Lactobacillus fermentum ME-3 A New Frontier in Glutathione Therapy

 

 

GreenMedInfo

 

Lactobacillus fermentum ME-3 (often referred to as ME-3) is a strain of probiotic bacteria that was discovered and isolated at the University of Tartu, Estonia in 1995. At the time, scientists were surveying a wide range of Lactobacillus bacteria, looking for strains that might exhibit antioxidant activity. When ME-3 was tested, it was found to express extremely high antioxidant activity.[1] Subsequent studies revealed that Lactobacillus fermentum ME-3 synthesizes glutathione.

Glutathione, which is made in all cells throughout the body, is referred to as the Master Antioxidant.[2] It is also important for functioning of the immune system[3] and a critical regulator of detoxification in all cells.[4] Because glutathione levels are so important to these major body systems, it has become recognized as a key biomarker of aging.[5]

The purpose of this article is to explain Lactobacillus fermentum ME-3’s remarkable benefits and to summarize the overall importance of glutathione to human health.

Structure of Glutathione

Glutathione is composed of three amino acids: glutamate, cysteine and glycine. Glutathione’s power as an antioxidant is due to its sulfhydryl (-SH) group on the cysteine portion of the structure shown above. Glutathione can “donate” the hydrogen proton from the sulfhydryl group, which neutralizes free radicals.[6]

A substantial body of research links glutathione depletion with a greater incidence of many diseases and accelerated aging. For example, it has been reported that low plasma glutathione levels represent an increased risk for cardiovascular disease,[7] diabetes,[8]rheumatoid arthritis,[9] and Alzheimer’s disease.[10]

In addition to synthesizing glutathione, Lactobacillus fermentum ME-3 is also able to recycle oxidized glutathione (GSSG), which is inactive, back to its active state (GSH), which is reduced glutathione.[11]

Glutathione levels have also been shown to parallel telomere length and telomerase activity, which is an important indicator of lifespan.[12] Telomeres have been compared to the little protective plastic tips on the ends of shoelaces. Telomers are repetitive sections of DNA at the end of a strand of DNA that protect chromosomes. Each time a cell divides, the telomers shorten. Low levels of glutathione are associated with an accelerated rate of telomere shortening.[13] Both telomers and glutathione are now recognized as biomarkers of aging.

Glutathione depletion is also associated with progressive loss of mitochondrial function due to mitochondrial DNA (mDNA) damage.[14] In animal studies, protecting mitochondrial DNA from damage is directly proportional to longevity.[15] In a human clinical trial with elderly adults, it was reported that higher glutathione levels are associated with a lower incidence of illnesses and higher levels of self-perceived health. These studies suggest that glutathione levels may be a potential marker of physiological and functional aging.[16]

Glutathione’s antioxidant activity is especially important for systems in the body that have a high rate of metabolic activity such as the immune system[17], nervous system[18], gastrointestinal system[19], and the liver[20].

Lactobacillus fermentum ME-3 also produces the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD).[21] Mitochondria consume over 90 percent of the oxygen used by cells, which makes them especially vulnerable to oxidative free radical damage.[22] In fact, it is estimated that from 1-3% of the oxygen entering the mitochondrial electron transport chain is converted into the singlet oxygen free radical (O2), which makes it the most abundant free radical occurring in the human body.[23] Manganese superoxide dismutase (MnSOD) is critically important because it is the primary antioxidant that neutralizes the highly reactive superoxide free radical. Because MnSOD constitutes the first line of defense in cells against oxidative stress in mitochondria,[24] it is sometimes referred to as the Guardian of the Powerhouse.[25]

Lactobacillus fermentum ME-3 provides additional antioxidant power because it helps regenerate or recycle other oxidized antioxidants such as vitamin Cvitamin E, lipoic acid and coenzyme back to their active forms. Because Lactobacillus fermentum ME-3 produces two of the body’s most powerful antioxidants, glutathione and MnSOD, it has been shown to have the highest Total Antioxidant Activity (TAA) and the highest Total Antioxidant Status (TAS) of any probiotic tested to date.[26]

Lactobacillus fermentum ME-3 has also been shown to have a positive effect on important cardiovascular risk factors as evidenced by the results from the following 2-week double-blind, placebo-controlled human clinical trial. Subjects taking ME-3 had reductions in oxidized LDL-cholesterol and triglycerides along with an increase in both HDL-cholesterol and paraoxonase. In addition to having antioxidant activity, paraoxonase enzymes are important because they detoxify some key agricultural pesticides.[27] During this clinical trial, the values of these markers all got slightly worse for the placebo control subjects.

Glutathione is also a key regulator of detoxification in all cells, but especially in the liver. Although detoxification clinical trials have not been conducted with ME-3 specifically, scientists conclude that ME-3’s ability to increase glutathione levels will result in improved detoxification.

Glutathione regulates many important detoxification processes including toxic metals such as mercury[28] and cadmium[29], reactive oxygen species (ROS)[30] and a wide range of xenobiotics[31]. Glutathione also gets depleted during the process of detoxifying substances that many people are commonly exposed to such as alcohol[32]artificial sweetenerssuch as aspartame[33]tobacco smoke[34], and the commonly used analgesic acetaminophen[35].

Lactobacillus fermentum ME-3 produces short-chain fatty acids (SCFAs), hydrogen peroxide, and nitric oxide.[36] These postbiotic metabolites help promote healthy bacterial balance in the gastrointestinal tract.

Lactobacillus fermentum ME-3 also helps lower several key inflammatory markers such as high sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6). Studies show that ME-3 also stimulates production of the peptide adiponectin and reduces levels of glycated hemoglobin.[37] These functions each play a role in managing inflammatory activity.

Organophosphates are one of the most commonly used pesticides worldwide. They are sprayed on commercial food crops and are a primary ingredient in many pesticide and insecticide products used in residential homes and gardens. They are also used commercially in plasticizers, as antifoaming agents in lubricants and hydraulic fluids and flame-retardants.

Lactobacillus fermentum ME-3 upregulates the activity of a paraoxonase enzyme called PON1, which helps detoxify organophosphates.[38] A 2004 report stated the following, “Almost every person is, or has been, exposed to organophosphate insecticides in their home, work or environment.”[39] In a study titled Forth National Report on Human Exposure to Environmental Chemicals, it was reported that 93% of children tested had measurable metabolites of organophosphates.[40] Studies have linked childhood organophosphate exposure a to higher incidence of ADHD[41] and autism[42].

In order to be effective, a probiotic must be able to withstand and survive exposure to the extremely acidic condition in the stomach. Studies with Lactobacillus fermentum ME-3 reveal that it survives at pH values ranging from 4.0 to 2.5 without a loss in viable cell count. Even at pH 2.0, the ME-3 strain survived for up to 6 hours. When exposed to bile acids, ME-3 survived for 24 hours without significant loss of live bacteria.[43] Thus, while testing in the human body has not been conducted, in vitro testing suggests that Lactobacillus fermentum ME-3 can tolerate exposure to harsh acidity in the stomach as well as exposure to bile acids in the small intestine. Hence, Lactobacillus fermentum ME-3 thrives and survives in conditions that simulate the harsh environments of the human gastrointestinal tract.

Lactobacillus fermentum ME-3: Summary of Human Clinical Trials

 

  1. Reduction in Oxidized LDL-Cholesterol: The first column shows that individuals taking ME-3 had a 16% reduction in the levels of oxidized LDL-cholesterol compared to placebo controls.[44]
  2. Reduced 8-Isoprostanes: The second column reports that people taking ME-3 had a 20% reduction in levels of 8-isoprostanes, which indicates reduced amounts of free radical damage due to ME-3’s antioxidant activity.[45]
  3. Elevated Glutathione: The study reported in the third column shows that people taking ME-3 had a remarkable 49% increase in the ratio of reduced to oxidized glutathione.[46]
  4. Probiotics, Oxidative Stress, Inflammation and Diseases: [47] The fourth column reports the increase in Total Antioxidant Activity (TAA) gained by the individuals taking Lactobacillus fermentum ME-3. (data for this comes from the following 2 studies; individual results are not shown on graph)

In the late 1980s, Drs. Calvin Lang and John Richie began studying glutathione’s effect on aging. In their initial study, they administered a glutathione precursor to the drinking water of mosquitoes which resulted increased glutathione levels 50-100%. Boosting glutathione resulted in a 30-38% increase in lifespan over controls.[48] To date, in all other animal models that have been tested, boosting glutathione has resulted in better health and increased longevity.[49]

Glutathione deficiency is associated with increased risks to chronic degenerative diseases and increased glutathione levels are associated with better health and increased longevity. An increasing body of scientific research supports the ‘Glutathione Deficiency Hypothesis’, which suggests that glutathione deficiency is a primary biochemical mechanism of aging that can be effectively modified by boosting glutathione levels. Consequently, it has been suggested that glutathione levels are effective and reliable biomarker of aging.[50] Thus, increasing glutathione levels by taking Lactobacillus fermentum ME-3 is an effective proactive step people can take to improve their health and increase their longevity.

AVAILABILITY OF LACTOBACILLUS FERMENTUM ME-3:

The patent for Lactobacillus fermentum ME-3 is held by the University of Tartu in Estonia. World-wide distribution rights have been signed to VF Bioscience/Belgium. To locate products containing ME-3, type Lactobacillus fermentum ME-3 in the search field of your internet browser.

 

References

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[2] Lang CA. The Impact of Glutathione on Health and Longevity. Journal of Anti-Aging Medicine. * Jul 2004;4(2).

[3] Droge W, Breitkreutz R. Glutathione and immune function. November 2000;59(4):595-600.

[4] Townsend D, et al. The Importance of glutathione in Human disease. Biomedicine & Pharmacotherapy. May 2003;57(3-4):145-155.

[5] Lang CA. The Impact of Glutathione on Health and Longevity. Journal of Anti-Aging Medicine. * Jul 2004;4(2).

[6] Meyer AJ and Hell R. Glutathione homeostasis and redox-regulation by sulfhydryl groups. Photosynth Res. 2005 dec;86(3):435-57.

[7] Shimizu H, Kiyohara Y, Kato I, Kitazono T, Tanizaki Y, Kubo M, Ueno H, Ibayashi S, Fujishima M, Iida M. Relationship Between Plasma Glutathione Levels and Cardiovascular Disease in a Defined Population. Stroke. 2004;35:2072-2077.

[8] Hakki Kalkan I and Suher M. The relationship between the level of glutathione, impairment of glucose metabolism and complications of diabetes mellitus. Pak J Med Sci. 2013 Jul;29(4):938-42.

[9] Hassan MQ, et al. The glutathione defense system in the pathogenesis of rheumatoid arthritis. J Appl Toxicol. 2001 Jan-Feb;21(1):69-73.

[10] Mandal PK, et al. Brain glutathione levels—a novel biomarker for mild cognitive impairment and Alzheimer’s disease. Biol Psychiatry. 2015 Nov 15;78(10):702-710.

[11] Kullisaar T, Songisepp EAunapuu MKilk KArend AMikelsaar MRehema AZilmer M. Complete glutathione system in probiotic Lactobacillus fermentum ME-3. Applied Biochemistry & Microbiology; Sep 2010, 46(5):481.

[12] Borrás C, Esteve JM, Viña JR, Sastre J, Viña J, Pallardó FV. Glutathione regulates telomerase activity in 3T3 fibroblasts. J Biol Chem. 2004;279(33):34332–34335.

[13] Borras C, et al. Glutathione regulates telomerase activity in 3T3 fibroblasts. J Biol Chem. 2004 Aug 13;279(33):34332-5.

[14] Wei YH, Ma YS, Lee HC, Lee CF, Lu CY. Mitochondrial theory of aging matures—roles of mtDNA mutation and oxidative stress in human aging. Zhonghua Yi Xue Za Zhi (Taipei) 2001;64(5):259–270.

[15] Barja G, Herrero A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J. 2000;14(2):312–318.

[16] Julius M, Lang CA, Gleiberman L, Harburg E, DiFranceisco W, Schork A. Glutathione and morbidity in a community-based sample of elderly. J Clin Epidemiol. 1994 Sept;47(9):1021-26.

[17] Droge W, Breitkruetz R. Glutathione and immune function. Proc Nutr Soc. 2000 Nov;59(4):595-600.

[18] Cooper AJ, Kristal BS. Multiple roles of glutathione in the central nervous system. Biol Chem. 1997 Aug;378(8):793-802.

[19] Hoensch H, Morgenstern I, Petereit G, Siepmann M, Peters WHM, Roelofs HMJ, Kirch W. Influence of clinical factors, diet, and drugs on the human upper gastrointestinal glutathione system. Gut 2002;50:235-240.

[20] Han D, Hanawa N, Saberi B, Kaplowitz N. Mechanisms of Liver Injury. III. Role of glutathione redox status in liver injury. American Journal of Physiology – Gastrointestinal and Liver Physiology Published 12 June 2006 Vol. 291 no. 1, G1-G7.

[21] US Patent, 20040151708 A1:. http://www.google.com/patents/US20040151708.

[22] Fariss MW, Chan CB, Paetl M, van Houten B, Orrenius S. Role of Mitochondria in Toxic Oxidative Stress. Molecular Interventions. April 2005; 5(2):94-111.

[23] Piechota-Polanczyk A and Fichna, J. Review article: the role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases. Naunyn Schmiedebergs Arch Pharmacol. 2014;387:605-620.

[24] Bag A, Bag N. Human Manganese Superoxide Dismutase Target Sequence Polymorphism and Ovarian Cancer. Ann Med Health Sci Res. 2014 Mar-Apr; 4(Suppl 1): S69–S70.

[25] Holley AK, et al. Manganese superoxide Dismutase: Guardian of the Powerhouse. International Journal of Molecular Sciences. Dec 2011;12(10):7114-62.

[26] Hutt P, Shchepetova J, Lõivukene KKullisaar TMikelsaar M. Antagonistic activity of probiotic lactobacilli and bifidobacteria against entero- and uropathogens. Journal of Applied Microbiology. 2006;100:1324-1332.

[27] Kullisaar T, Shepetova J, Zilmer K, Songisepp E, Rehema A, Mikelsaar M., Zilmer M. An antioxidant probiotic reduces postprandial lipemia and oxidative stress. Central European Journal of Biology. 2011 Feb;6(1):32-40.

[28] Kromidas L, Trombetta LD, Jamall IS. The protective effects of glutathione against methylmercury cytotoxicity. Toxicol Lett 1990;51:67-80.

[29] Singhal RK, Anderson ME & Meister A (1987) Glutathione, a first line of defense against cadmium toxicity. FASEB J 1, 220–223.

[30] Mailloux RJ, McBride SL, Harper ME. Unearthing the secrets of mitochondrial ROS and glutathione in bioenergetics. Trends Biochem Sci. 2013 Dec;38(12):592-602.

[31] Koob M, Dekant W. Bioactivation of xenobiotics by formation of toxic glutathione conjugates. Chem Biol Interact. 1991;77(2):107-36.

[32] Yeh MY, Burnham EL, Moss M, Brown LA. Chronic alcoholism alters systemic and pulmonary glutathione redox status. Am J Respir Crit Care Med. 2007 Aug 1;176(3):270-6.

[33] Abhilash M, Paul MV, Mathews V, Varghese R, Nair H. Effect of long term intake of aspartame on antioxidant defense status in liver. Food and Chemical Toxicology. June 2011;49(6):1203-1207.

[34] van der Toorn M, Smit-de Vries MP, Slebos DJ, de Bruin HG, Abello N, van Oosterhout AJ, Bischoff R, Kauffman HF. Cigarette smoke irreversibly modifies glutathione in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2007 Nov;293(5):L1156-62.

[35] Hinson JA ,Roberts DW, James LP. Mechanisms of Acetaminophen-Induced Liver Necrosis. Handb Exp Pharmacol. 2010; (196): 369–405.

[36] Mikelsaar M, Zilmer M., Lactobacillus fermentum ME-3 – an antimicrobial and antioxidative probiotic. Microb Ecol Health Dis. 2009 Apr; 21(1):1–27.

[37] US Patent WO 2014102692 A1: Method of treatment using Lactobacillus fermentum me-3. http://www.google.com/patents/WO2014102692A1?cl=en

[38] Mikelsaar M, Zilmer M., Lactobacillus fermentum ME-3 – an antimicrobial and antioxidative probiotic. Microb Ecol Health Dis. 2009 Apr; 21(1):1–27.

[39] Casida J, Quistad G. Organophosphate Toxicology: Safety Aspects of Nonacetylcholinesterase Secondary Targets. Chemical Research in Toxicology. 2004 Aug;17(8):983-992.

[40] CDC. Fourth National Report on Human Exposure to Environmental Chemicals. Available at http://www.cdc.gov/exposurereport/pdf/FourthReport.pdf.

[41] Bouchard MF, Bellinger DC, Wright RO, Weisskopf MG. Attention-Deficit/Hyperactivity Disorder and Urinary Metabolites of Organophosphate Pesticides. Pediatrics. June 2010:125(6):e1270-e1277.

[42] Shelton JF, Geraghty EM, Tancredi DJ, Delwiche LDSchmidt RJRitz B, Hansen RL, Hertz-Picciotto I. Neurodevelopmental Disorders and Prenatal Residential Proximity to Agricultural Pesticides: The CHARGE Study. Environ Health Perspect. 2014 Oct;122(10):1103-9.

[43] Songisepp E. Evaluation of technological and functional properties of the new probiotic Lactobacillus fermentum ME-3. Doctoral Thesis: University of Tartu; 2005.

[44] Tiiu Kullisaar, Epp Songisepp and Mihkel Zilmer (2012). Probiotics and Oxidative Stress, Oxidative Stress – Environmental Induction and Dietary Antioxidants, Dr. Volodymyr Lushchak (Ed.), ISBN: 978-953-51-0553-4, InTech, Available from: http://www.intechopen.com/books/oxidative-stress-environmental-induction-anddietary-antioxidants/probiotics-and-oxidative-stress.

[45] Songisepp E, Kals J, Kullisaar T, Mändar R, Hütt P, Zilmer M, Mikelsaar M. Evaluation of the functional efficacy of an antioxidative probiotic in healthy volunteers. Nutr J. 2005 Aug 4;4:22.

[46] Mikelsaar M, Zilmer M., Lactobacillus fermentum ME-3 – an antimicrobial and antioxidative probiotic. Microb Ecol Health Dis. 2009 Apr; 21(1): 1–27.

[47] Mikelsaar M and Zilmer M,. Lactobacillus fermentum ME-3 – an antimicrobial and antioxidative probiotic. Microb Ecol Health Dis. 2009 Apr; 21(1): 1–27.

[48] Rishie JP, et al. Correction of a glutathione deficiency in the aging mosquito increases its longevity. Proc Soc Exp Biol Med. 1987 Jan;184(1):113-117.

[49] Lang CA, et al. Blood glutathione: a biochemical index of life span enhancement in the diet restricted Lobund-Wistar rat. Progress in Clinical and Biological Research. 1989;287:241-246.

[50] Julius M. et al. Glutathione and morbidity in a community-based sample of elderly. J Clin Epidemiol. 1994 Sept;47(9):1021-26.



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