Hypocholesterolaemic effects of probiotic
1. Introduction
There is growing interest in the use of nutraceutical products which includes probiotics, prebiotics and related metabolites with cholesterol-lowering properties to prevent cardiovascular diseases (CVDs) [1]. Probiotics are beneficial bacteria that influence the health of the host by improving their microbial balance. Modifications of intestinal flora have been shown to be beneficial on lipid metabolism in mice [2-6], rats [7-11], guinea pigs [12] and pigs [13]. In contrast, studies in humans [14,15] indicated that the role of fermented milk products as hypocholesterolaemic agents were inconsistent but more reliable effects were documented in the recent clinical studies [16-19]. The cholesterol-lowering effect of probiotics was found to be highly strain-specific as different strains exhibited different levels of cholesterol-lowering activity [20-22]. Therefore, it is important to identify probiotic strains that exhibit excellent cholesterol-lowering ability.
Cholesterol-reducing mechanism(s) by probiotics remain to be elucidated. Deconjugation of bile salt by the bile salt hydrolase (BSH) enzyme and subsequent co-precipitation of cholesterol at acidic pH is one of the models frequently used to explain hypocholesterolaemic effects of probiotics [21,23]. Other studies have shown reduction of cholesterol through assimilation of cholesterol into bacterial cell membrane [24-28], adhesion of cholesterol onto bacterial cell surface [28] and through the binding of bile acids to bacterial exocellular polysaccharides [29]. A recent study showed the ability of probiotics to be able to produce protein(s) with cholesterol-lowering effect [30]. Probiotics are able to grow in prebiotics (indigestible carbohydrate) producing short chain fatty acids (SCFAs). Butyrate, a SCFA has the ability to inhibit liver cholesterol synthesis [31]. The role of probiotics as hypocholesterolaemic agents should be further explored.
2. Cardiovascular disease and treatments
Hypercholesterolemia is the major cause of coronary diseases. Diseases related to hypercholesterolemia have been projected to be the number one leading cause of death in the world by 2020 [32]. In fact, Roth
Cholesterol-lowering drugs that are available have different mechanisms of actions. Statins (3-hyroxy-3-methylglutaryl coenzyme A reductase inhibitors) are generally able to inhibit cholesterol synthesis in the liver and peripheral tissues. They have been extensively studied and found to possess better therapeutic effects than other lipid lowering drugs [34]. A recent meta-analysis that involved 14 studies with over 90000 patients for 5 years showed that statins reduced the risks of major cardiovascular events and overall mortality [35]. Yet, another meta-analysis of 11 studies showed no reduction in mortality with the use of statins [36]. A similar conclusion was observed in the recent Cochrane review [37]. However, Blaha
Non-pharmacological treatment serves as a supportive therapy to reduce cardiovascular risk in otherwise healthy people. The common recommendations are dietary modifications, exercise and weight control. Modification of diet will allow lower drug doses that will reduce the adverse effects of drugs. Clifton
3. Definitions of probiotics
Over the years, probiotics have been defined in several ways. The term probiotic was coined by Lily and Stillwell [45] to describe growth-promoting factors produced by microorganisms. Parker [46] subsequently defined it as organisms and substances, which contribute to intestinal microbial balance. However, Fuller [47] pointed out that this definition was too broad and redefined probiotic as a live microbial feed supplement, which beneficially affects the health of the host animal by improving its intestinal microbial balance. Havenaar
4. Characteristics and health benefits of probiotics
Evidence is emerging that the intestinal flora does not exist as an entity by itself, but is constantly interacting with the environment, the central nervous system, the endocrine and the immune system [51-54]. There is growing scientific evidence to support the concept that maintenance of gut microflora may prevent or treat intestinal disorders [55-57]. Therefore, attempts have been made to improve health status by modulating the indigenous intestinal microbiota through probiotics [58,59]. However, for probiotics to be effective the selection of strains must be based on criteria that are coherent with the claim the probiotic is used for. Rational selection and validation of promising microbial strains should be based on scientific evidence obtained from
5. Hypocholesterolaemic effects of probiotics
There has been considerable interest in the beneficial effects of lactobacilli and bifidobacteria on lipid metabolism since the discovery that fermented milk containing a wild
Mice | L. reuteri L. fermentum SM-7 | Serum TC lowered Serum TC lowered Serum LDL-C lowered Serum TC and LDL-C lowered | Taranto Ngyuen Jeun Pan |
Rats | A mixture of probiotic microorganisms or L. acidophilus B. longum SPM1207 B. longum SPM1207(sonication killed) L. plantarum Lp91 L. plantarum 9-41-A | Serum TC lowered Serum TC and LDL-C lowered Serum TC and LDL-C lowered Plasma TC and LDL-C lowered Plasma HDL-C increased Serum TC and LDLC lowered | Fukushima and Nakano (1995, 1996, 1999) Usman and Hosono (2000) Lee Shin Kumar Xie |
Human | Probiotic-fermented milk product L. acidophilus L1 B. longum BL1 L. acidophilus L. fermentum L. acidophilus and B. lactis L. reuteri NCIMB 30242 | Serum Total Cholesterol Variable data from 1974-1997 Variable data from 1988-1998 Serum TC lowered Serum TC lowered No changes in blood lipid parameters No changes in blood lipid parameters Serum TC Serum HDL-C increased Serum TC and LDL-C | Taylor and Williams (1998) De Roos and Katan (2000) Anderson & Gilliland, 1999 Xiao Lewis and Burmeister (2005) Simons Ataie-Jafari et al (2009) Jones |
cholesterol by 7% as compared to the control group [4]. The
In a series of experiments in rats, Fukushima and Nakano [7,8], and Fukushima
In contrast to animal models, studies in humans conducted between 1974 to 1997 (reviewed by Taylor and Williams [14]) and from 1988 to 1998 ( reviewed by de Roos and Katan [15]) indicate that the role of fermented milk products as hypocholesterolaemic agents was equivocal, as the clinical studies performed gave variable results and no firm conclusions could be drawn. The contradictory results observed were mainly related to the experimental designs especially the use of inadequate sample size and variations in the baseline levels of blood lipids [68]. Anderson and Gilliland [16] conducted a randomised, placebo-controlled, crossover 10-week study that involved 48 hypercholesterolaemic subjects. The subjects consumed milk fermented containing
A meta-analysis based on six studies was conducted by Agerhol-Larsen
6. Proposed mechanisms of cholesterol reduction by lactic acid bacteria in vitro
Although studies have shown that some lactic acid bacterial strains have a hypocholesterolaemic effect on the host, the mechanism(s) involved is not fully understood. Different hypotheses have been advanced to explain the hypocholesterolaemic effect of lactic acid bacteria
Based on their findings, Gilliland
However, Klaver and Van der Meer [23] proposed another mechanism of cholesterol reduction by lactic acid bacteria. They pointed out that the experimental set up to prove the cholesterol assimilation as hypothesized by Gilliland
In an attempt to determine the validity of the hypothesis of assimilation and/or precipitation of cholesterol by
More recently, another mechanism was hypothesized by Kim
7. Cholesterol reduction by lactic acid bacteria in vivo
It has been suggested that assimilation of cholesterol during growth of probiotic lactic acid bacteria and binding of cholesterol to their cellular membrane would result in less cholesterol available for absorption, leading to reduced serum cholesterol of the host [24]. Fukushima and Nakano [7] suggested that the hypocholesterolaemic effects could also be due to the ability of probiotic organisms to inhibit hydroxymethylglutaryl coenzyme A (HMG CoA) reductase. It is well documented that suppression of HMG CoA reductase is correlated with the inhibition of cholesterol synthesis. Short chain fatty acids (SCFA) have also been implicated to be involved in the reduction of cholesterol. Hara
8. Enterohepatic circulation of bile acids
Bile acids are synthesised from cholesterol in the liver and stored in the gall bladder. The steroid is conjugated with an amide bond at the carboxyl C24 position to one of two amino acids, glycine and taurine [92], before it is excreted into the small intestine. The conjugated bile salts are amphipathic in nature and form micelles that facilitate digestion, emulsification and absorption of lipids from the small intestine [93]. The conjugated bile salts are readily absorbed in the gastrointestinal tract by active transport mechanisms and are returned to the liver; this process is known as enterohepatic circulation. A large pool of bile acids accumulates and undergoes a number of enterohepatic cycles daily [94].
The conversion of cholesterol to bile acids is the major route by which cholesterol is metabolized. To date, only two studies have shown the ability of probiotics strains [5,95] to be able to up-regulate CYP7A1 an enzyme that catalyzes the conversion of cholesterol to bile acids. An increase in CYP7A1 leads to reduction in hepatic cholesterol levels [5,95] and increase fecal cholesterol [95] and bile acids [5] excretion in hamsters and mice respectively. However, in the intestine, the bile salts may also be deconjugated by probiotics strains through bile salt hydrolase activity resulting in free bile salts. Free bile salts are more likely to be excreted via the faeces than the conjugated ones [96-98].
9. Significance of bile salt deconjugation by probiotic strains
The peptide-like bond between the bile acid and taurine or glycine is not cleaved by most proteolytic enzymes, but it is by bile salt hydrolase (BSH), an intracellular enzyme [99]. Deconjugation of bile salts
The significance of BSH activity other than its hypocholesterolaemic effect, is far from understood. However, it has been suggested that certain BSH-active bacteria are able to utilise the amino portion of the deconjugated bile salt. Van Eldere
10. Conclusion
The consumption of probiotics is gaining popularity especially in the maintenance of health and prevention of disease. In particular, the role of probiotics as a hypocholesterolaemic agent has been explored extensively. Progress has been made in the recent years on the selection, identification and characterization of strains that actually fulfill the criteria of true probiotic microorganisms and that are able to exert cholesterol reducing effects
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