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In 1995, group of scientists were testing a wide range of Lactobacillus bacteria for antioxidant activity. While most failed, a strain named Lactobacillus fermentum ME-3 exhibited extremely strong antioxidant activity. Further testing revealed that Lactobacillus fermentum ME-3, which is often just called ME-3, was found to synthesize glutathione. Glutathione is a tripeptide amino acid that is made in every cell throughout the body.
This article will discuss the discovery and scientific research on Lactobacillus fermentum ME-3 and review the functions of glutathione, including recent studies which suggest that glutathione is an effective and reliable biomarker of aging.
Since glutathione's antioxidant activity is crucial for every cell in the body, the discovery of a strain of probiotic bacteria that could synthesize glutathione and boost glutathione levels in humans has significant health and medical implications.
The history of the discovery of L. fermentum ME-3 began in 1994, when joint research study was initiated between the University of Linkoping in Sweden and the University of Tartu in Estonia. The purpose of this collaboration was to examine associations between allergies and intestinal microbiota in two comparative populations: Estonians with a low prevalence and Swedes with a high prevalence of allergy. As part of this study, on March 2, 1995, Professor Marika Mikelsaar isolated five strains of Lactobacillus fermentum from the intestinal tract of a healthy one-year old Estonian child. Overall, more than 200 human strains of Lactobacillus bacteria were collected for this study.1
 In 1996, the Dutch company MONA engaged the University of Tartu to test both the MONA and the University of Tartu's department of microbiology's collection of Lactobacillus acidophilus strains for antioxidant properties. There was significant disappointment when none of the L. acidophilus strains exhibited good antioxidant activity. However, upon testing the lactobacilli strains from the previous Swedish/Estonian study, it was discovered that the Lactobacillus fermentum ME-3 strain isolated from one of the Estonian children exhibited extremely high antioxidant activity.
Initial studies showed that Lactobacillus fermentum ME-3 bacteria contain glutathione.2 Subsequent investigation revealed that ME-3 bacteria do not just contain glutathione; the bacteria are actively synthesizing glutathione. Follow-up studies revealed that ME-3 boosts glutathione via three independent mechanisms: synthesis, transport, and redox recycling. Thus, in addition to synthesizing glutathione, ME-3 is also able to extract glutathione from the surrounding environment, and it can recycle oxidized or "used up" glutathione back to its active or reduced form. Consequently, scientists are calling Lactobacillus fermentum ME-3 "A Complete Glutathione System" and emphasize that nothing previously has been found to have the capability of boosting glutathione levels by three different mechanisms at the same time.3
Since ME-3 produces glutathione, it makes sense that many of ME-3's benefits parallel the primary benefits of glutathione in humans.
Glutathione Overview
Glutathione is one of the most important antioxidants in the body, and it is frequently referred to as "The Master Antioxidant."4 An increasing number of studies link glutathione depletion with an increase in oxidative stress and a greater incidence of disease and accelerated aging. For example, reduced plasma glutathione levels have been shown to represent an increased risk for cardiovascular disease.5 Glutathione depletion has also been shown to be a primary cause of the neurodegeneration that leads to Parkinson's disease.6 Similarly, increased oxidative stress in Alzheimer's disease has been attributed to decreased levels of glutathione in the brain.7 In one review paper, the authors state the following:
Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neuro-degenerative diseases.8
The Benefits of Lactobacillus fermentum ME-3
After discovering that Lactobacillus fermentum ME-3 expresses strong antioxidant activity, follow-up studies began to reveal that ME-3 produces a wide range of additional health benefits. ME-3's multiple benefits fall within four categories: antioxidant activity, immune system support, anti-inflammatory activity, and detoxification. Consequently, scientists have been studying ME-3 for the past 20 years, and its unique health-promoting benefits are summarized below.
ME-3's Antioxidant Activity: In 1956, Denham Harmon, MD, introduced the Free Radical Theory of Aging in an article titled "Aging: a theory based on free radical and radiation chemistry."9 Although the idea was initially met with skepticism, free radicals and free radical damage are now recognized as one of the primary causes of the aging process.10 In fact, free radical damage is now associated with all of the common diseases of aging.11 In addition to synthesizing glutathione, ME-3 also produces the antioxidant enzymes glutathione peroxidase and glutathione reductase, which contribute to glutathione function and regeneration.12
Researching Lactobacillus fermentum ME-3's antioxidant activity also revealed that it produces the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD).13 Because mitochondria utilize about 90% of inhaled oxygen, they are highly vulnerable to free radical oxidative damage.14 MnSOD is the primary antioxidant that neutralizes highly reactive superoxide radicals (O2−), which are primarily generated within mitochondrial membranes.15 Consequently, MnSOD also plays a critical role protecting cells against free radical oxidative stress.
Lactobacillus fermentum ME-3 provides additional antioxidant support because it helps regenerate other oxidized antioxidants such as vitamin C, vitamin E, lipoic acid, and coenzyme Q10 back to their active forms. Lactobacillus fermentum ME-3 has the highest Total Antioxidant Activity (TAA) and the highest Total Antioxidant Status (TAS) of any probiotic tested to date.16 Its antioxidant-related effects are listed in Table 1. .pdf17-29
Promotes Cardiovascular Health: Lactobacillus fermentum ME-3 has a beneficial effect on several cardiovascular risk factors. In a two-week double-blind, placebo-controlled trial, individuals taking ME-3 achieved reductions in oxidized LDL-cholesterol (71 U/l to 63 U/l), BDC-LDL (23.8 umol/l to 22.0 umol/l), and triglycerides (2.1 mmol/l to 1.9 mmol/l) and beneficial increases in PON (110.0 U/l to 133.4 U/l) and HDL-cholesterol (1.4 mmol/l to 1.5 mmol/l).30 At the end of this trial, these same markers had gotten slightly worse for the placebo subjects.
Enhances Detoxification: Glutathione is a critical regulator of detoxification in every cell of the body, but especially in the liver and kidneys. Glutathione detoxifies toxins in food, heavy metals, air pollutants, pharmaceuticals, and a wide range of other toxins. Because ME-3 synthesizes glutathione, scientists conclude it will increase the body's detoxification capabilities. It is important to realize that glutathione gets depleted during the process of detoxifying things that are quite common in many people's lives such as alcohol,31 artificial sweeteners such as aspartame,32 and tobacco smoke.33 Acetaminophen, which is a common ingredient in many OTC and prescription analgesics, depletes glutathione very rapidly which is why acetaminophen overdose is the leading cause of acute liver failure in the United States.34
Promotes Liver Health: The liver is the primary organ for detoxification. There are two main phases of detoxification in the liver, which are called Phase 1 and Phase 2 detoxification pathways. A significant number of free radicals are generated during Phase 1, which can result in liver damage if adequate antioxidants (especially glutathione) are not available to quench them.35
Reduces Inflammation: Lactobacillus fermentum ME-3 has been shown to significantly inhibit levels of several key inflammatory markers, including glycated hemoglobin (HbA1c), high sensitivity C-reactive protein (hs-CRP), and interleukin 6 (IL-6); and it is also capable of stimulating production of the anti-inflammatory and anti-diabetic peptide adiponectin.36
Promotes Healthy Bacterial Balance: ME-3 produces significant amounts of short-chain fatty acids (SCFAs), hydrogen peroxide, and nitric oxide.37 These postbiotic™ metabolites function in several ways to promote the growth of beneficial bacteria and suppress the growth of pathogens, which help maintain a healthy microbiome.
Detoxifies Organophosphate Pesticides: Organophosphates were developed in the 1940s as highly toxic biological warfare agents. Today, they are one of the most widely used pesticides worldwide. In addition to being sprayed on agricultural food crops, they occur in many pesticide and insecticide products commonly used on residential lawns and gardens. They are also used in plasticizers, as antifoaming agents in lubricants and hydraulic fluids, and in flame retardants.
Lactobacillus fermentum ME-3 increases the activity of paraoxonase enzymes (called PON1), which helps detoxify organophosphates.38
In a US government-funded study titled Fourth National Report on Human Exposure to Environmental Chemicals, it was reported that 93% of children tested had measurable metabolites of organophosphates.39 Also, a 2004 report stated, "Almost every person is, or has been, exposed to organophosphate insecticides in their home, work or environment."40 These compounds are highly toxic, especially to the developing nervous system in young children. Studies have linked childhood organophosphate exposure to higher incidence of ADHD41 and autism.42 A probiotic such as ME-3 that improves detoxification of organophosphates may help reduce the risks to neurological diseases such as autism and ADHD.
Immune Function: Lymphocytes are a critical component of the immune system. Their primary job is to defend us against bacteria, viruses, and other foreign invaders. When faced with a challenge, the body dramatically increases the production of lymphocytes to fight the infection. Glutathione is required for the production and function of lymphocytes. Thus, glutathione levels are a critical regulator of immune function.43
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