Magnesium Malate: Supports Natural Energy Production

Magnesium malate is a type of magnesium that is made by combining elemental magnesium with malic acid. This is considered a magnesium salt of malic acid, and offers some distinct benefits over other forms of magnesium. Magnesium helps control hundreds of processes in our body ranging from digestion to brain health. Magnesium is a cofactor involved in the absorption of many nutrients, and different types of magnesium offer different types of benefits. This specific type of magnesium has been shown to be easily absorbed and well-suited for supporting natural energy levels.

Malic Acid + Magnesium

Magnesium malate is a combination of malic acid and magnesium known to increase absorbability. Malic acid is  found in many fruits such as oranges, and has many notable health benefits. Forms of magnesium such as magnesium oxide offer elemental magnesium by weight—but they are poorly absorbed by the human body. Compounds like Magnesium Malate and Dimagnesium Malate are comprised of elemental magnesium bonded with a malic acid compound to produce an organic form of magnesium (sometimes referred to as a magnesium salt). This type of compound allows more magnesium to be absorbed before side effects like diarrhea occur. Magnesium Malate is a preferred choice over other forms of magnesium for several reasons. It is cheaper than many amino acid chelate forms like magnesium glycinate, lysinate, or glucarate—but still offers a higher level of bioavailability than oxides and sulfates. Magnesium malate also offers the benefits of malic acid, such as the support of cellular energy production (Krebs Cycle) and the chelation of heavy metals such as aluminum.

Importance of Magnesium

In 2012, a review of medical data found that nearly 50% of Americans weren’t getting the recommended daily intake (RDI) of magnesium from diet alone. 1 Assuming that the 320-420 mg/day RDI of magnesium is an effective amount of magnesium, that means 1 out of 2 people in America are likely magnesium deficient. It’s very likely that number is higher, considering some prior research found as many 68% of Americans consumed less than the RDI of magnesium 2 Many factors come into play when considering how much magnesium we may be, or may not be, getting from our food. Topsoil mineral depletion, overally processed foods, and genetic modification may all play a role in providing less magnesium to we’ve evolved to expect from certain foods. In addition, many health conditions such as Candida overgrowth and parasitic infections can cause intense magnesium competition in the body, often limiting the effective amounts.

1 out of 2 people in America are likely magnesium deficient

Plants and animals alike rely on elemental magnesium to facilitate hundreds of vital processes. In humans, magnesium is involved in all processes that utilize Adenosine Triphosphate (ATP) which is commonly considered our primary source of energy.  ATP is like a universal energy molecule, which can be transferred between different types of cells, and is produced through such processes as glycolysis 3. Think of it like crude oil that gets turned into kerosene, gasoline, or even jetfuel depending on which type of vehicle it’s being used in. Magnesium has the unique ability to form compounds known as chelates, which are certain types of organic molecules made of centralized metal compounds. Magnesium is able to form ATP chelates which allow it to effectively transfer intracellular energy in our body.4 In considering which magnesium supplements may offer you the most benefit, oftentimes it’s best to consider which type of molecule magnesium has been combined with. In this case, malic acid has been shown to offer several notable health benefits—particularly to pain reduction and energy production.

Benefits of Magnesium Malate

Benefits of Magnesium Malate + Malic Acid

The benefits of magnesium malate are best discussed in the context of the benefits of malic acid. Different types of magnesium supplements may be absorbed better than others, and provide different amounts of magnesium. Regardless of the unique composition—they are all effectively supplying your body with the same magnesium compound. The benefits of different types of magnesium can be seen in the compounds they’ve been bonded with, such as malic acid in the case of magnesium malate. While these compounds still provide elemental magnesium, they are also supplying additional compounds that provide distinct benefits aside from magnesium. With that in mind,  it’s best to consider the benefits of magnesium malate as being largely attributable to malic acid.

Reduces Fibromyalgia Related Pain

Fibromyalgia is a complex disease which causes sometimes debilitating pains. It’s symptoms often come and go with little predictability. The causes of fibromyalgia aren’t currently well-understood, and there isn’t currently an FDA-approved treatment for it. Several studies of natural fibromyalgia treatments have found a remarkable connection between usage of compounds such as malic acid in reducing fibromyalgia pain. One such study done in 1995 found that among 24 patients suffering from fibromyalgia all given the malic acid compound saw a significant reduction in fibromyalgia-related pain5 This study utilized a 200mg malic acid + 50mg magnesium compound that was administered initially over a period of two-months. A second phase of this study involved the participants increasing dosage every 3-5 days until the achieved desired pain-reducing effects. During the first, fixed dose trial, there were little effects seen from the malic acid + magnesium treatment. However, when patients increased their dosage and received treatment over a longer period of time there were significant reduction in all pain-related symptoms. Another study conducted in 1992 found that fibromyalgia pain, as measured by the tender point index (TPI), was reduced by 300% after a period of 4-8 weeks of treatment with magnesium + malic acid. This study used a range of malic acid of 1200-2400mg and magnesium in range of 300-600mg.6 Noteworthy is that non-placebo receiving participants in this study noticed subjective decreases in pain as little as 48 hours after beginning treatment with magnesium + malic acid. In addition to the benefits of malic acid, elemental magnesium has been shown to be an indicator of lowered levels of C-reactive protein—a type of universal biomarker for inflammation.7 Fibromyalgia is thought to be integrally influenced by inflammation, and magnesium’s correlation to C-Reactive protein could offer further insight into the benefit of magnesium compounds towards reducing fibromyalgia symptoms.

Vital to Cellular Energy Production

In 1953 a man named Hans Kreb received a Nobel Prize for his description of a biological process within the body responsible for cellular energy production. This process is known as the Citric Acid Cycle (sometimes called Krebs Cycle) and helps generate and process energy within our body. This process involves many different enzymes and intermediary metabolites, but ultimately functions to utilize ATP. This process is regarded as one of the most fundamental cellular processes in aerobic lifeforms such as humans, and many believe it likely integral to the origin of life. 8 In the later stages of the Krebs Cycle, an enzyme named Fumarase acts on a Fumarate molecule to transform it into ionized malic acid (malate). This step directly precedes the formation of Nicotinamide Adenine Dinucleotide (NAD+) which leads directly to energy utilization by the mitochondria.9 Malic acid is present in many natural foods such as apples and oranges. This compound exists as the non-ionized form, and must undergo transformation within the Krebs Cycle before being able to be useful in the production and utilization of ATP. Ionized malic acid, such as that found in Magnesium Malate supplements, conceivably offers the human body a more efficient intermediary to utilize within the final stages of the Krebs Cycle. This has been noted in anecdotal accounts as an effective way to treat symptoms of chronic fatigue and boost overall baseline energy levels.

Aluminum Detoxing/Chelation

Aluminum is a potentially hazardous compound that is being increasingly linked to many neurological disorders such as Alzheimer’s Disease. The specific action of aluminium in neural tissues isn’t completely known, but there is enough evidence to suggest a causative correlation.10 Several studies have shown the ability of carboxylic acids such as malic acid, citric acid, and tauric acid to offer aluminum chelating action, potentially viable solutions for reducing overall aluminum toxicity. To understand how this process works, it helps to realize that aluminum and magnesium are both metals. Aluminum is capable of bonding with compounds like citric and malic acid the same way that magnesium is. When you consume foods high in these types of natural acids, research has shown some evidence of lower aluminum presence. 11 12 13 This type of effect has largely been investigated in animal studies only, though there are some reports of similar effects being noted in uncontrolled human trials 14 This effect has been noted in varying degrees of efficiency among several acids, with several forms of aluminum compounds as well. Aluminum toxicity stemming from vaccination is a very debated topic in recent years. While much focus is given to the efficacy of vaccines in general, many argue that preservative agents used in vaccines are capable of harmful toxic effects as well. Adjuvants such as aluminum draw criticism for adding unrelated toxic load to the administered host. In a New Zealand animal study, researchers found that compounds such as malic acid were able to reduce the amount of these types of aluminum compounds present in the blood stream after injection. While promising, this study was conducted with levels of Aluminum that are likely far beyond those found in practical applications.

Magnesium Malate vs. Magnesium Citrate

Magnesium Malate vs. Citrate

In the world of Chemistry, when a acidic and alkaline (basic) compounds are combined they often form a neutral compound referred to as a salt. Malic Acid and Citric acid are both hydrogen ion-containing molecules, which effectively classifies them as acids. Elemental magnesium is considered an Alkaline Earth Metal, and is naturally found in a silvery metallic form. This is considered an inorganic form of magnesium, and isn’t readily available to the body. Creating magnesium salts such as citrates or malates transforms elemental magnesium into an organic magnesium which can be effectively utilized by our bodies for purposes of nutrition.

Comparing magnesium citrate vs. magnesium malate is effectively comparing the differences in malic acid vs citric acid with regards to their effect on the absorption and utilization of magnesium in our body. These types of magnesium provide the action of their respective acids (malic and citric) when consumed, and are effectively compared in that regard. For example, malate is an integral component to the production of ATP (cellular energy), and malic acid is regarded as providing that benefit. There is very little research on the differences in efficacy for different types of magnesium. Limited research suggests that chelates such as magnesium glycinate are most effective for acute short-term dosing, while magnesium citrate provides better absorption over the long term. 15 Magnesium Citrate and Malate have both demonstrated the ability to be better utilized by the body compared to forms such as oxide and chloride.

Another important consideration to make when comparing magnesium malate vs. citrate is in their respective amounts of elemental magnesium. Each of these types of magnesium contain compounds in addition to magnesium, and the listed amount on the label accounts for the acid + magnesium total, not always the magnesium. To understand this type of difference, you have to calculate the elemental weight of magnesium for each type. This is done by subtracting the molecular weight of magnesium from the molecular weight of the specific magnesium type, then calculating the overall percentage using that figure. The formula for such a calculation is as follows:

Formula for Calculating Elemental Magnesium Percentage

Using this formula, the following elemental magnesium percentages can be calculated as 15.54% elemental magnesium for Magnesium Malate, and 11.39% elemental Magnesium for Magnesium Citrate. This reveals roughly 4% greater amount of elemental magnesium found within magnesium malate than in magnesium citrate. There isn’t enough research currently to state conclusively any differences in bioavailability between the two types. To summarize, magnesium Malate offers approximately 4% more elemental magnesium than magnesium citrate, and it’s benefits are commonly regarded with context to it’s malic acid component.

Potential Side Effects

Magnesium supplements in general are noted as having very few side effects. Some topically-applied sprays and oils have been reported as causing rashes or itching, though these aren’t relevant to orally-administered forms such as magnesium malate. One side effect typical to all magnesium supplements is gastrointestinal distress. The human body has a certain level of magnesium homeostasis it tries to maintain, and when too much magnesium is present it signals the release of excess amounts. This typically results in loose or watery stools, and diarrhea in cases of massive over-consumption. Magnesium malate offers a more highly-absorbed form of magnesium—meaning your tissues, organs, and cells can receive more magnesium than when taking other types such as magnesium oxide or carbonate. Many lower-absorbed magnesium supplements can cause gastrointestinal distress such as diarrhea, long before your body is able to  absorb a therapeutic amount. These side effects aren’t regarded as serious in most cases, and are often seen as an easy way to test to see if you need more magnesium.

Final Considerations

Magnesium is an essential compound that controls hundreds of processes in our body. It aids in nervous system function, digestive actions, and in the generation of cellular energy. Magnesium malate is a specific type of magnesium compound that has been combined with malic acid—known also for many health benefits. Malic acid has been shown to be effective as a heavy metals chelating agent, vital in the production of energy, and potentially a treatment for fibromyalgia related pain. Magnesium compounds in general, but specifically magnesium malate, are poorly researched currently. The majority of research is either conducted in animals or only within small isolated human trials. While confirmation for the health benefits of magnesium malate may take years to confirm in clinical settings, many anecdotal reports describe very positive experiences. Magnesium malate has very rare and very mild side effects associated with it, and is generally regarded as safe to experiment with. Always check with your doctor before beginning a new supplement or changing your current medication.

The Article Magnesium Malate: Supports Natural Energy Production was originally published on the Isotrope website

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Probiotics: A Guide For Those With Food Sensitivities

Probiotics are valuable tools in helping to balance the bacterial communities found in our digestive system. Many chronic health conditions are slowly having their roots traced back this balance. Gut bacteria have been shown capable of physically altering the composition of our brain, influencing emotions, and have been connected to chronic health conditions such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This systemic connection between gut bacteria and health has led many to use probiotic supplements. Some of the best probiotics will affect many people differently and, in some cases, those heralded as most-beneficial may actually make things worse. This article discusses some important considerations to make before deciding whether probiotics may offer you benefit, which types may be most-beneficial and why.

D-Lactic Acid vs. L-Lactic Acid

Lactic acid is a compound produced naturally by the human body and is used in many processes such as energy production. This compound is found in nature in one of two isomer forms; D-Lactic Acid or L-Lactic acid. Both of these variations are found in the human body, but only L-Lactic acid is actually produced by the body naturally. D-Lactic acid is produced by many difference types of bacteria, and is considered an accurate biomarker for bacterial overgrowth when found in excess. Much of the data we have for bacteria and lactic acid levels produced by them come from the study of food preservation. Eggs, for example, are thought to be past their shelf life when 200mg/kg of L-Lactic acid is observed [2]. This type of science highlights that bacteria are commonly known to produce types of lactic acid, and that measurements of lactic acid can indicate amount of growth.

Measuring the ratio between types of lactic acid is also a useful indicator to suggest pathogenic bacterial overgrowth. For example, patients suffering from Chronic Fatigue Syndrome have been found to have higher levels of D-Lactic acid in their blood [1]. Recent research has even shown that ME/CFS can be accurately predicted in 82% of cases by analyzing fecal bacteria and serum inflammatory biomarkers. The takeaway here is that a disproportionate increase of certain types of intestinal bacteria is associated with chronic health issues. These types of bacteria are often noted as producing high levels of D-type lactic acid, though many beneficial bacteria also produce it to some degree. This isn’t usually an issue, but can become troublesome when these bacteria outnumber L-Lactic acid producers.

Histamine Intolerance

Another very important consideration to make when selecting a probiotic is the impact it will have on histamine levels. Histamine is a neuroregulatory molecule that our bodies use for a wide array of functions. It plays a role in cognitive function, digestion, and allergic reactions. Our bodies have several types of histamine receptors; H1, H2, H3, and H4. These sites are found in our body where histamine attaches to help facilitate some other process. Histamines are commonly associated with allergies and symptoms such as watery eyes, stuffy nose, and itchy skin. These symptoms are natural reactions to foreign invaders such as pollen or black pepper—but also sometimes become chronic in response to a seemingly-unknown cause. There are several fairly common genetic mutations that can affect your body’s ability to regulate histamine. These may affect the histamine production and removal at any stage during its lifecycle—all ultimately having potential to underlie histamine intolerance. Histamine is produced through the conversion of histidine via the L-Histidine Carboxylase (HDC) enzyme. Other enzymes, Diamine Oxidase (DAO) and Histamine N-methyltransferase (HMT), are responsible for getting rid of histamine. Any issues in the production of HDC, DAO, or HMT could potentially cause disturbances in histamine regulation. There are certain common genetic mutations known to be connected with these issues with DAO activity. Minor alleles for rs2052129, rs2268999, rs10156191 and rs1049742 are associated with lowered DAO activity while rs2071514, rs1049748 and rs2071517 are associated with more robust protective levels [14]. These types of variants strongly influence the production and activity of DAO—and thus histamine—but aren’t enough to predict histamine intolerance alone.

The Bacteria Connection

Certain types of bacteria produce histamine in much higher levels than others. These aren’t necessarily bad bacteria, though they may cause great difficulty for those suffering with histamine intolerance issues. Many of these bacteria are common in consumer probiotics, and include such names as Lactobacillus casei, Lactobacillus bulgaricus, and Lactobacillus rheuteri. Other bacteria such as Lactobacillus Acidophillus are considered to be more histamine-neutral—but still produce some levels of histamine. In the vast majority of multi-strain consumer probiotics, histamine producing, histamine neutral, and histamine reducing bacteria are all found together. This diversity is generally regarded as beneficial and supportive of optimal digestive health. For those with histamine-related issues however, they can cause symptoms to worsen. Adverse reactions to probiotics commonly regarded as beneficial can be a likely signal of histamine imbalance or gut bacteria dysbiosis. A careful examination of which types of probiotic bacteria are low-histamine producers, or even histamine-lowering, may offer viable options for those managing histamine issues.

Probiotic Bacteria Research

The amount of data present for differentiation among probiotic bacteria is sparse. The majority of data comes from food preservation sciences, some from animal studies, and only a small amount from human studies. Many different bacteria strains are present in consumer probiotics that haven’t been well studied under controlled environments. We took a quick survey of the 100 best-selling probiotics on Amazon.com and found nearly 100 unique bacteria types. While such species as Lactobacillus Acidophillus are common among many, other rarities such as Azomonas agilis are found in only a handful. We consider the presence of multiple sources of data important when classifying anything, but especially in classification of probiotic bacteria. For this reason, much consideration found in this article is focused on those most-commonly studied bacteria that were also found among the list of most-common consumer probiotics. Even among individual bacteria species there are variances in how unique strains perform with regards to histamine and lactic acid production. At this point, the following attempt to identify low-histamine and low d-lactic acid producers is really just a best guess.

Beneficial Bacteria

In one study investigating the presence of biogenic amines in cider generated a considerable amount of data related to histamine production. This study investigated the potential of several bacterial strains to produce histamine, tyramine, and putrescine—all markers of food spoilage. Among the data, researchers noted that non-histamine producers included Lactobacillus brevis CECT216 and Lactobacillus plantarum [5]. In another study investigating various biogenic amines produced by lactic acid bacteria, researchers also found Lactobacillus plantarum, Lactococcus lactis, Lactobacillus casei, and Lactobacillus bulgaricus to not produce histamine [6]. Additionally, researchers also found that Klebsiella oxytoca, Citrobacter freundii and Enterobacter cloacae all to produce large amounts of histamine. These bacteria are often found in higher amounts among patients suffering from gut dysbiosis [6].

Lactobacillus Rhamnosus was found to produce small amounts of each, but nearly 400% more L-Lactic acid

One study investigating the ability of Bifidobacterium longum spp. Infantis and Lactobacillus rhamnosus was also able to isolate certain amines produced by each. Bifidobacterium longum subsp. Infantis CECT 7210 was found to produce a near-zero amount of D-lactic acid and no histamine whatsoever. While Lactobacillus Rhamnosus was found to produce small amounts of each, but nearly 400% more L-Lactic acid [7]. This study ultimately concluded that the Bifidobacterium longum subsp. Infantis strain showed strong potential as an antiviral and immunological enhancing therapy. In a previous article on Bifidobacterium and histamine, we discussed a study that found both Bifidobacterium infantis and Bifidobacterium longum to exert histamine-lowering effects in animal studies [8]. This benefit was seen in pretreatment in mice prior to allergen exposure. Researchers found that mice in the test group were seen to not only show lower overall levels of histamine, but to also have a smaller degree of genetic expression associated with histamine reactions.

One study found that several different Lactobacillus plantarum species were able to actually reduce histamines and other biogenic amines found in wine. It was ultimately found that the most beneficial strains of Lactobacillus plantarum in lowering histamine content were, in order of most effect, NDT 03, NDT 16 and NDT 21 [9]. Lactobacillus Rhamnosus GG is a strain of bacteria that has been extensively studied compared to other types. This strain in particular has shown the ability to colonize up within the human GI tract [10]. For anyone trying to establish a stronger presence of beneficial bacteria, this would likely be experienced as a positive aspect. These species-specific clarifications aren’t always made in consumer probiotics, illustrating how different brands may offer different results based on no other merit than ingredient source. In addition to impact probiotics potentially have on lactic acid and histamine levels, there are other considerations to make as well.

Oligosaccharides & Inulin Fibers

Additional ingredients found in probiotics should also be carefully scrutinized. Many probiotics contain pre-biotic ingredients such as Fructooligosaccharides (FOS), Mannanoligosaccharides (MOS), or insoluble fibers meant to help bacteria ferment and colonize. These materials are very effective in providing a food source for probiotic bacteria—but may also nourish any existing harmful bacteria. As an example, consider gut bacteria as a balance. On one side of the scale you have good bacteria—on the other side you have the bad bacteria. If you take prebiotic-containing probiotics, there’s a chance that for every increase you see in good bacteria—you’ll also see an increase in existing bad bacteria. This would help introduce new good bacteria, but not work to counterbalance bad bacteria effectively. This might result in a net-increase of lactic acid or histamine—ultimately worsening your existing condition.

The ability of FOS and MOS type compounds to sustain bacteria is well established and often used in laboratory simulations as well in consumer goods. The assertion we’re making that it could present as a hurdle along the path towards restoring gut-bacteria balance is not well-studied. This notion should only be considered as conversational at best. For otherwise healthy individuals, these types of compounds are beneficial in helping to maintain existing bacterial balances. That’s to say; if you’re happy where you are these compounds will likely work to reinforce your current bacterial profile. For those with a strong presence of dangerous bacteria or low diversity of good bacteria, these are likely to impact them negatively.

High Fiber Fruits & Vegetables

Fibrous fruits and vegetables are often regarded as essential to digestive health. They contain many minerals and vitamins essential to health like magnesium, calcium, and vitamin D. These types of foods have been shown in research to help address several digestive issues such as constipation, traveler’s diarrhea, and irritable bowel syndrome [11].  High fiber diets have also been associated with lower rates of any type of death—referred to as all-cause mortality [12]. High fiber diets have been found to be very beneficial in most circumstances, but for those with bacterial dysbiosis they have the potential to cause great harm.

We enter another area of discussion not supported by current data—though worth consideration. Our digestive tract is host to a yet unknown amount of bacteria, both beneficial and potentially harmful. Much of their primary energy is derived from undigested carbohydrates including celluloses, fruit pectins, gums, oligosaccharides, and sugar alcohols [13]. Foods high in these types of compounds are known to stimulate bacterial fermentation, sometimes as much as 30 grams of bacterial for every 100 grams of fermented carbohydrate! Carbs, sugars, and fiber can all help sustain bacterial growth in our digestive tract. In the presence of favorable bacterial balance such diets will help sustain their presence. It’s likely that such high-fiber diets would help sustain any bacterial balance—even if it were largely comprised of potentially harmful types like  Klebsiella or Citrobacter.

Food Intolerances & Probiotics

Many times those suffering from food intolerances find themselves on woefully-restrictive diets. Giving up carbs, alcohol, sugar and grains seem like huge steps for most. For those suffering from food intolerances these concessions are often only distant memories. Foods like broccoli, carrots, eggs, and especially fruits can wreak all kinds of havoc. One potential explanation is that high fiber diets promote the growth of bad bacteria just as much as they do good bacteria. Such cases are likely found among those with very few types of bacteria, and large proportions of high histamine or D-lactic acid producers. In these cases, many probiotics often cause constipation, acidic stomach, and brain fog. To make this consideration, we’re assuming if fiber can cause good bacteria to grow, it will also cause bad bacteria to grow. Another assumption we’re making is that if you take probiotics and have a bad reaction it may be due to increases in histamine levels or D-lactic acid. Neither of these two notions is well-substantiated by data, but we believe both to be important considerations for those struggling finding an effective probiotic.

The Best Probiotics for Sensitive Individuals

Picking a quality probiotic is a lot of guess work, even when adequately educated. Different strains have been shown to provide dramatically different impacts on levels of histamine and lactic acid. Among the many data sources we’ve cataloged, it seems the best probiotics for sensitive individuals are as follows:

  • Lactobacillus rhamnosus,
  • Bifidobacterium infantis
  • Bifidobacterium longum

There were many bacteria that have been noted as being low-histamine producers, but were still high D-lactic acid producers. Inversely, there are also many bacteria that are noted as being low D-lactic acid producers but high histamine producers. These three bacteria were among the most-commonly studied in the data we’ve seen that exhibit an overall impact of not increasing histamine or D-Lactic acid. Bifidobacterium infantis and Bifidobacterium longum have both been noted to reduce histamine levels, and also have do not increase D-lactic acid levels. Lactobacillus rhamnosus does produce a small amount of D-lactic acid, but it’s a near-negligible amount. It is a high-producer of L-lactic acid, and has been shown to lower histamine levels as well as downregulating the genes associated with mast cell activity (involved in histamine release) [15].  Bifidobacterium are regarded as being native colonizers to the human gut, and are generally regarded as non-lactic acid producers. Most all Lactobacillus types produce lactic acid—having been named for such. There are likely many other bacteria that should be considered for use among highly-sensitive induvial but these represent those best described in currently-available data.

Final Considerations

Existing data describing the impact of common probiotics on histamine and lactic acid levels is sparse. This article draws on data spanning from food science, to human study, and also among animals. There is a high degree of variation in how this data is presented among researchers, as well as how they’ve chosen to identify specific bacteria strains. Probiotics offer a strong hope in the ability to help address many health conditions. Research has tied imbalances of bacteria to chronic health conditions such as ME/CFS, allergies, and even anxiety. It seems safe to say better health is seen among those with a well-balanced microbiome. For those working towards establishing or maintaining such a balance, there are often many unknown hurdles that impede progress. Histamine and D-lactic acid are two compounds with the potential to cause many issues. Making careful consideration of how probiotics impact levels of these compounds may help overcome many issues. Additionally, ingredients such as MOS, FOS, and high dietary fiber may also present challenges for those with high levels of unwanted bacteria.  If you are struggling to rebuild your gut health and have been struggling with probiotics, the above-mentioned bacteria are likely all excellent choices for you to further investigate. There is always the possibility they will impact you negatively as well, and consultation with your doctor and quality laboratory analysis is the only way to truly diagnose your particular circumstance.

References

  1. Sheedy JR, Wettenhall RE, Scanlon D, Gooley PR, … DE Meirleir KL. (2009). Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo, 23(4):621-8. http://iv.iiarjournals.org/content/23/4/621.long
  2. Megazyme International. (2014). D-Lactic Acid and L-Lactic Acid Assay Procedures. https://secure.megazyme.com/files/Booklet/K-DLATE_DATA.pdf
  3. Manome A, Okada S, Uchimura T, Komagata K. (1998) The ratio of L-form to D-form of lactic acid as a criteria for the identification of lactic acid bacteria. J Gen Appl Microbiol, 44(6):371-374. http://doi.org/10.2323/jgam.44.371
  4. Takahashi, K., Terashima, H., Kohno, K., & Ohkohchi, N. (2013). A Stand-Alone Synbiotic Treatment for the Prevention of D-Lactic Acidosis in Short Bowel Syndrome. International Surgery, 98(2), 110–113. http://doi.org/10.9738/CC169
  5. Garai G, Dueñas MT, Irastorza A, Moreno-Arribas MV. (2007). Biogenic amine production by lactic acid bacteria isolated from cider. Lett Appl Microbiol. 45(5):473-8. http://doi.org/ 10.1111/j.1472-765X.2007.02207.x
  6. Bover-Cid S, Holzapfel WH. (1999). Improved screening procedure for biogenic amine production by lactic acid bacteria. Int J Food Microbiol. 53(1):33-41. https://doi.org/10.1016/S0168-1605(99)00152-X
  7. Moreno Muñoz, J. A., Chenoll, E., Casinos, B., Bataller, E., Ramón, D., Genovés, S., … Rivero, M. (2011). Novel Probiotic Bifidobacterium longum subsp. infantis CECT 7210 Strain Active against Rotavirus Infections. Applied and Environmental Microbiology, 77(24), 8775–8783. http://doi.org/10.1128/AEM.05548-11
  8. Dev S, Mizuguchi H, Das AK, Matsushita C, Maeyama K, et al. (2008). Suppression of histamine signaling by probiotic Lac-B: a possible mechanism of its anti-allergic effect. J Pharmacol Sci. 107(2):159-66. Epub 2008 Jun 5. http://doi.org/10.1254/jphs.08028FP
  9. Capozzi, V., Russo, P., Ladero, V., Fernández, M., Fiocco, D., Alvarez, M. A., … Spano, G. (2012). Biogenic Amines Degradation by Lactobacillus plantarum: Toward a Potential Application in Wine. Frontiers in Microbiology, 3, 122. http://doi.org/10.3389/fmicb.2012.00122
  10. Kontula, P., Nollet, L., Saarela, M., … Von Wright, Atte., (2009). The Effect of Lactulose on the Survival of Lactobacillus rhamnosus in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) and in vivo. Microbial Ecology in Health and Disease 14(2), 90-96 http://www.tandfonline.com/doi/abs/10.1080/08910600260081739
  11. Cummings JH, Christie S, Cole TJ. (2001) A study of fructo oligosaccharides in the prevention of travellers’ diarrhoea. Aliment Pharmacol Ther. 15(8):1139-45. http://doi.org/10.1046/j.1365-2036.2001.01043.x
  12. Chuang SC, Norat T, Murphy N, Olsen A, … Vineis P.(2012) Fiber intake and total and cause-specific mortality in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr. 96(1):164-74. http://doi.org10.3945/ajcn.111.028415.
  13. Slavin, J. (2013). Fiber and Prebiotics: Mechanisms and Health Benefits. Nutrients, 5(4), 1417–1435. http://doi.org/10.3390/nu5041417
  14. Maintz L, Yu CF, Rodríguez E, Baurecht H, Bieber T, Illig T, Weidinger S, Novak N.(2011). Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities. Allergy. 66(7):893-902. http://doi.org.10.1111/j.1398-9995.2011.02548.x
  15. Oksaharju, A., Kankainen, M., Kekkonen, R. A., Lindstedt, K. A., Kovanen, P. T., Korpela, R., & Miettinen, M. (2011). Probiotic Lactobacillus rhamnosus downregulates FCER1 and HRH4 expression in human mast cells. World Journal of Gastroenterology : WJG, 17(6), 750–759. http://doi.org/10.3748/wjg.v17.i6.750

The Article Probiotics: A Guide For Those With Food Sensitivities was originally published on the Isotrope website

Researchers Connect Chronic Fatigue Syndrome to Gut Bacteria Imbalance

Researchers from Cornell University have finally shed light on the biological markers associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This 2016 study found that analysis of inflammatory biomarkers and gut bacteria is able to predict the presence of ME/CFS [1]. This work offers greater insight into a mystifying health condition that, until now, Science has been unable to describe with any notable significance.

What is Chronic Fatigue Syndrome?

Chronic Fatigue Syndrome is a complex and often debilitating disorder characterized by extreme bouts of fatigue. These symptoms are often brought after seemingly normal activity and have been noted as commonly starting after acute illnesses such as the flu. ME/CFS fatigue is often accompanied by physical pain, insomnia, and impaired cognitive function. Until now there has been little insight as to the origins of Chronic Fatigue syndrome or potential treatments. Most therapeutic approaches for ME/CFS are focused on symptom management [3]. Certain supplements such as magnesium malate, melatonin, and turmeric are often used as a means of supporting energy levels, promoting more restful sleep, and reducing symptoms of inflammation. While helpful in many cases, those suffering from CFS have had very few options for addressing potential underlying causes. Sadly, many ME/CFS patients have been diagnosed with mental disease in the face of medical misunderstanding. This new research shows that the impact of our gut bacteria play a critical role in the development of ME/CFS, offers insight into potential future treatments, and clearly identifies this condition as having physiological markers.

Understanding the Microbiome

The human body is host to a diverse community of bacteria that, depending on the species, may help or hinder natural biological processes. Many bacteria such as Bifidobacterium species have been known to serve supportive roles in our body—such as reducing histamine levels. Broader studies have even shown that different genera of bacteria have the potential to alter our moods, emotions, and may impact symptoms of diseases such as Autism and Schizophrenia. Many of these bacteria are found in our digestive tract where they work to digest food, synthesize vitamins and help protect us from harmful pathogens [4]. The awareness and study of these bacteria are not new, though Science is still learning their potential impact on human health. Generally speaking, it seems that a diverse range of ‘good’ bacteria is most-closely associated with better health.  Cornell researchers found that CFS patients had a low diversity of bacteria—which would support such notions.

Previous Understanding

Previous research into the relationship between ME/CFS and gut bacteria found promising results with probiotic therapy. CFS patients are often known to exhibit GI issues such as diarrhea, nausea or constipation [5]. These are all regarded as potential symptoms of microbial dysbiosis—but on their own offer little insight into specific disease etiology. Other research has shown that certain types of bacteria, known to produce higher levels of D-Lactic Acid, are associated with CFS. This research found that ME/CFS patients were more likely to have higher overall bacterial counts, larger predominance of gram-negative bacteria, higher counts of E.Faecalis and S.sanguinis, and that larger overall production of the D-type Lactic acid is seen [6]. Other works have shown that CFS also typically exhibits symptoms of inflammatory disease, noted by increased levels of C-reactive protein and inflammatory cytokines. Overall, past research has shown strong potential that chronic fatigue syndrome is likely associated with gut-bacteria balances and the presence of inflammatory cytokines in the blood stream. This notion has been confirmed by new research from Cornell, and offers much promise in the future diagnosis and treatment of ME/CFS.

Bacteria & Biomarkers

The Cornell study investigated 48 patients with an existing ME/CFS diagnosis, 34 of whom reported symptoms of gastrointestinal distress. In this study, 25 members of the test group indicated they had experienced a rapid onset of symptoms after such acute illness as the flu. Cornell researchers also investigated the connection of leaky gut syndrome to CFS. This analysis was conducted through the measurement of plasma levels of C-reactive protein (hsCRP), lipopolysaccharides (LPS), and intestinal fatty acid binding protein (I-FABP). Conceivably, these markers would be seen in elevated number in the presence of intestinal damage such that gut bacteria and other compounds could freely enter the blood stream. Levels of soluble CD14, a biomarker for detecting bacterial infections, were also measured.  Researchers found that levels of nearly all these compounds were higher in ME/CFS patients, which LPS, sCD14, and LBD all being the most statistically significant (P<0.0005).

ME/CFS can accurately be identified by the measurement of certain inflammatory biomarkers and microbial analysis of stool samples

The second scope of investigation in this study performed stool analysis to identify the presence and composition of bacteria in ME/CFS patients relative to healthy control subjects. This was designed as an effective means to identify any bacteria species, or bacterial imbalances that may contribute to the presence of ME/CFS. Researchers broke down analysis into Phylum-level and Family-level and found significant differences between healthy patients and those with ME/CFS. Researchers noted that such bacteria types as Bifidobacterium and Faecalibacterium were much higher in healthy individuals. After collecting data and structuring it for analysis, researchers then applied a deep-learning algorithm as a means to establish a way to effectively diagnose ME/CFS. This took into account data from test and control groups, and was able to correctly identify a ME/CFS diagnosis with 82% accuracy when taking into account stool data and inflammatory markers, and 75% accuracy when taking into account stool samples alone. This illustrates that ME/CFS can accurately be identified by the measurement of certain inflammatory biomarkers and microbial analysis of stool samples.

Looking Ahead

Chronic fatigue syndrome is a debilitating disease that can sometimes last for years. Currently there is no FDA approved treatment for ME/CFS and our current understanding hardly offers any hope to those suffering from the condition. Previous research has shown a potential connection between alterations in gut bacterial as a potential identifier for ME/CFS, but didn’t offer much specific insight. This new research from Cornell has shown that ME/CFS can be accurately predicted by inflammatory markers in the blood and by stool analysis for microbial composition. This knowledge may help pave the way for better understanding how treatments with specific probiotics and live-bacteria foods may help address symptoms of ME/CFS. A likely place to start would be in the supplementation of the Bifidobacterium and Faecalibacterium bacteria types and, drawing from previous research, the avoidance of D-Lactic acid producing bacteria.

References

  1. https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-016-0171-4
  2. https://www.cdc.gov/me-cfs/index.html
  3. https://www.cdc.gov/me-cfs/treatment/index.html
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3426293/
  5. Borody TJ, Nowak A, Finlayson S. The GI microbiome and its role in chronic fatigue syndrome: a summary of bacteriotherapy. ACNEM J. 2012;31(3):3–8.
  6. http://iv.iiarjournals.org/content/23/4/621.long

The Article Researchers Connect Chronic Fatigue Syndrome to Gut Bacteria Imbalance was originally published on the Isotrope website

Bifidobacterium Shown to Reduce Histamine Levels

Probiotics are some of the most popular—yet also enigmatic—supplements on the market. Beneficial bacteria such as Bifidobacterium are included in many consumer supplements,  along with a plethora of other species. Researchers are still actively trying to define how the many variations of these bacteria might contribute to human health. To help better understand two specific species, this article takes a closer look at a 2008 study demonstrating anti-histamine action of Bifidobacterium infantis and Bifidobacterium longum [3].

Histamine Lowering & Natural Allergy Relief

Allergies extend much further beyond seasonal sniffling. Many chronic health conditions can find their roots, at least partially, in unbridled histamine production. Histamines are compounds that are neuroregulatory and can be found concentrated in various levels among different organs and areas of the human body. L-Histidine decarboxylase (HDC) actively converts histidine into histamine, which utilized by a series of different histamine receptors; H1, H2, H3 and H4. Levels of histamine are controlled by diamine oxidase (DAO). Environmental, dietary or genetic factors affecting HDC or DAO production can cause issues with histamine dysregulation. Simply put; if your body is not making enough HDC you won’t make enough histamine and if your body isn’t making enough DAO you’ll likely have too much histamine. These two compounds are fundemental variables in the equation that governs histamine balance. As they relate to probiotics, histamines and other biogenic amines such as tyramine have been shown to be produced by certain bacterial species. Generally speaking, bacteria can be classified as histamine producing, histamine lowering or histamine neutral [1]. This isn’t a widely used classification system per-se and adopted here only for simplicity. There is a popular hypothesis that the modern obsession with hygiene has reduced exposure to many beneficial bacteria that help regulate histamine action in our body [2]. Further investigation into the ability of specific bacteria types’ impact on histamine regulation has supported this concept for the most part. One possible approach at overcoming this shortage of bacterium is by through supplementation with probiotics.

Probiotics Investigation

In this particular study, researchers from several universities collaborated to determine the potential impact of Bifidobacterium infantis and Bifidobacterium longum on histamine regulation. Bacteria from the Bifidobacterium genus are often studied for their potential impact on human health—because they are naturally occurring in our digestive systems. Their impact on histamine regulation was measured in this study in two dimensions. The first; researchers determined the ability of the Bifidobacterium bacteria to reduce allergy symptoms and second; researchers analyzed the specific impact the on histamine-regulating genes. These investigations were conducted on laboratory mice that had been sensitized to a common human allergen, toluene 2, 4-diisocyanate (TDI). The mice in the test group were given a pre-treatment of a liquid suspension of the two Bifidobacterium species [3].

Bifidobacterium Show Promising Results

Researchers administered TDI to the nasal passages of the test group to provoke an allergic response. After a period of time, a liquid suspension of the Bifidobacterium infantis and longum was administered. Researchers found that allergy symptoms were significantly (P<0.01) reduced in those mice receiving the probiotic treatment. Researchers noted that genetic expressions of histamine related genes (H1R) increased 250% after initial TDI treatment. Among those mice receiving a probiotic treatment, H1R expression was reduced by 60% (P<0.01) which resulted in significantly (P<0.05) lower histamine levels. In addition to the reduction of histamine regulating genetic groups, researchers also demonstrated that the Bifidobacterium treatment was able to significantly (P<0.05) suppress certain cytokine action as well. These compound included interluken 4 (IL-4) and interluken 5 (IL-5) [3].

Cellular Pathways & Oil Refineries

Genetic expressions, cytokines, histamine regulating bacteria; these factors comprise a complex maze of biology difficult to understand. Research such as this has helped to offer a lot of insight into the scientific understanding of bacterial roles played in our immune system and overall health. Even with detailed summaries of findings however, many such results aren’t well applied by the general public. The basic concepts discussed in this study can be simplified to provide a bit more practical understanding—for those not interested in lowering H1R expression in their pet hamsters. Cellular pathways are like roadmaps we use to understand how one compound enters the body, get transformed into another compound, gets put to use and then gets recycled or eliminated.

Cellular Pathways are like maps describing the process of extracting crude oil from the deserts of Saudia Arabia and eventually turning it into gasoline to fuel our cars. There’s the refinement process to actually convert the crude oil into gas, which in this case is like the transformation of histidine into histamine by L-Histidine Decarboxylase. Not often considered however are the engineering teams needed to make the oil rigs, the shipment containers, the storage facilities and, of course, the cars themselves. There are a lot of peripheral processes involved of making both gasoline and histamine—and we’ve much less idea of how histamine is made and regulated.

Basic Takeaways

This study helps support the notion that probiotic bacteria such as Bifidobacterium infantis and Bifidobacterium longum both likely play a role in the process. They found that each bacterium showed the potential to help lower overall histamine levels involved with allergic reactions. This discovery is important because it helps support the idea that maintaining healthy and diverse levels of intestinal bacteria can likely help reduce symptoms of allergies. This was only a study conducted on mice and doesn’t on its own stand as any beacon of discovery. These types of bacteria play an active role in helping to synthesize nutrients like Magnesium, B Vitamins and many, many other vital nutrients. For those suffering from allergies or histamine intolerance, probiotics such as Bifidobacterium infantis and Bifidobacterium longum may offer some powerful relief.

References

  1. Maintz, N. Novak. (2007), Histamine and histamine intolerance. The American Journal of Clinical Nutrition, 85(5) 1185-1196. http://ajcn.nutrition.org/content/85/5/1185.long
  2. Schaub, R. Lauener, E. Mutius. (2006), The many faces of the hygiene hypothesis. Journal of Allergy and Clinical Immunology, 117(5) 969-977. http://dx.doi.org/10.1016/j.jaci.2006.03.003
  3. S.Dev, H. Mizuguchi, A.K. Das, et al. (2008), Suppression of Histamine Signlaing by Probiotic Lac-B: a Possible Mechanism of Its Anti-Allergic Effect. Journal of Pharmacological Sciences, 107(2) 159-166. http://doi.org/10.1254/jphs.08028FP

The Article Bifidobacterium Shown to Reduce Histamine Levels was originally published on the Isotrope website

Researchers Identify Cellular Process of Tumor Formation

Research published earlier this year sheds light on a fundamental process which drives cell growth and death among epithelial tissues such as gut lining and skin [1]. A disruption to the processes governing the growth and death of cells is at the root of tumor formation and health conditions associated with inflammation. Researchers led by Dr. Jody Rosenblatt at the Huntsman Cancer Institute at the University of Utah in Salt Lake City believe this new insight will help elucidate the underlying mechanisms of tumor growth.

A Balancing Act

Epithelial cells can be found throughout our bodies in organs, our digestive tract, and skin. These types of cells form a protective barrier to safeguard against pathogens like bacteria. The density of this lining is determined by the amount of cells found there, which is controlled by cellular signaling process to control the creation of new cells or the removal of existing ones. An imbalance in this process—in either direction—can cause the disruption of normal biological function. An example of too few cells can be seen in conditions such as leaky gut syndrome, where holes in the epithelial lining of the intestines allow undigested food particles into the blood stream. An example of too many cells can be seen in the growth of tumors. Dr. Rosenblatt and her team discovered the underlying system our bodies use to regulate and maintain this balance is a mechanical one that detects stretching and overcrowding of cells.

Stretching to Accommodate

This research showed that epithelial cells detect changes in density by producing signals in response to stretches and contractions. When there are too few cells their walls are stretched, signaling new cell formation. When the cells are overcrowded, their walls are compressed and signal cell death. Essentially, this process of cell density regulation is a process of tension detection.  There’s a sheer elegance of this process—as with many systems of balance—and it turns out the thresholds at which these signals initiate are tightly established.  Dr. Roseblatt’s team found that an increase of pressure of 1.6 times (~Phi for those paying attention) was the point at which cell death was triggered. Dr. Rosenblatt describes this process as such:

“What we found boils down to really simple principles. It’s all mechanical tension. If the cells get too crowded – 1.6-fold more crowded – then they pop some cells out that later die. The extrusion of cells enables the cell sheets to return to densities they like.”

“If the cells become too sparse, then they activate cells to divide – and that signal to divide comes from mechanical stretch. To test this, we stretched cells and found that stretch could trigger cells to divide within only one hour! The process also showed us that stretch is a normal trigger for cell division.”

Fundamentals

Dr. Rosenblatt’s team found this process is regulated, at least partially, by the protein Piezo1. This protein along with its close relative Piezo2 are thought to be integral to the unique cation channels used for the detection of mechanical pressures in our bodies—such as sound or touch. Exactly how these proteins function or underlying cellular processes for the detection of pressures, is still largely unknown. Animal studies have shown that Piezo1 to induce cellular current in response to pressure [2].  This makes a strong case for the role of Piezo-class proteins as being integral for cellular responses to mechanical pressure. Dr. Rosenblatt’s work seems to back up this notion, and casts valuable insight onto the underlying process of tumor formation.

References

  1. https://www.nature.com/nature/journal/v543/n7643/full/nature21407.html
  2. https://www.ncbi.nlm.nih.gov/pubmed/22343900

The Article Researchers Identify Cellular Process of Tumor Formation was originally published on the Isotrope website

Cellular Pathway for Insulin Release Described by New Research

Researchers from Uppsala University have identified a critical aspect of how our bodies produce insulin, perhaps paving the way for more effective future diabetes treatments. This study found that levels of the Epac2A protein compound are directly correlated to insulin release. By utilizing specialized microscopy techniques the research team was able to visualize the binding of Epac2A and cyclic Adenosine Monophosphate (cAMP) for the first time. This process was shown to be a primary pathway for the movement of Epac2A to the cellular membrane receptor sites which regulate granular insulin release [1]. This represents a deep insight to a before undescribed link between Epac2A, cAMP, and insulin release.

Shedding Light on Long Held Suspicions

Cyclic AMP has been well studied as a facilitator of intracellular transportation. This molecules’ role in cytosis has been well agreed upon—though many of its dynamics still aren’t well understood.  Previous research has shown that cAMP is integrally involved in the release of insulin, and also that Epac2A levels seem to be involved. [3] This research does well to identify many of the moving parts of the process underlying cellular insulin release, though there has still been much mystery as to how they all fit together. This new research shows that cAMP binds to the Epac2A protein and rapidly transports it to the cellular membrane, where it then binds to sites responsible for regulating insulin release. This suggests two important new understandings that one; Epac2A plays a direct role in regulating insulin granule release from pancreatic B-cells and two; cellular cAMP levels likely correlate to the effectiveness of this mechanism.

Understanding Cyclic Adenosine Monophosphate (cAMP)

Adenosine Triphosphate (ATP) is often associated with energy levels by nutritionists and doctors alike. This molecule plays an integral role in our bodies’ abilities to transfer energy to different areas, but it isn’t a direct source in most cases. It’s like crude oil, which can be further refined by different cells into different types of fuel to suit their purpose. Cyclic Adenosine Monophosphate (cAMP) is produced inside cells after the conversion of ATP via the enzyme Adenylate Cyclase. Once cells have generated cAMP, they utilize it through the binding with different proteins. In this case of this new study, researchers identified the messenger pathways with heightened activity after the binding of Epac2A and cAMP. This pathway was shown to transport the Epac2A compounds directly to the cellular plasma membrane, where they are then used to regulate insulin release. Simply put; it seems that both cAMP levels and Epac2A levels likely correlate directly to insulin-release.

Approaches of Treating Diabetes

Diabetes is now commonly being treated with drugs that inhibit the action of a compound known as dipeptidyl peptidase (DPP). These inhibitors, such as Sitagliptin (Januvia), work to effectively increase levels of a compound named Glucagon-Like Peptide (GLP). This class of compounds describes types of secretory hormones released by the gastrointestinal tract in response to eating, notably GLP-1. Previous research has shown GLP-1 to bind to increase intracellular cAMP levels after binding to pancreatic beta cell receptor sites. This entire process can be summarized by regarding DPP as increasing GLP which in turn increases cAMP, resulting in an increased release of insulin into the bloodstream. [2] This new research now sheds like on the final stages of this process by which cAMP ushers the Epac2A protein to the cellular membrane where it regulates insulin release.

Promising Natural Treatments

Research such as this offers great clarification towards complicated biochemical processes in our bodies. These new understandings will likely fuel the development more effective diabetes medications which take into account newly understood subtleties of cellular insulin release. This new understanding can also serve to help identify potential existing compounds that haven’t necessarily been investigated for their role in treating diabetes. With the concepts of this new research in mind, there are a few natural compounds that may show future promise in their ability to help treat diabetes naturally, or at least slow its progression.

Berberine

Berberine is a compound found naturally in plants such as the Indian Barberry tree, Goldenseal, and Yellowroot. This compound has demonstrated the ability to impact blood glucose levels as significantly as other pharmaceuticals such as Metformin [4]. Berberine has also been shown to decrease serum lipid levels and total cholesterol significantly—something not seen with Metformin. Other research has shown that Berberines anti-glycemic action can be explained by its action as a DPP inhibitor, similar to the drug Sitagliptin mentioned above [5]. Further research is needed to better describe the role Berberine plays in this type of action, though it’s overall impact on blood glucose levels much better established.

Forskolin

Forskolin is an extract from the roots of the Coleus Forskohlii plant commonly marketed as a weight loss supplement. Much of that hype was generated from celebrity personalities such as Dr. Mehmet Oz sensationalizing the results of a study among 23 women. This study was a far cry from being comprehensive, and concluded only that forskolin may be useful as a means of mitigating fat gain. [6] Dr. Oz has subsequently been investigated by a Senate Subcommittee for making false claims about weight loss supplements. Forskolin has a considerable amount of research demonstrating its ability to increase cAMP levels. One study investigating signaling pathways involved in immunosuppressive diseases such as HIV round that Forskolin was an activator of adenylate cyclase which significantly increased intracellular cAMP levels [7]. The primary focus of this study was on signaling pathways involved in immunosuppression, though it provides valuable insight into forskolin as a potential treatment for diabetes in the future. In addition to this research, many other studies have investigated forskolin for various applications, all concluding that it has a serious impact on cAMP levels. [8][9][10]

Final Thoughts

Diabetes is a disease that has been rapidly increasing in prevalence within the United States in recent years. The most-recent data suggests that among the entire US Population; 15% of people are diabetic and another 38% are pre-diabetic [11]. This implicates more than 160 Million people as suffering from insulin-related issues. This new research provides valuable understanding of the cellular signaling pathways involved in reduced insulin production. By applying this knowledge, as well as using it to consider previous research, future diabetes treatments will likely become more efficient and effective. The understanding of the role cAMP plays in transporting Epac2A to the cellular membrane highlights the potential of natural compounds such as Forskolin as potential diabetic therapies.

References:

  1. http://diabetes.diabetesjournals.org/content/early/2017/06/29/db17-0050
  2. http://diabetes.diabetesjournals.org/content/64/4/1262.long
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148290/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410097/
  5. http://www.tandfonline.com/doi/full/10.1080/14756360802610761
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2129145/
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591623/
  8. https://www.ncbi.nlm.nih.gov/pubmed/6299378
  9. http://dx.doi.org/10.3109/10520295.2014.883463
  10. http://molpharm.aspetjournals.org/content/22/1/109.long

Heavy Metals Testing Ensures Better Supplement Safety

Heavy Metals‘ is a term used to describe certain elements which are known toxins to the human body. Lead, mercury, cadmium, arsenic, and chromium are the elements that are most-often discussed in the context of supplements and nutritional products. Heavy metal testing is a cornerstone of any GMP-certified manufacturer’s quality assurance program, and an absolute must to ensure consumer safety.

Toxic Heavy Metals

Heavy metals testing helps to identify the amount of certain toxic elements within consumer products, especially supplements. The most-commonly tested for compounds are those which are found in the highest amounts naturally in living matter like plants. These are of the highest concern because they are most-likely to be in organic compounds such as foods and dietary supplements. The term ‘heavy metals’ is a bit non-descriptive of the actual cause for concern—which is focused only on a handful of elements. The FDA doesn’t explicitly state which compounds qualify as toxic metals, though it is generally regarded as being lead, mercury, cadmium, arsenic, and chromium. These are inorganic metals that have been known to cause toxic effects in their naturally occurring forms.

Sources of Heavy Metals

Heavy metals are naturally occurring compounds found in the Earth’s crust. These compounds are generally regarded as being unable to be created or destroyed; only able to be redistributed throughout the soil. For this reason, every farm on Earth has a unique profile of heavy metals found in its soil. In most cases the levels of these compounds aren’t of concern. Most cases of contamination stem from man-made issues such as pollution and commercial waste disposal. Many plants absorb these heavy metals as they grow as part of their natural growth cycles. This causes no issues in most cases, though science has shown that sometimes different species are capable of absorbing higher levels [1. https://bmcplantbiol.biomedcentral.com/articles/10.1186/1471-2229-13-103]. There are many other potential avenues by which supplements can be exposed to these types of materials. Water supplies and non-Food Grade manufacturing equipment can also pose potential exposure risks. Heavy metal contamination is still a risk even in the face of robust quality assurance measures. Shifts in topsoil composition, wearing of equipment, and undetected contamination all pose very real threats. The best approach for manufacturers to ensure consumer safety is to establish effective pre-production and post-formulation testing practices.

FDA Regulation

The FDA has a complex set of guidelines to ensure supplements sold in US markets aren’t a danger to consumers. This set of rules is referred to as the Current Good Manufacturing Practices (cGMP), and is often seen as a certified seal on dietary supplements. Violating cGMP guidelines results in action from the FDA, but supplement makers aren’t required to submit products to regulatory testing before sale. Instead, cGMP outlines manufacturers should develop and have in place a robust series of quality assurance practices and monitoring systems to ensure “identity, purity, strength, and composition” [2. https://www.fda.gov/Food/GuidanceRegulation/CGMP/ucm110858.htm] The FDA conducts random inspections of manufacturers to ensure adherence to cGMP, but there is no formal certification program manged by the FDA. Third party agencies such as NSF International offer registration programs where manufacturers can gain cGMP certification. This is a popular means of boosting consumer credibility, and supplements labeled as being NSF-GMP registered are of a much higher-quality than non NSF-GMP supplements. Typically, these products will bear an NSF certification on the label, but if you are unsure you should check with your supplement brand before purchasing.[4. http://www.nsf.org/consumer-resources/look-for-the-nsf-mark]

Per-Ingredient Regulation

In one response to how manufacturers should consider toxic substances and how they relate to natural compounds, the FDA responded as such: “We do not have a “zero tolerance” policy for such unavoidable contaminants but we have issued some regulations and guidance to address certain common contaminants” [3. https://www.federalregister.gov/d/07-3039/p-1503] There’s a lot of discussion surrounding this topic, and the essence is that GMP asserts that manufacturers establish and maintain a method of testing for these contaminants. The types of ingredients to be tested are subject to manufacturer knowledge, and their testing methods are established by the manufacturer as well. This is (kind of) an honor system inasmuch as the effectiveness is established by the manufacturer, and it’s adherence to that established quality program is what’s enforced by the FDA. With specific regard to heavy metals, the FDA has relied on manufacturers to establish their own upper limits on an ingredient-specific basis. In our opinion, this is pretty Willy Nilly and it’s best to defer to trusted third party organizations such as the American Herbal Products Association (AHPA) for more holistic guidance.

Upper Limits for Heavy Metals

The AHPA is a consumer advocacy organization that is heavily focused on natural plant-based ingredients found in consumer products. As a demonstration of their commitment to consumer safety, they devote a considerable amount of effort into aggregating industry standards, regulatory guidelines, and current scientific data to establish best-practices for heavy metals found in consumer goods. The latest guidelines, updated July 2012 [4. http://www.ahpa.org/AboutUs/AHPASPolicies/GuidancePolicies.aspx], lists the following recommendations for heavy metals and consumer goods:

  • Inorganic Arsenic: 10mcg/day
  • Cadmium: 4.1mcg/day
  • Lead: 6mcg/day
  • Methyl-Mercury: 2.0mcg/day

It’s important to note that these are recommendations for products based on their daily recommended dosages. For example, a product containing 1.0mcg of trace methyl-mercury per serving should advise to not exceed 2 servings per day. Unfortunately, this still places a lot of burden on consumers to consider the net total of heavy metals they are exposed to on a daily basis. For example; if one product you take contains 8mcg of inorganc arsenic per daily recommended dose—you could take it and still be within APHA guidelines. If you were taking a second product that contained 4mcg  of inorganic mercury as well—that’d but your daily total to 12mcg of inorganic arsenic.

California & Scary Labels

Some States such as California have established their own guidelines for disclosing potentially dangerous products to consumers. Legislation such as the 1986 Safe Drinking Water and Toxic Enforcement Act (Proposition 65) require manufactures attach warning labels to products containing any traces of harmful compounds such as mercury and lead.[5. https://oehha.ca.gov/proposition-65/general-info/proposition-65-plain-language] These labels are often very scary, and contain statements like “This product contains a compound known to the State of Californian to cause Cancer and birth defects.” The truth is that most of these toxic heavy metal compounds are found naturally in the Earth’s crust. Plants used in herbal supplements naturally absorb trace amounts of these compounds when they grow. For example; you’d likely get the same trace amounts of heavy metals from a whole food vitamin C supplement that you would from eating the foods listed on the label. The only difference is that in California bananas aren’t labeled as carcinogenic—but the supplement would be. Buying form supplement brands that contract with quality manufacturers can help ensure you aren’t being exposed to dangerous levels of these compounds.

GMP Manufacturing

GMP manufacturing guidelines are a powerful framework to help consumers ensure adequate safety from their supplements. The ambiguous nature by which the FDA regulates many such facets of product quality still allows this to leaves much interpretation up to manufacturers. For this reason, it’s important for supplement brands to assert the practices established and maintained by themselves or manufacturers to safeguard against these types of issues. When purchasing supplements, always look for labeling to indicate NSF-GMP compliance. The vast majority of supplement brands don’t actually manufacturer their own products, but contract out that process to larger more qualified facilities. This is ideal in many cases as it allows larger manufacturers to dedicate more resources to maintaining GMP practices effectively, while brands can focus on R&D and product development. This separation between seller and manufacturer can cause some disconnect in monitoring GMP practice however, and you should always seek to understand where a brand manufacturers their supplements. There are several steps that consumers can take to help ensure supplements are produced in quality GMP conditions.

1. Ask Brands Where Their Supplements Are Made

Most supplement brands don’t make their own products. They conceive the formulation in many cases, but the vast majority of supplement brands utilize contract manufacturers. In most cases this is actually a good thing for consumers, as it ensures new brands are able to have access to cGMP certified manufacturing facilities. Before buying supplements from a new brand, you should always ask them who manufacturers their products. Many times, you will get a response similar to ‘we manufacture all our own … ” when they really don’t. There’s no advantage in misrepresenting oneself here; if your brand won’t tell you exactly where their product comes from you shouldn’t buy from them. Open and transparent manufacturing is the best way to ensure quality throughout the supply chain. Modern logistics have allowed brands to offer better products to larger markets, especially in the context of supplements and food. Anyone with a bit of extra cash can start a supplement company, but only those willing to invest in quality manufacturing and quality assurance should be considered. If a brand isn’t open about where their products are made, it’s likely because they’re skimping on quality control and ingredient quality in order to make larger profits.

2. Check Manufacturer NSF-GMP Facility Registration

When manufacturers describe where and how their products are made, it’s important you audit their responses. NSF International maintains a full listing of supplement manufacturers that have been registered through their cGMP certification program. This includes cGMP and cGMP For Sport as well, and can take some time to peruse in it’s entirety. Some brands have invested a considerable amount of money into maintaining their own manufacturing facilities. These are typically the practitioner chain brands, but some other supplement brands have made such investments as well. If you don’t see you brand on that list don’t worry—it’s more than likely the use a contract manufacturer. If your brand tells you their manufacturers name, and you don’t see them on they list—then you should reconsider the products you buy.

3. Check FDA Warning Letter database for Manufacturer and Retailer

Another valuable tool for consumers to use in assuring supplements are safe is the FDA warning letters database. The FDA makes public all findings of cGMP violations—spanning from mislabeling to inadequate qualification of raw material providers. These letters offer insight into manufacturers that have had infractions in the past, as well as the steps taken to regain compliance. Additionally, NSF International maintains an active listing of complaints, notices, and enforcement actions of manufacturers that are found to violate the terms of their NSF-GMP certifications. By consulting these two resources, you can stay up-to-date on violations of supplement manufacturers. It’s important to note; there are reports of companies that receive violation notices simply closing their doors and opening as another business to clear this record.

Final Considerations

Heavy metals are a bit of a misnomer, though the term has come to be accepted as a description for potentially toxic compounds such as lead, methyl-mercury, cadmium, inorganic arsenic, and chromium. These compounds are natural components of the Earth’s crust, and are absorbed by plants during their natural growth cycles. Herbal supplements are therefore susceptible naturally for these types of trace elements to be found, though usually they are present in safe amounts. Manufacturing processes often expose products to these types of compounds. To ensure consumer safety, it’s vital that manufacturers adhere to rigid quality heavy metals testing programs as an integral part of their overall quality assurance program. The FDA’s cGMP guidelines help to establish best practice within the industry. Organizations like NSF International help protect consumers by offering cGMP certification programs. This certification ensures products are meet identity, purity, strength, and composition standards set forth by the FDA. By being mindful of total heavy metal contents of all your supplements, and checking that your brands are NSF-GMP certified—you can rest assured you are doing as much as possible to avoid heavy metal toxins in your products.