jul;271(1 Pt 1):G137-46.

[8] Miele L, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009 Jun;49(6):1877-87.

[9] Cani PD, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008 Jun;57(6):1470-81.

[10] Cani PD, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007 Jul;56(7):1761-72.

[11] LeBlanc JG, et al. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol. 2013 Apr;24(2):160-8.

[12] den Besten G, et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013 Sep;54(9):2325-40.

[13] Wilson MD, Rudel LL. Review of cholesterol absorption with emphasis on dietary and biliary cholesterol. J Lipid Res. 1994 Jun;35(6):943-55.

[14] Woollett LA, et al. Micellar solubilisation of cholesterol is essential for absorption in humans. Gut. 2006 Feb;55(2):197-204.

[15] Iqbal J, Hussain MM. Intestinal lipid absorption. Am J Physiol Endocrinol Metab. 2009 Jun;296(6):E1183-94.

[16] Dong Z, Lee BH. Bile salt hydrolases: Structure and function, substrate preference and inhibitor development. Protein Sci. 2018 Aug 10.

[17] Ridlon JM, et al. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014 May;30(3):332-8.

[18] Gérard P. Metabolism of cholesterol and bile acids by the gut microbiota. Pathogens. 2013 Dec 30;3(1):14-24.

[19] Bustos AY, et al. New insights into bacterial bile resistance mechanisms: the role of bile salt hydrolase and its impact on human health. Food Res Int. 2018 Oct;112:250-62.

[20] Matsubara T, et al. FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 2013 Apr 10;368(1-2):17-29.

[21] Jones ML, et al. Cholesterol lowering with bile salt hydrolase-active probiotic bacteria, mechanism of action, clinical evidence, and future direction for heart health applications. Expert Opin Biol Ther. 2013 May;13(5):631-42.

[22] Jones ML, et al. Cholesterol-lowering efficacy of a microencapsulated bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242 yoghurt formulation in hypercholesterolaemic adults. Br J Nutr. 2012 May;107(10):1505-13.

[23] Agoston-Coldea L, et al. Apolipoproteins A-I and B-markers in coronary risk evaluation. Rom J Intern Med. 2007;45(3):251-8.

[24] Jones ML, et al. Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial. Eur J Clin Nutr. 2012 Nov;66(11):1234-41.

[25] Martoni CJ, et al. Changes in bile acids, FGF-19 and sterol absorption in response to bile salt hydrolase active L. reuteri NCIMB 30242. Gut Microbes. 2015;6(1):57-65.

[26] Jones ML, et al. Improvement of gastrointestinal health status in subjects consuming Lactobacillus reuteri NCIMB 30242 capsules: a post-hoc analysis of a randomized controlled trial. Expert Opin Biol Ther. 2013 Dec;13(12):1643-51.

[27] Kilkkinen A, et al. Vitamin D status and the risk of cardiovascular disease death. Am J Epidemiol. 2009 Oct 15;170(8):1032-9.

[28] Jones ML, et al. Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25-hydroxyvitamin D: a post hoc analysis of a randomized controlled trial. J Clin Endocrinol Metab. 2013 Jul;98(7):2944-51.

[29] Jones ML, et al. Evaluation of safety and tolerance of microencapsulated Lactobacillus reuteri NCIMB 30242 in a yogurt formulation: a randomized, placebo-controlled, double-blind study. Food Chem Toxicol. 2012 Jun;50(6):2216-23.

[30] Veiga P, et al. Correlation between faecal microbial community structure and cholesterol-to-coprostanol conversion in the human gut. FEMS Microbiol Lett. 2005 Jan 1;242(1):81-6.

[31] Lichtenstein AH. Intestinal cholesterol metabolism. Ann Med. 1990 Feb;22(1):49-52.

[32] Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011 Mar;12(3):204-12.

[33] Caesar R, et al. Effects of gut microbiota on obesity and atherosclerosis via modulation of inflammation and lipid metabolism. J Intern Med. 2010 Oct;268(4):320-8.

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