The beneficial effects of probiotics on intestinal health and immune function are well recognised, but the influence of gut microbiota on health extends beyond these two areas. Relationships have been established between gut flora disbalances and disorders such as cardiovascular diseases, metabolic abnormalities, reduced insulin sensitivity and neurodegenerative diseases. This means that probiotic strains with specific properties could be used in prevention or treatment.
Lactobacillus fermentum ME-3 is a patented strain of bacteria that can improve antioxidant defence, raising glutathione levels. Several clinical studies have shown that consumption of ME-3 can lower the risk of cardiovascular disease development by reducing the formation of oxidised low-density lipoprotein (LDL) – oxLDL – particles. Research is ongoing to evaluate its potential in other applications, such as prevention of metabolic syndrome or diabetes. Its antioxidant capacity makes it a promising probiotic for the prevention of many age-related conditions.
Plasma lipid profile regulation
Probiotics can aid cardiovascular health by reducing cholesterol levels, doing so through several mechanisms:
hydrolysis of bile acids by the bile salt hydrolase enzyme, which in turn will lower cholesterol since new bile acids are then synthesised from cholesterol in the liver transformation of dietary cholesterol into non-absorbable coprostanol direct incorporation of cholesterol into the bacteria inhibition of cholesterol absorption by gut epithelial cells.
Specific strains of L. acidophilus, L. plantarum, L. reuteri and B. longum display such cholesterol-lowering functions, but the decrease of total cholesterol or LDL cholesterol is moderate (between five and 13% in most studies).
A moderate effect on LDL levels is observed after eight weeks of L. fermentum ME-3 consumption (5% decrease); but the benefits are more pronounced on triglycerides, which drop by more than 9% after only two weeks and 17% at eight weeks. High-density lipoprotein (HDL) levels increase by 7% at eight weeks. The mechanisms involved have not been fully investigated, although full genome sequencing of ME-3 has shown that it contains the gene coding for BSH.
Prevention of oxLDL formation
Lowering LDL levels is usually considered to prevent cardiovascular disease, although accumulating evidence suggests that LDL particles by themselves are not dangerous. Atherosclerosis development does not involve native LDL particles; it only occurs when LDL gets oxidised.
oxLDL particles cause inflammatory lesions in blood vessels and activate immune cells; macrophages, loaded with oxLDL, accumulate at the site of the lesion and form the core of atherosclerotic plaques. Formation of oxLDL is normally minimised by antioxidant molecules in the LDL particles (vitamin E and ubiquinol); but, in the case of excessive and/or long-term chronic oxidative burden, these defences can be overwhelmed.
The best way to prevent atherosclerosis, therefore, is not to decrease the levels of LDL particles, but to prevent their oxidation instead. Numerous clinical studies have demonstrated the capacity of L. fermentum ME-3 to reduce the formation of oxLDL. This unique property, combined with the LDL-lowering and anti-inflammatory effects of the strain, makes ME-3 a perfect candidate for developing innovative and efficient strategies for cardiovascular disease prevention.
Mechanisms of antioxidant action
The mechanisms by which L. fermentum ME-3 reduces oxidative burden and prevents blood lipid oxidation have been investigated. The most remarkable property of ME-3 is its ability to produce glutathione, an essential antioxidant that scavenges free radicals and is used by the enzyme glutathione peroxidase to inactivate lipid peroxides. Glutathione also contributes to maintaining other antioxidants like vitamin C and E in their active forms.
L. fermentum ME-3 contains a complete enzymatic system, enabling not only synthesis of glutathione but also redox regeneration of reduced glutathione. Consumption of ME-3 leads to an elevation of glutathione levels in the serum and an improvement of the glutathione redox ratio (oxidised glutathione/reduced glutathione). The overall improvement of oxidative status can be measured through serum antioxidant capacity, peroxidised lipoproteins or isoprostanes; this effect is systemic, observed not only in the blood but also on urinary or skin markers.
Besides its effects on glutathione, ME-3 also raises the levels of paraoxonase – an antioxidant enzyme produced by the liver and transported in the blood by HDL particles. Paraoxonase protects LDL particles against oxidation; it also inactivates toxic derivatives of homocysteine, a molecule associated with inflammation and cardiovascular disease. Its induction is another mechanism by which ME-3 improves antioxidant status and prevention of cardiovascular disease development.
Clinical studies on ME-3-based finished products
L. fermentum ME-3 is available in food supplements commercialised under the brand name Reg’Activ (Reg’Activ CardioWellness in North America, Reg’Activ Cholesterol in Europe and Asia). The formulations combine the strain with functional ingredients that complement its action on cardiovascular health. A placebo-controlled, double-blind clinical study involving 45 subjects has been performed on the finished product. Over four weeks, it saw total cholesterol decrease by 12.3%.
The ME-3-based formulation had a significant effect on cardiovascular risk factors: over the four weeks, on LDL (17.0% decrease), triglycerides (12.5% decrease) and oxLDL (15.4% decrease). There was also an improvement of parameters related to inflammation and pre-diabetes: inflammatory markers saw decreases after four weeks of treatment (high-sensitivity C-reactive protein (hsCRP) saw a 31.0% decrease and interleukin 6 saw a 22.0% decrease), as well as the triglyceride/HDL ratio, decreasing by 17.0%, which is known to tightly correlate with the risk of insulin resistance. Glycated hemoglobin (HbA1c), a marker for sustained hyperglycemia, also showed a significant decrease of 3.2%.
This data suggests that ME-3 could be beneficial for preventing or treating not only cardiovascular diseases but also metabolic disorders such as metabolic syndrome and diabetes.
L. fermentum ME-3 and metabolic disorders
The improvement of parameters related to metabolic health has also been observed in other studies; ME-3 consumption has been seen to lead to an improvement of three markers: hsCRP, HbA1c and adiponectin. hsCRP and HbA1c are related to low-grade inflammation and sustained hyperglycaemia, respectively, which are two hallmarks of metabolic syndrome. Both markers decrease following consumption of ME-3.
ME-3 also causes an increase in adiponectin levels (an adipokine hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation). Adiponectin plays a role in the suppression of diabetes and non-alcoholic fatty liver disease; in combination with leptin, it can reverse insulin resistance.
Modulation of adiponectin levels is a novel mechanism of action for a probiotic, which confirms the potential of L. fermentum ME-3 as an innovative and efficient approach to treating or preventing metabolic disorders.
Other applications
The unique properties of L. fermentum ME-3 make it suitable for many more applications than just cardiovascular and metabolic health. Many physiological functions are influenced by glutathione levels, such as immunity, nervous system function and liver function. Skin health is also an interesting area of application, in medical (inflammatory skin diseases) and cosmetic (anti-ageing) aspects.
The probiotic has been tested on atopic dermatitis patients and led to a significant improvements of disease severity index and oxidative stress markers in skin biopsies.
Another promising application is the support of detoxification processes. The glutathione-dependent detoxification pathway is one of the main mechanisms for neutralising and removing toxins from the body, and excess free radicals are generated during detoxification. Therefore, ME-3’s ability to increase glutathione levels and total antioxidant activity may support detox processes. ME-3 will also contribute to detoxification through induction of paraoxonase, as this enzyme, besides its antioxidant potential, is capable of hydrolysing organophosphate molecules.
The Westernisation of diets and lifestyles, combined with overall ageing, is associated with a growing list of chronic diseases. There is an urgent need for preventive or curative strategies that are efficient, affordable and devoid of side effects. Probiotic-based approaches are promising and, among the few strains that could be used, L. fermentum ME-3 is one of the best characterised. Its remarkable antioxidant activity makes this a multitasking probiotic that can provide a wide range of health benefits.
References available on request.
