Hydrogen Therapy

The Emergence of A New Field of Medicine and How You Can Benefit From It Right Now (with a little help from your friends ... READ ON)

By Durk Pearson & Sandy Shaw

H ydrogen therapy for the prevention and treatment of a variety of diseases—particularly those associated with ROS (reactive oxygen species) and inflammation—has become a hot research subject. Many reports in peer-reviewed scientific and medical journals, including in vitro and animal studies, plus some clinical trials in humans, have already been published. Diseases that may be beneficially affected by hydrogen therapy include, to name a few, atherosclerosis, ischemia-reperfusion injury (as occurs in heart attacks and strokes), diabetes, stress-induced cognitive impairments, Parkinson’s disease (as shown in animal models), and various aspects of the metabolic syndrome (e.g., insulin sensitivity, glucose tolerance, and endothelial function).

As reported in an excellent review1 on the “recent progress toward hydrogen medicine,” the author describes various methods being used in published animal and human studies to administer hydrogen: inhalation of hydrogen gas, oral ingestion by drinking hydrogen water, hydrogen baths (because hydrogen easily penetrates the skin and distributes throughout the body via blood flow),1 injection of hydrogen saline, direct absorption of hydrogen (as in hydrogen containing eye drops), and INCREASED PRODUCTION OF HYDROGEN BY GUT BACTERIA. Note: One reason for the use of hydrogen water and hydrogen saline is that it is possible to reliably control the dose administered to experimental animals, which is important in determining results such as dose-response relationships. In the case of gut bacteria-provided hydrogen, it is less easy to determine the hydrogen “dose,” although one way to at least partially overcome this problem is to measure the hydrogen gas excreted by the lungs.

Hydrogen Is a Selective Antioxidant, Scavenging Dangerous Radicals But Not Radicals Important as Physiological Signaling Molecules

Hydrogen and carbon dioxide, as well as (in some people) methane, are gases released by colonic bacteria in the fermentation by the bacteria of carbohydrates that reach the lower digestive tract. Hydrogen has been known to have antioxidant properties for a long time, but its recognition as having some advantages over conventional antioxidants and its potential use as a therapeutic agent have only recently been explored.2,2c

One of the most interesting findings concerning hydrogen as an antioxidant is the discovery that it is a novel antioxidant because it scavenges the toxic hydroxyl radical (the strongest of the oxidant species)2c and the potent oxidant peroxynitrite (formed by the reaction of superoxide and nitric oxide), but is far less effective in scavenging physiological radicals such as superoxide and nitric oxide, important (at low concentrations) as signaling molecules.2 Moreover, hydrogen is able to diffuse extremely rapidly into tissue and “effectively reaches the nucleus and mitochondria,”1 suggesting “preventive effects on lifestyle-related diseases, cancer, and the aging process.”1 Hydrogen also passes through the blood-brain barrier, although most antioxidant compounds cannot do this.1

Safety of Hydrogen

Hydrogen (H2) is reported to have no cytotoxicity even at high concentrations.1 “The safety of H2 for humans is demonstrated by its application in Hydreliox, an exotic, breathing gas mixture of 49% H2, 50% helium and 1% O2, which is used to prevent decompression sickness and nitrogen narcosis during very deep technical diving.”1

From time immemorial human beings have absorbed quantities of lactic microbes by consuming in the uncooked condition substances such as soured milk, kephir, sauerkraut, or salted cucumbers which have undergone lactic fermentation. By these means they have unknowingly lessened the evil consequences of intestinal putrefaction.

— Elie Metchnikoff, The Prolongation of Life
(the English translation, Putnam, 1908), pg. 171

Every unhealthy change in the quality of beer coincides with a development of microscopic germs which are alien to the pure ferment of beer.

— L. Pasteur, Studies on Fermentation: The Diseases of Beer
MacMillan & Co. 1879 (English translation) (pg. 19)

Hydrogen Is a Free Gift From Your Gut Bacteria ... No Prescription Required
LCFOS Is a Food (Prebiotic) for Gut Bacteria That Produce Hydrogen

There are many papers on the effects of various types of non-digestible carbohydrates (foods, called prebiotics, for gut bacteria) that reach the lower digestive tract and are there converted to (mostly) hydrogen by gut bacteria in the process of their extracting energy from them. NOTE: There is considerable variation in the individual response to prebiotics. For example, the microbiota of people with “high” BMI (overweight or obese) have been found to generate less hydrogen because they are able to digest carbohydrates more efficiently than those with a lean BMI, leaving less to reach the colonic bacteria. Long-chain fructo­oligo­saccharides (LCFOS), however, cannot be digested by humans, even obese ones.

LCFOS as a Food for Hydrogen-Producing Gut Bacteria

A recent paper2b studied the release of hydrogen gas and short chain fatty acids by various fermentable dietary fibers by fecal bacteria. The authors proposed, and we agree with their suggestion, that “a slow, extended fermentation profile would be desirable to provide low initial gas and short chain fatty acid over a longer period of time.”2b If gas were released at a high volume very rapidly, it might cause abdominal bloating and discomfort and flatus frequency. The authors also suggest that “... the availability of SCFA [short chain fatty acids produced by the gut bacteria] throughout the entire length of colon is sought after because 50% to 60% of large intestinal cancer occurs in the distal colon and the evidence indicates that, in majority of the cases, chronic inflammation of this site promotes the development of this type of cancer. Butyrate [a short chain fatty acid] is particularly important in this context as it has anti-inflammatory action apart from being the main energy source for colonocytes.”2b LCFOS was reported to have (and the graph showed) slow and moderate but incomplete fermentation. We thought that the overall increase in gas production by gut bacteria fermentation of LCFOS and its timing looked particularly good for the supplement we were developing for our own use.

In the paper,2b the authors also explain that “[t]he distal colon is typically the site of protein fermentation, which leads to the production of such compounds as ammonia, phenol, p-cresol, and indoles resulting in a risk of mucosal insult. Enhancement of carbohydrate substrate availability to the distal colon microbiota may accordingly improve gut health by production of beneficial SCFA [short-chain fatty acids] and promotion of saccharolytic bacteria.”2bb In another paper,2c the authors found that higher degree of polymerization of LCFOS fructans preferentially supported the growth of bifidobacteria in rats; the bifidobacteria group includes many gut bacteria found to be beneficial in humans, though this particular group does not produce hydrogen.

Another paper2d compares the effects of short chain versus long chain LCFOS. LCFOS and fructooligosaccharides are fructans (fructose oligosaccharides), which are fructose polymers used by plants to store carbohydrates. As noted in the paper2d “[i]ngestion of fructans is limited by various abdominal symptoms such as osmotic diarrhea, pain, bloating, and flatulence due to colonic fermentation and production of bacterial end-products,” including hydrogen gas. These side effects occur more frequently with the shorter-chain inulin fructans and with higher doses.2d “A dose of 5 g/d seems to be well tolerated,”2d whereas higher amounts may induce one or more of the aforementioned annoying side effects, primarily flatulence. A further way to limit the likelihood of having uncomfortable bloating from gas is to take a small quantity of simethicone to break up gas bubbles. See more on that below.

The longer chain fructans also had a longer transit time as compared to the shorter chain ones,2d which is likely to be advantageous in terms of reaching the lower digestive tract for fermentation by gut microbes.

Inulin Reduces Stink of Flatus Gas

One nice aspect of inulin is that, while it increases the gas output of your digestive tract, it reduces the “smelly” aspects of that gas. In one study of growing pigs,2 a 5% inulin extract (derived from chicory) was given as a dietary supplement and was found to significantly decrease the fecal excretion of skatole (the foul stench in farts that results from the microbial degradation of tryptophan) as compared to pigs fed the corn and soybean meal diet alone with no inulin supplementation. (Skatole, mg/kg, in the control group was 18.93 as compared to 9.07 in the inulin-supplemented animals). This study, published in the Journal of Animal Science, was funded, we suspect, by hog farmers hoping to destink their operations and reduce complaints by neighbors. Though we don’t suppose you get complaints from neighbors about your stinky farts, you’ll have one less thing to worry about if you take a dietary supplement that increases gas production by gut bacteria without the stench.

Benjamin Franklin on the Invention of Non-offensive Farts

Benjamin Franklin had plenty to say about farts, as in his published article, “To the Royal Academy of Farting” (c. 1781). There he proposed that the invention of ways to promote pleasant smelling wind would be of great benefit to mankind. He perceived serious social risks of “permitting this Air to escape and mix with the Atmosphere, [as it] is usually offensive to the Company, from the fetid Smell that accompanies it.” In fact, he noted, “all well-bred People therefore, to avoid giving such Offence, forcibly restrain the Efforts of Nature to discharge that Wind.” In fact, he warns ominously, this unnatural retention of gas as “[t]hat retain’d contrary to Nature, such as habitual Cholics, Ruptures, Tympanies, &c. often destructive of the Constitution, & sometimes of Life itself. Were it not for the odiously offensive Smell accompanying such Escapes, polite People would probably be under no more Restraint in discharging such Wind in Company, than they are in spitting, or in blowing their Noses.”

Thus, Franklin proposed that there should be a prize made available “[t]o discover some Drug wholesome & not disagreeable, to be mix’d with our common Food, or Sauces, that shall render the natural Discharges of Wind from our Bodies, not only inoffensive, but agreeable as Perfumes.” “For the Encouragement of this Enquiry, (from the immortal Honour to be reasonably expected by the Inventor) let it be considered of how small Importance to Mankind, or to how small a Part of Mankind have been useful those Discoveries in Science that have heretofore made Philosophers famous ... What Comfort can the Vortices of Descartes give to a Man who has Whirlwinds in his Bowels!”

“And surely such a Liberty of Expressing one’s Scent-iments, and pleasing one another, is of infinitely more importance to human Happiness than that Liberty of the Press, or of abusing one another, which the English are so ready to fight & die for.”To read the entire essay by Franklin, if you must, see URL: http://www.TeachingAmericanHistory.org/library/ index.asp?documentprint=470

Using a GRAS Food Ingredient to Break Up Gas Bubbles to Reduce the Chances of Discomfort

We considered the use of a very wide variety of carbohydrates that are able to pass incompletely digested or undigested into the lower intestinal tract as fuel for fermentation by hydrogen producing colonic microbiota. Many carbohydrates that pass into the lower digestive tract would not be suitable for such use; for example, some dietary carbohydrates such as cellulose, and methyl cellulose are not digested in the upper digestive tract, but also pass through the lower digestive tract essentially unmetabolized. Human colonic microbiota cannot ferment them. Other carbohydrates such as lactulose or short and even medium-chain fructooligosaccharides are so rapidly fermented to release gases (mostly hydrogen, but some people’s microbiota also produce methane) that they can result in pain, bloating, and even explosive expulsion of foamy diarrhea, an embarrassing incident that may require a rush to the toilet and a change of pants, known colloquially as a “plotch.” (Sometimes science is not pretty.)

Durk found out many things by experimenting on his favorite guinea pig—himself—with many different types of carbohydrates in the development of a tolerable food for hydrogen producing resident colonic microbes. Some of these experiments were remarkably unpleasant, messy, and even painful. The final result was to identify a specific LCFOS as the type of carbohydrate that would reach the lower digestive tract, there to be fermented by intestinal microbes to produce hydrogen gas at the right places at the right rate.

There was still sometimes a problem, depending on other foods consumed, with the hydrogen being trapped as bubbles in the feces, which prevented venting the excess hydrogen without risk of a plotch. The addition of a GRAS (Generally Recognized As Safe) food grade physiologically inert silicone defoaming agent caused the bubbles to break and vent without unpleasant incident. With this addition, we can consume a carefully selected LCFOS at doses discovered by experiment to increase gas production without discomfort or (needless to say) plotches.

As we mentioned above, the amount of gas released differs among individuals in response to the ingestion of nondigestible carbohydrates (prebiotics) that are the fuel gut microbiota convert to hydrogen and short chain fatty acids. Though we have chosen a specific prebiotic (LCFOS) for our own use to help avoid that problem, there is still a possibility that some people may release enough gas to cause bloating and discomfort. To help prevent this, we suggest the use of simethicone, an FDA approved GRAS, Generally Recognized as Safe, dietary ingredient used daily by many millions of people to relieve the discomfort of gas. It is synthetic but quite safe and really works.

Dietary Ingestion of Inulin May Increase Satiety in Response to Food Intake

A paper3b examined the effects of either inulin or oligofructose on gastrointestinal peptides that have been shown to play a role in food intake or satiety. The authors had previously found that the addition of inulin-type fructans at the dose of 10% (w/w) in the diet for several weeks decreased triglyceride (fat) accumulation in the liver and epididymal mass, both in normal and obese Zucker fa/fa rats. “Most of the effects of inulin-type fructans on lipid metabolism correlated with a decrease in food-derived energy intake, mainly due to a lower calorific value of the fructans-containing diet.” The authors wanted to find out what mechanisms were responsible for the satiating effect of inulin-type fructans.

Gastrointestinal peptides that have been identified as being important modulators of appetite through peripheral (vagus nerve) effects and/or by acting directly on the arcuate nucleus of the brain include GLP-1 (glucagon-like peptide-1), oxyntomodulin and PYY. Hence, the authors looked at the effects of inulin-type fructans of different degrees of polymerization on GLP-1 and PYY in male Wistar rats—oligofructose, oligofructose-enriched inulin, and LCFOS. Portal concentration of both peptides was almost doubled after oligofructose treatment. Moreover, they cite a human study in which human volunteers taking about 20 g oligofructose/d for 7 d increased serum GLP-1 (see 3c).

Selected Studies on the Use of Hydrogen in the Prevention or Treatment of Disease

There are many reports of hydrogen therapy in the literature, with more being published at a rapid pace. We mention here a few examples.

Water Containing Dissolved Hydrogen Prevented the Decline in the Proliferation of Progenitor Neural Cells and Impairment of Cognitive Function in Stressed Mice

“Here we show that when chronic physical stress was applied to mice, continuous consumption of hydrogen water reduced oxidative stress in the brain, and prevented the decline in the proliferation of progenitor neural cells and the impairment of cognitive function.”4 In this study, hydrogen water (3.5 ml at 0.8 μM) was placed into the stomach of each rat by a catheter. Thus, the hydrogen water may have prevented the impairment of neurogenesis that is reported to occur in stressed animals.

Inhalation of Hydrogen Gas Reduces Infarct Size in the Rat Model of Reperfusion Injury in Heart Attacks

While the reintroduction of blood flow during a heart attack by, for example, drugs that break up blood clots, can improve the survival of experimental animals or humans, it also leads to heart damage as a result of reperfusion. The reperfusion damage has been attributed largely to hydroxyl radicals.5 It has been noted that “[s]tudies in animal models of acute myocardial infarction show that reperfusion injury accounts for up to 50% of the final size of a myocardial infarct.”5 In one study,5 hydrogen gas administered to isolated, perfused rat hearts, enhanced the recovery of left ventricular function following anoxia-reoxygenation. In another part of the study, rats were subjected to coronary artery occlusion for 30 minutes followed by reperfusion for 24 hours. Hydrogen gas was administered at the onset of ischemia (reduced blood flow) and continued for 60 minutes after reperfusion.

Even though blood flow was impaired in the ischemia myocardium, hydrogen gas levels were increased by the administration of the gas. “The peak level of hydrogen in the ischemic myocardium was reached at approximately two-thirds of the value observed in the non-ischemic myocardium.”5 “In the absence of H2 gas inhalation, infarct size following ischemia-reperfusion was 41.6 ± 2.5% of the area at risk; by comparison, inhalation of 0.5–2% H2 gas significantly reduced infarct size, with 2% H2 gas providing the most prominent effects (21.2 ± 1.6% area at risk).”5

In another study,6 hydrogen-rich saline protected rat myocardium against ischemia/reperfusion injury. In this study, the hydrogen was administered as an intraperitoneal injection before reperfusion in animals that underwent 30 min. occlusion of the left anterior descending coronary artery followed by 24-hour reperfusion.

Cultured Chondrocytes From Hog Cartilage or From Rat Meniscus Fibrecartilage Protected From Oxidative Stress and Peroxynitrite Derived From Nitric Oxide
We Hypothesize That Hydrogen May Reduce Pain, Too

Interestingly, peroxynitrite, a potent oxidant derived from the chemical reaction of superoxide radicals with nitric oxide, has been linked to PAIN; hence, reducing peroxynitrite may be an effective way to decrease pain associated with oxidative stress/inflammation-induced arthritis.6a,6b In fact, another paper6c discussed different types of pain and the role played by superoxide and peroxynitrite but proposes targeting peroxynitrite over that of superoxide because of the physiological signaling of superoxide. “It may be PN [peroxynitrite] is a more attractive target, in that unlike SO [superoxide] it has no currently known beneficial role.”6c Since hydrogen preferentially scavenges hydroxyl radicals and peroxynitrite over that of superoxide and hydrogen peroxide, it may be beneficial in pain relief, though we have not yet seen a published paper where this hypothesis is tested experimentally. A review paper6d on reactive oxygen and nitrogen species in pain agrees with other researchers “targeting PN [peroxynitrite] may be a better therapeutic strategy [for treating pain] than targeting SO [superoxide]. This is because, unlike PN, which has no currently known beneficial role, SO may play a significant role in learning and memory.”

Researchers7 treated cultured chondrocytes with SNAP (S-nitroso-N-acetylpenicillamine), a donor of nitric oxide, in the presence or absence of H2. “It is known that the matrix proteins of cartilage (including aggrecan and type II collagen) and matrix metalloproteinases (such as MMP3 and MMP13) are down- and up-regulated by ONOO- [peroxynitrite], respectively. H2 restoratively increased the gene expressions of aggrecan and type II collagen in the presence of H2. Conversely, the gene expressions of MMP3 and MMP13 were restoratively downregulated with H2. Thus, H2 acted to restore transcriptional alterations induced by ONOO.”7 The researchers concluded that “... novel pharmacological strategies aimed at selective removal of ONOO- may represent a powerful method for preventive and therapeutic use of H2 for joint diseases.”7

Consumption of Hydrogen Water Prevents Atherosclerosis in Apolipoprotein E Knockout Mice

Mice and rats are typically resistant to developing atherosclerosis. Hence, a common model for rodent atherosclerosis is to study animals knocked out for the Apo E gene, which makes them susceptible to atherosclerosis by reducing their ability to remove cholesterol from cells. In a study of Apo E knockout mice,7b treatment with hydrogen dissolved in water prevented the rapid atherosclerosis that usually occurs in these genetically disabled animals. Atherosclerotic lesions were found in the aortae of 6-month old Apo E knockout mice, whereas in Apo E knockout mice that had drunk hydrogen water, the volume of atherosclerotic lesion was significantly reduced.

The authors say that “[w]hen the preventive effect of atherosclerotic lesions in this study is compared with the previous data that Apo E-/- [Apo E knockout] mice was used, the efficacy of hydrogen water seems to be greater than folic acid, vitamin E, iron, and alpha-lipoacid [we assume they meant alpha lipoic acid]. “7b (references were given here and have been deleted). The reference to iron is an oddity, with the title of the paper cited suggesting that iron overload diminishes atherosclerosis in Apo E-deficient mice. The effect of iron overload in normal animals (without Apo E knocked out) would be expected to be the exact opposite, that is, to increase atherosclerosis.

Drinking Hydrogen Water Ameliorated Cognitive Impairment in Senescence-Accelerated Mice

The senescence-accelerated prone mouse 8 (SAMP8) is a frequently used model for the study of and treatment of age-related changes. In this recent study,8 researchers investigated the effects of drinking hydrogen water for 30 days on the spatial memory decline and age-related brain alterations in this animal model as compared to SAMR1 mice, senescence-accelerated resistant mouse 1. The results revealed increased brain serotonin levels and elevated serum antioxidant activity. Additionally, during 18 weeks of hydrogen water drinking, the researchers observed decreased neurodegeneration in the hippocampus, while marked loss of neurons in the hippocampus was noted in the control, aged mice receiving regular water.

Results included, for example, that the SAMP8 mice treated with hydrogen water had significantly faster escape latencies on days 5, 6, and 7 in the Morris water maze test (where they had to find a hidden platform in a pool of opaquely dyed water to escape drowning) as compared to the SAMP8 mice given regular drinking water without hydrogen gas dissolved in it. Then, on day 8, with the platform removed (oh no), the mice were observed for how much time they spent looking for the platform in its former location as a measure of memory retention. Though there was no statistically significant difference in time spent in the target zone between the SAMP8 mice receiving hydrogen water and those receiving regular water, the number of passes across the platform’s prior location was significantly higher in the hydrogen water treated SAMP8 mice as compared to the regular water receiving SAMP8 mice. This, the authors suggest, indicated that “HW [hydrogen water] prevented the loss of some cognitive abilities in the SAMP8 mice.”8

Hydrogen Saline Provides Neuroprotection Against Oxidative Stress in a Cerebral Ischemia-Reperfusion Model in Rats

Here,9 the authors investigated the possible protective effects of hydrogen saline against damage by hydroxyl radicals and peroxynitrite in a middle cerebral artery occlusion rat model of stroke. Hydrogen saline was found in the preliminary studies to significantly reduce the infarct ratio (dead/injured cells) when applied at 0 or 3 hours AFTER reperfusion, but there was only a slight reduction when injected at 6 hours after reperfusion. Hence, the remaining experiments in this study were performed with hydrogen saline administered 3 hours AFTER reperfusion. “Neurological scores were dramatically reduced in the MCAO [middle carotid artery occlusion] group (p<0.05 vs. sham) and hydrogen saline treatment at 3 h after reperfusion significantly improved the neurological function (p<0.01 vs. MCAO group) even though some neurological dysfunction was still observed (p<0.05 vs. sham group).” In other words, there was improvement in the hydrogen saline group, but their neurological scores did not recover to that of the control group not receiving MCAO treatment.

In addition, inflammation (as assessed by measures of the inflammatory cytokines Il-1beta and TNF-alpha (tumor necrosis factor-alpha) was decreased by hydrogen saline treatment. Oxidative stress can lead to inflammation following ischemic stroke; hence, the decrease in levels of IL-1beta and TNF-alpha indicated increased protection against oxidative stress.

The authors further note that the therapeutic effects of hydrogen saline were more profound than those they found in studies using hydrogen inhalation. Also, they found the effects of intravenous administration of hydrogen inferior to those of intraperitoneal treatment, which they propose “may be explained by rapid elimination of hydrogen through pulmonary gas exchange.”9

Hydrogen-Rich Saline Protects Against Intestinal Ischemia-Reperfusion Injury in Rats

In another study of hydrogen in an animal (rat) model of ischemia-reperfusion injury,9b the superior mesenteric artery of the small intestine was clamped and ischemia maintained for 45 minutes and then reperfusion initiated by the removal of the clamp. Assessed by microscopic examination, protection by hydrogen was observed. In addition, there were significant reductions in measures of inflammation (the cytokines TNF-alpha, IL-1beta, and IL-6), lipid peroxidation (MDA, malondialdehyde), and protein carbonyl and myeloperoxidase activity, while no significant changes were observed in the animals treated with nitrogen-rich saline.

Inhalation of Hydrogen Gas Suppressed Liver Damage in Mice Exposed to Ischemia/Reperfusion Injury

Another study of an animal(mouse) model of ischemia-reperfusion injury9c (reported by a different group of scientists from those performing the studies cited in 9b) showed protective effects in mice with complete occlusion for 90 minutes of the portal triad to the left lobe and the left middle lobe of the liver, followed by reperfusion for 180 minutes. Hydrogen inhalation suppressed liver cell death and reduced levels of serum alanine aminotransferase and malondialdehyde. In contrast, helium gas provided no protection.

Subjects at Risk of Metabolic Syndrome Show Improvements Following Treatment with Hydrogen Rich Water

Metabolic syndrome is a cluster of symptoms that, when severe enough, are categorized as diabetes 2. Risk factors for the metabolic syndrome include obesity, insulin resistance, hypertension, and dyslipidemia. A recent study10 examined the effects of treatment with hydrogen rich water on antioxidant status of 20 subjects for 8 weeks who were at risk of developing full-blown metabolic syndrome in an open label (not blinded) pilot study.

Though there was no significant change in fasting glucose levels during the 8 week study, there was a 39% increase (p<0.05) in antioxidant enzyme superoxide dismutase (SOD) and a 43% decrease (p<0.05) in thiobarbituric acid reactive substances (TBARS, a measure of lipid peroxide formation) in urine. Subjects also had an 8% increase in HDL-cholesterol and a 13% decrease in total cholesterol/HDL-cholesterol from baseline to week 4. The authors conclude: “The [hydrogen rich water generated via a magnesium stick] represents a potentially novel therapeutic and preventive strategy for metabolic syndrome.”10

Hydrogen-rich Water Improves Lipid and Glucose Metabolism in Patients with Type 2 Diabetes

In another study,10b 30 patients with type 2 diabetes controlled by diet and exercise therapy and 6 patients with impaired glucose tolerance were treated with hydrogen-rich water in a randomized, double-blind, placebo-controlled, crossover study. The patients received either 900 mL/d of hydrogen-rich pure water or 900 mL/d of placebo pure water for 8 weeks with a 12-week washout period between treatments. Intake of the hydrogen-rich water was associated with significant decreases in modified low density lipoprotein (LDL) cholesterol, small dense LDL, and urinary 8-isoprostanes (a measure of free radical oxidative damage) by 15.5% (p<.01), 5.7 %(p<.05), and 6.6% (p<.05), respectively. In 4 of the 6 patients with impaired glucose tolerance, the hydrogen-rich water normalized their oral glucose tolerance test.

As the authors explained, the modification of LDL by acetylation, carbamylation, glycation, glycoxidation, or oxidation lead to increased uptake of LDL by macrophages in the process of becoming atherogenic foam cells. Hydrogen-rich water was able to reduce the modification of LDL to gain a net electronegative charge, decreased small, dense LDL, and decreased urinary 8-isoprostanes, all of which would be expected to have anti-atherogenic effects. The researchers conclude that “a sufficient supply of this water may prevent or delay development and progression of T2DM [type 2 diabetes mellitus] and insulin resistance by providing protection against oxidative stress. However, because of the small sample of patients in this study, the results should be interpreted with caution.”10b

Hydrogen in Drinking Water Protects Mice Against Dopaminergic Cell Loss by a Parkinson’s Disease Toxin

A frequently used model of Parkinson’s disease is to treat rodents with MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a toxin that induces a Parkinson’s disease-like condition by damaging or killing dopaminergic neurons in the nigrostriatal area of the brain. Using this procedure, a study10c reported that a low concentration of hydrogen in drinking water of experimental mice reduced oxidative stress induced by MPTP and significantly decreased cellular 8-oxoguanine, a marker of DNA damage, and 4-hydroxynonenal, a marker of lipid peroxidation, as compared to controls (receiving regular water). Interestingly, the researchers reported that “[t]he effects of H2 water were dose-dependent, with a maximal effect at a much lower concentration (0.08 ppm) than saturated concentration of H2 (1.5 ppm).”10c

There is also a very recent review article on the effects of hydrogen in animal models of Parkinson’s disease.10d

Molecular Hydrogen Protects Rats Against Neurotoxin-induced Degeneration in a Rat Model of Parkinson’s

In a different study10e using the neurotoxin 6-hydroxydopamine-induced nigrostriatal degeneration in rats as a model for Parkinson’s disease, researchers found hydrogen in water (~50% saturated) prevented both the development and progression of nigrostriatal degeneration as compared to rat’s drinking water containing no dissolved hydrogen gas. In this study, they found protective effects of both pre- and post-treatment of the neurotoxin-exposed rats to prevent dopaminergic cell loss.

Breath Hydrogen Correlated with Satiety in Healthy Humans Consuming Indigestible Carbohydrates in the Evening Meal

In another study,11 researchers examined the effect of including indigestible carbohydrates in the evening meal of healthy human subjects on glucose tolerance, inflammatory markers, and satiety in the next day’s breakfast. Breath hydrogen was measured as an indicator of fermentation of indigestible carbohydrates by colonic bacteria.

The evening meal was either enriched with barley kernel based bread, which contains high levels of low GI (glycemic index) indigestible carbohydrates in the form of HAB (high amylose barley kernels), HBB (high beta-glucan barley kernels) or OB (ordinary barley kernels) or with whole wheat bread flour. There was also a whole wheat bread that consisted of whole wheat + dietary fiber + RS (resistant starch). The results included finding that an evening meal of barley-kernel bread significantly improved glucose tolerance at the following standardized breakfast as compared to the whole wheat bread. In fact, the barley kernel bread (OB) reduced the IAUC (incremental area under the curve) for glucose during 0-120 minutes by 28% as compared to the whole wheat bread evening meal. Interestingly, the whole wheat bread + dietary fiber + resistant starch, which had a predicted glycemic index of 85 reduced the blood glucose after the standardized breakfast (0–120 minutes) by about 26% as compared to the whole wheat bread without the fiber and resistant starch. The authors suggest that maybe low GI isn’t per se necessary for the glucose tolerance advantage the next day. We’re not so sure—a predicted GI of 85 doesn’t constitute a measured GI.

One limitation of the study was that the subjects ate the test meals at home, so that except for filling out a written form, compliance could not be determined.

The researchers also reported finding that the evening meal with barley-kernel bread resulted in lower concentrations of IL-6 and higher concentrations of adiponectin, suggesting antiinflammatory properties of the barley-kernel bread. At breakfast, the hydrogen excretion (as measured in exhaled breath) correlated positively to reported satiety. The evening meal with the HAB (high beta-glucan barley kernels) resulted in a higher satiety score after the standardized breakfast as compared with all the other evening meals.

Are the Benefits of Decreased Carbohydrate Digestion by Alpha-Glucosidase Inhibitors Related to Increased Hydrogen Gas in the GI Tract

An interesting hypothesis paper11b asks whether the benefits (such as improved glucose tolerance and insulin sensitivity) that has been reported in studies of type 2 diabetics given alpha-glucosidase inhibitors (which reduce the ability of the upper digestive tract to digest dissacharides such as sucrose) might be due to increased hydrogen gas produced by gut microbes from the undigested dissacharides that reach the lower digestive tract.

This is something we have also wondered. The authors of this paper did an experiment to test their hypothesis. They examined whether the administration of alpha-glucosidase inhibitors increases the level of hydrogen production in the gastrointestinal tracts of 11 healthy volunteers. The volunteers received acarbose (a drug used in the treatment of diabetes that inhibits alpha-amylase and alpha-glucosidase) at a dosage of 300 mg/day (100 mg, three times a day) for 4 days under free feeding conditions. On day 4, they measured the levels of exhaled hydrogen and methane gases using a Breath Gas Analyzer Model TGA-2000 (TERAMECS, Kyoto, Japan) and found that acarbose treatment significantly increased the exhaled hydrogen at every time point examined as compared to the hydrogen exhaled prior to treatment. It was reported to have modest effects on methane production. (Two of the 11 volunteers had no changes in their hydrogen exhalation in response to acarbose.)

The authors propose that the amount of hydrogen gas produced as a result of acarbose treatment was sufficient (judging from other studies of hydrogen treatment) to reduce systemic oxidative stress.

Dietary Turmeric Increased Breath Hydrogen in Human Study

One way that may help to increase the hydrogen produced by your gut microbiota is to eat foods rich in turmeric (such as curries) or to take supplemental turmeric powder in capsules. (We didn’t include it in our inulin formulation, which is designed to be taken as a powder mixed with water or other liquid, because of the effect on flavor.) In a human study,12 scientists tested the hypothesis that turmeric might increase bowel motility by activating hydrogen-producing bacterial flora in the colon. They had eight healthy subjects consume a curry and rice dish either with or without turmeric. They then measured breath hydrogen every 15 minutes for 6 hours by gas chromatography with a semiconductor detector. They found that “[c]urry with turmeric significantly increased the area under the curve of breath hydrogen and shortened small-bowel transit time, compared with curry not containing turmeric.”

The graph showing breath hydrogen vs. time after ingestion of the meal showed that up to about 3 hours after eating, the turmeric containing meal increased breath hydrogen significantly as compared to the meal without turmeric. The curry without turmeric showed a slight increase in breath hydrogen at about one hour after the meal but this increase was not significant. “... breath hydrogen curves in both curry with turmeric and turmeric knockout curry indicated two peaks. The initial peak time, late peak time, and peak-to-peak time tended to be shortened by turmeric, but this was not statistically significant.”12

The researchers didn’t restrict the ingestion of food by study subjects that contained nondigestible carbohydrates before the experiment except asking them to fast (drinking water was OK) for the 12 hours before the ingestion of the test meals.

To explain what caused the initial rise in breath hydrogen following a meal (the postprandial state), the authors hypothesize that the so-called gastro-ileal reflex causes the entry to non-absorbable substrates into the colon. They further suggest that there could be non-absorbable carbohydrates left in the ileum from the previous meal. However, as they describe it, “the detailed mechanism of the initial rise of breath hydrogen has not been established.” In their study, the subjects eating the curry with turmeric ingested 0.5 g turmeric containing 5.48 mg curcumin, 1.62 mg demethoxycurcumin, and 1.15 mg bismethoxycurcumin, as well as other bioactive molecules present in turmeric, such as zingiberene, curcumenole, curcmol, eugenol, tetrahydroxycurcumin, triethylcurcumin, turmerin, turmerones, and turmeronols. The researchers didn’t identify which of these components was responsible for stimulating the increase in breath hydrogen.

One question we had was whether this study was really blind with respect to the subjects eating the meals. Could they tell when a curry contained no turmeric (which might effect both taste and color) and might this knowledge have an effect on the outcome of the experiment?

Determining Normal Flatus Production: More Complicated Than You Think

Just to add a little note of frivolity here, we point out that there have been studies (though not many) on the normal production of flatus in humans. In one such study,13 scientists report that on a fiber free diet (a liquid diet that contained no complex polysaccharides), hydrogen was almost absent from the flatus—there was less than 1–3 ml/24 hours of hydrogen in the flatus (one subject produced 21 ml) as compared to their normal diet, less than 3% of the amount produced on their normal diets. We suspect that the production of hydrogen in the gut by resident bacteria may contribute significantly to how dietary fiber provides important health benefits, such as reducing the risk of colon cancer and cardiovascular disease.

The procedure used by the scientists in the study described in reference #13 shows you what you have to go through just to determine what might seem to some a silly physiological measurement. There were ten healthy volunteers, five men and five women, aged 19–25 years (betcha they were starving students doing it for a few bucks). Flatus gas was collected by means of a flexible gas impermeable rubber tube held in place with surgical tape or the subject’s underwear that was attached at the other end to a plastic T-connector that was attached to a laminated gas bag impermeable to gas diffusion. The patency of the gas collection device was determined by having two volunteers wearing the device and having the lower parts of their bodies submerged in warm water for an hour during which time observers checked for leaks (bubbling) and that gas was collected in the bags.

Gas was collected separately for overnight, for the fiber-free liquid diet, as well as for a 24-hour period following test meals consisting of 200 g of baked beans in tomato sauce. Detailed instructions (which we will not go into here) were given to subjects as to how to proceed when they needed to defecate. The authors note that the liquid diet was sipped through a straw, resulting in some air swallowing, another complication of the determination.

And so, in this way, the scientists got measurements for the production of flatus by healthy young people. Of course, it could all be done again (not with the same subjects of course) for getting measurements of flatus produced by subjects consuming LCFOS-containing diets. Another simpler way to determine how much hydrogen is generated by colon bacteria is to measure breath hydrogen, as the hydrogen generated in the colon is eventually mostly excreted from the body in the lungs. You would still need to account for hydrogen taken up by gut bacteria for their own use. As the authors note, slower passage of gas through the colon allows more time for bacterial use of fermentation gases.

Protection by Hydrogen Against Radiation

As the damage caused by radiation is largely a result of hydroxyl radicals and hydrogen is a potent scavenger of hydroxyl radicals, it is unsurprising that studies have reported protection by hydrogen against radiation injury, though scavenging hydroxyl radicals is not necessarily the only mechanism of its protective effects. One study14 explained that “[t]he gastrointestinal tract is one of the most susceptible organs to radiation. As low as 1 Gy of radiation induces a dramatic increase in apoptosis [programmed cell death] in mouse small intestinal crypt within 3–6 h after exposure, predominantly in the stem cell region.” In their study, the researchers tested the protective effects of hydrogen-rich saline against gamma radiation to cultured lymphocytes and the gastrointestinal tract in mice. In the mice, for example, plasma SOD (superoxide dismutase) and GSH (glutathione) concentrations were significantly higher at 12 hours after irradiation in the hydrogen treated group as compared to the controls. The plasma malondialdehyde (a lipid peroxidation product) and intestinal 8-OHdG (a breakdown product of damaged DNA) concentrations at 12 hours of irradiation in the hydrogen treated group was significantly lower than that of the control group.

In another radiation study15 by the same group published in a different journal that same year, hydrogen-rich water was tested for its possible protection of the heart from damage by ionizing radiation in mice. The authors hypothesized that the hydrogen-rich water would protect against the hydroxyl radicals produced during irradiation. They found decreased myocardium degeneration, decreased myocardium malondialdehyde, decreased 8-hydroxydeoxyguanosine (8-OHdG) levels, and increased levels of endogenous antioxidants in the hearts of irradiated, hydrogen-water-treated mice as compared to irradiated but untreated mice.

Thus, hydrogen might be a useful prophylactic under conditions where you may be exposed to radiation. However, it is probably NOT a good idea to use hydrogen at the same time you are receiving irradiation therapy for cancer because of the risk that treatment effects (the desired toxicity of the radiation to cancer cells) would be reduced.

Possible Protection by Hydrogen Against Mitochondrial Diseases Involving Increased Oxidative Stress

One of the problems with the use of antioxidants in lifespan studies is that most antioxidants are not able to enter the mitochondria, where much of the generation of ROS (reactive oxygen species) takes place. In fact, proponents of the mitochondrial theory of aging propose that antioxidants have not generally been very effective in lifespan studies precisely because they are unable to target ROS in mitochondria and that mitochondria-targeted antioxidants are, therefore, needed. Hydrogen may be a good way to overcome that problem as it easily enters mitochondria.

A paper published early this year16 proposed the use of hydrogen “to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases.” The author included very preliminary evidence of possible improvements in small numbers of patients with mitochondrial disorders treated with hydrogen. As the author noted, the mechanism(s) for hydrogen’s beneficial effects are still unclear.

Improved Survival by Mice in a Model of Septic Shock

The authors of a recent paper17 report on the results of a study of mice in a model of multiple organ dysfunction syndrome (MODS), progressive deterioration of multiple organs as occurs, for example, in patients with severe sepsis, septic shock, shock, multiple trauma, severe burns, or pancreatitis. MODS is said to be the leading cause of death in critically ill patients.17

The mice were subjected to treatment with zymosan, a substance derived from the cell wall of the yeast Saccharomyces cerevisiae, that can lead to life-threatening systemic inflammation. The authors had already published a study18 in which hydrogen inhalation in septic mice (sepsis induced by cecal ligation and puncture) had been shown to significantly improve the survival rate and decrease organ damage. In their study of zymosan-induced generalized inflammation,17 the inhalation of 2% hydrogen for 60 minutes starting at 1 and 6 hours after zymosan injection significantly improved the 14-day survival rate of the injected mice from 10% (no hydrogen treatment) to 70% (hydrogen inhalation). Moreover, the zymosan-injected hydrogen treated mice had significant attenuation of damage markers and decreased levels of oxidative products, increased activities of antioxidant enzymes (such as superoxide dismutase), and reduced levels of early and late proinflammatory cytokines (tumor necrosis factor alpha and HMGB1) in serum and in tissue.17

CAUTIONARY NOTE ON THE CONSUMPTION OF HIGH FIBER DIETS
Fermentable Dietary Carbohydrates May Be Detrimental to Patients with Irritable Bowel Syndrome

Patients with irritable bowel syndrome (IBS) appear to be sensitive to increased “osmotic effects and gas production related to their rapid fermentation by bacteria in the small and proximal large intestine.”19 In fact, IBS patients may improve on a diet with low quantities of fermentable carbohydrates such as fructooligosaccharides. In a recent study,19 researchers studied 15 healthy volunteers and 15 patients with IBS for their response to either a low FODMAPs (Fermentable Oligo- Di- and Mono-saccharides and Polyols) or high-FODMAPs diet. The amount of hydrogen produced by subjects (the area under the curve) was significantly higher during the high-FODMAPs diet as compared to the low-FODMAP diet for both the healthy volunteers and the patients with IBS. On the other hand, IBS patients produced more hydrogen gas than healthy controls during both low-FODMAP and high-FODMAP diets. The only noticeable change in the healthy subjects was increased flatus, whereas the IBS subjects had significantly higher levels of typical IBS symptoms (abdominal pain, bloating, and flatus). The IBS group, but not the healthy controls, also had upper gastrointestinal symptoms and lethargy during the high fructooligosaccharides diet.

Reduction of short-chain poorly absorbed carbohydrates in the diet reduces symptoms of irritable bowel syndrome. Increased hydrogen produced in IBS from short chain fructooligosaccharides influenced the amount of hydrogen and methane produced and induced gastrointestinal and systemic symptoms experienced by patients with IBS; normals only experienced increased flatus. Hence, it may be inadvisable for IBS patients to consume diets enriched in fermentable carbohydrates.

How Can YOU Benefit from Hydrogen Protection?

A 2% (by volume) mixture of hydrogen in air is not flammable or explosive, but the equipment to reliably and accurately provide this breathing mixture is expensive and must be maintained by skilled technicians. We suspect that at some time in the future, hospitals will make this available for use by patients suffering from a wide variety of diseases involving free radical damage. Do NOT try this at home (unless you really are a rocket scientist). Remember the Hindenburg!

Water with hydrogen gas dissolved at saturation concentrations or less is safe, but must either be made immediately before use or kept in a tightly sealed glass or metal container. Hydrogen will quickly escape through ordinary plastic bottles. A further disadvantage of hydrogen water is that the duration of the hydrogen boost is short because the ingested dissolved hydrogen will quickly escape through your lungs. Nevertheless, animal experiments have shown substantial benefits from this route of hydrogen administration.

Continuous colonic bacterial fermentation generation of hydrogen is simple, safe, and provides sustained elevated tissue and blood levels of dissolved hydrogen gas. We have chosen this method for our own use. (Durk really is a rocket scientist and considered the 2% hydrogen in air approach, but decided that the LCFOS method was a lot safer, vastly less expensive, and just about as effective as hydrogen inhalation.)

We have carefully studied the scientific literature as to the amount of hydrogen produced, its time course of production, and the potential for discomfort from producing too much hydrogen too fast too far up in the gut. Of the many available fermentable fibers, we have chosen LCFOS, which we have combined with a small amount of foam breaking simethicone. We have found that without the latter, uncomfortable abdominal distention is more likely. Worse yet, without the foam breaker, one’s flatus can sometimes exit as a nasty brown fecal foam. You really don’t want to go there ...

References

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2. Hong et al. Hydrogen as a selective antioxidant: a review of clinical and experimental studies. J Int Med Res 38:1893-1903 (2010).
2a. Kaur et al. In vitro batch fecal fermentation comparison of gas and short-chain fatty acid production using “slowly fermentable” dietary fibers. J Food Sci 76(5):H137-42 (2011).
2b. Ito et al. Degree of polymerization of inulin-type fructans differentially affects number of lactic acid bacteria, intestinal immune functions, and immunoglobulin A secretion in the rat cecum. J Agric Food Chem 59:5771-8 (2011).
2c. Ohsawa et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Nat Med 13(6):688-94 (2007).
­­­­2d. Rumessen and Gudmand-Hoyer. Fructans of chicory: intestinal transport and fermentation of different chain lengths and relation to fructose and sorbitol malabsorption. Am J Clin Nutr 68:357-64 (1998).
2. Rideout et al. Excretion of major odor-causing and acidifying compounds in response to dietary supplementation of chicory inulin in growing pigs. J Anim Sci 82:1678-84 (2004).
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6. Sun et al. Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med 234:1212-9 (2009).
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6b. Yeo et al. Antinociceptive effect of CNS peroxynitrite scavenger in a mouse model of orofacial pain. Exp Brain Res 184(3):435-8 (2009).
6c. Janes et al. Anti-superoxide and anti-peroxynitrite strategies in pain suppression. Biochim Biophys Acta [online computer file] 1822:815-21 (2012).
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10b. Kajiyama et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res 28:137-43 (2008).
10c. Fujita et al. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. PLoS One 4(9):e7247 (2009).
10d. Fujita et al. Therapeutic effects of hydrogen in animal models of Parkinson’s disease. Parkinsons Dis 2011:307875-83 (2011).
10e. Fu et al. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci Lett 453:81-5 (2009).
11. Nilsson et al. Including indigestible carbohydrates in the evening meal of healthy subjects improves glucose tolerance, lowers inflammatory markers, and increases satiety after a subsequent standardized breakfast. J Nutr 138:732-9 (2008).
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© Copr. 2012 Durk Pearson & Sandy Shaw.® All Rights Reserved.

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