|Ahead of print publication
The overlooked benefits of hydrogen-producing bacteria
Yusuke Ichikawa1, Haru Yamamoto2, Shin-ichi Hirano3, Bunpei Sato1, Yoshiyasu Takefuji4, Fumitake Satoh1
1 MiZ Company Limited, Kamakura, Kanagawa, Japan; MiZ Inc., Newark, CA, USA
2 MiZ Inc., Newark; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
3 MiZ Company Limited, Kamakura, Kanagawa, Japan
4 Data Science, Musashino University; Keio University, Tokyo, Japan
|Date of Submission||23-Jun-2021|
|Date of Decision||15-Jul-2021|
|Date of Acceptance||01-Sep-2021|
|Date of Web Publication||12-May-2022|
MiZ Company Limited, Kamakura, Kanagawa; MiZ Inc., Newark, CA
Source of Support: None, Conflict of Interest: None
Intestinal bacteria can be classified into “beneficial bacteria” and “harmful bacteria.” However, it is difficult to explain the mechanisms that make “beneficial bacteria” truly beneficial to human health. This issue can be addressed by focusing on hydrogen-producing bacteria in the intestines. Although it is widely known that molecular hydrogen can react with hydroxyl radicals, generated in the mitochondria, to protect cells from oxidative stress, the beneficial effects of hydrogen are not fully pervasive because it is not generally thought to be metabolized in vivo. In recent years, it has become clear that there is a close relationship between the amount of hydrogen produced by intestinal bacteria and various diseases, and this report discusses this relationship.
Keywords: Bacteroides; Firmicutes; hydrogen; hydrogen-producing bacteria; hydroxyl radicals; IgA antibody; naked mole-rats; oxidative stress; reactive oxygen species
| Introduction|| |
Nowadays, various foods containing lactic acid bacteria or bifidobacteria are consumed worldwide. In the food industry, intestinal bacteria are classified into “beneficial bacteria” and “harmful bacteria” for commercial purposes, where beneficial bacteria, such as lactic acid bacteria and bifidobacteria, are those that have positive effects on human health, whereas harmful bacteria are those that cause opportunistic infections and induce diseases, such as sepsis, in humans. More specifically, beneficial bacteria digest dietary fibers to produce various short-chain fatty acids, which lead inhibitory T cells to maintain homeostasis in the intestinal tract.
Amongst these intestinal bacteria, those that produce hydrogen, known as hydrogen-producing bacteria, are anaerobic bacteria that do not possess the enzymes to eliminate reactive oxygen species, such as superoxide dismutase and catalase, and thus cannot grow in the presence of oxygen. However, these hydrogen-producing bacteria do possess hydrogenases that allow for the production of hydrogen., Whether or not a certain species of bacteria is hydrogen-producing can be determined by the presence of this enzyme. Hydrogenases are enzymes that reversibly catalyze the formation and decomposition of molecular hydrogen through a redox reaction. Until recently, hydrogen has been long considered to be an inert gas that cannot be metabolized in the living body, and thus had been ignored by modern medicinal principles. Yet, hydrogen is a notable substance that should garner greater attention. Although some hydrogen-producing bacteria can be classified as “harmful bacteria” with pathogenic properties, its prevalence is very low in the intestines. Most species of this bacteria are deemed as “Beneficial Bacteria,” and in this paper, we focus on these hydrogen-producing bacteria that bring extraordinary benefits to human health.
| “Super-Beneficial Bacteria” - Hydrogen-Producing Bacteria|| |
A hydroxyl radical is an extremely toxic and highly reactive reactive oxygen species that is constantly generated in the mitochondria from birth until death. Since hydrogen is the smallest diatomic molecule, it can easily permeate mitochondrial membranes to react with these hydroxyl radicals and prevent cells from oxidative stress without any side effects. Hydrogen has clinical benefits in many diseases, including neurological diseases, cardiovascular diseases, respiratory diseases, diabetes, liver and metabolic syndrome. More than 1000 papers have been published on the medical applications of hydrogen, including over 90 reports of human clinical trials. These papers confirm that hydrogen is highly effective in the treatment of a variety of diseases and that there are no safety issues. Hydrogen molecules are the only species within the human body that can directly eliminate hydroxyl radicals inside mitochondria. Thus, the effects of hydrogen-producing bacteria outperform other beneficial bacteria, such as lactic acid bacteria and bifidobacteria, that cannot produce hydrogen. Nonetheless, hydrogen-producing bacteria have been neglected by modern medicine, even though they have these remarkable health benefits as “Super-beneficial bacteria.”
| Benefits of Hydrogen-Producing Bacteria: “Bacteroides” and “Firmicutes”|| |
It is said that there are more than 100 trillion intestinal bacteria from 1000 different species in our large intestine. Among these, 70% are hydrogen-producing bacteria that possess hydrogenase, an enzyme that catalyzes the metabolism of hydrogen, as well as the ability to metabolize carbohydrates to produce acetic acid and butyric acid.
According to a metagenomics survey, Firmicutes and Bacteroides are the most prevalent hydrogen-producing bacteria and account for 92% of bacterial species in the human large intestine, where 51% are Firmicutes and the other 41% are Bacteroides., It is known that Firmicutes and Bacteroides have beneficial effects on human health, but the mechanisms by which they incite these effects are relatively unknown. As previously mentioned, given that hydrogen was considered to be an inert gas that is not metabolized in the body, little research was focused on the mechanisms of action by Bacteroides. Now, the core principles of these mechanisms can be explained.
Bacteroides bind to dimeric IgA antibodies to form colonies that anchor in the mucus near intestinal epithelial cells, from which they constantly produce hydrogen. It is said that approximately 10 L of hydrogen are produced daily in the human intestines. Hydrogen eliminates hydroxyl radicals in the intestinal epithelial cells and protects the intestinal wall from oxidative stress. Surplus hydrogen molecules penetrate the cell membrane by diffusion, and a handful of these particles circulate the entire body through the bloodstream [Figure 1].
|Figure 1: Dynamics of hydrogen generated by Bacteroides settled in the intestinal wall.|
Note: (1) Bacteroides bound to dimeric IgA antibody form colonies in intestinal epithelial cells. (2) Bacteroides produce hydrogen. (3) The produced hydrogen eliminates hydroxyl radicals generated inside the intestinal epithelial cells and protects the intestinal wall from oxidative stress. (4) Hydrogen may also be involved in activating the metabolism of Firmicutes by colonies of Bacteroides. (5) Excess hydrogen diffuses across the membrane and surplus hydrogen enters the bloodstream to travel throughout the body.
Click here to view
Membrane permeability and diffusivity are two of the unique characteristics that separate hydrogen from other pharmaceutical agents. While the concentration of hydrogen produced by intestinal bacteria is dependent on the pH and carbohydrate content of the colon, once hydrogen enters into the bloodstream, it can circulate to the head, penetrate the blood-brain barrier, and protect brain cells from oxidative stress.,, Since molecular oxygen, a larger diatomic molecule than molecular hydrogen, can penetrate the blood-brain barrier for respiration in the brain, molecular hydrogen must also be able to penetrate the blood-brain barrier. It has been reported that there are less Bacteroides in the intestines of patients with dementia than in healthy individuals. Although this report does not explicitly mention hydrogen, we can imagine that low levels of hydrogen, due to the small number of Bacteroides, cause hydroxyl radical attacks on DNA, proteins, and other biological agents in brain cells, which in turn causes dementia.
The Bacteroides and dimeric IgA antibody colonies described above also promote the metabolic function of Firmicutes, another hydrogen-producing bacterium that dominates the human colon, thereby protecting against the development of enteritis. Firmicutes are also known as butyrate-producing bacteria, and there are reports that elderly people with long, healthy lives have significantly high levels of butyric acid bacteria in their intestines. Butyric acid produced by Firmicutes suppresses colorectal cancer via the p21 gene, and it is known that the number of butyric acid bacteria is significantly lower in patients with ulcerative colitis and Crohn’s disease. It is possible that this is not only due to the effects of butyric acid, but also due to molecular hydrogen produced by these butyric acid bacteria. The mucus-associated functional factor, a gene with an unknown function, is thought to activate Firmicutes. If we consider that hydrogen protects against the development of enteritis, it is possible that interactions between hydrogen-producing bacteria, such as Bacteroides and Firmicutes, contribute to the maintenance of human health. In fact, there is a report that shows that by delivering hydrogen to the gastrointestinal tract via the ingestion of hydrogen water and regulating the activity of hydrogen-producing bacteria, the clinical characteristics of intestinal microflora disorders can be improved.
Calico Life Sciences LLC (South San Flancisco, CA, USA), a subsidiary of Google that is conducting research and development aimed at preventing aging and its associated diseases, uses naked mole-rats (Heterocephalus glaber) as laboratory animals.,, Naked mole-rats have a 10-fold longer lifespan than normal rodents and have greater resistance to cancer. It has been reported that Bacteroides and Firmicutes predominate the intestinal bacteria of these mice. It is possible that hydrogen produced by Bacteroides and Firmicutes is involved in the longevity and cancer resistance of the naked mole-rats.
With these characteristics, hydrogen can play a key role in alleviating intractable diseases such as Parkinson’s disease and cancer, that are caused by oxidative stress, which is often impossible to improve by means of modern medicine and pharmaceuticals. This is another reason why hydrogen-producing bacteria are known as “super-beneficial bacteria.”
| Hydrogen-Producing Bacteria and Diseases - Hydrogen May Be Involved in the Gut-Brain Interaction|| |
Comparing diseases that are caused by dysbiosis to those that have been confirmed to improve with hydrogen, it is evident that there is a clear overlap between these two groups., For instance, diseases associated with Bacteroides include intractable diarrhea, Crohn’s disease, irritable bowel syndrome, systemic inflammatory response syndrome,, inflammation, Parkinson’s disease, rheumatism, cancer, arterial disease, dementia, and premature birth The diseases associated with Firmicutes include intractable diarrhea, Crohn’s disease, irritable bowel syndrome, systemic inflammatory response syndrome, ulcerative colitis, and depression. The pathogenesis of diseases related to dysbiosis is associated with a decrease in the supply of hydrogen to the body due to a reduction in the number of hydrogen-producing bacteria. Diseases such as Parkinson’s disease,, rheumatism, cardiovascular disease, and Crohn’s disease have been confirmed to have a clear association with a decrease in the number of hydrogen-producing gut bacteria or with a reduction in the concentration of hydrogen in exhaled air. Since the amount of antioxidant hydrogen produced by hydrogen-producing bacteria in the large intestine is significantly reduced, the possibility that biological substances in cells, such as DNA or protein, are damaged by hydroxyl radicals greatly increases. It has also been demonstrated that hydrogen in the intestines is effective against hepatitis induced by concanavalin A.
As described previously, hydrogen molecules that enter the brain can protect nerve cells from oxidative stress to improve diseases caused by cranial nerve disorders, such as depression and dementia. The bidirectional relationship between the brain and the intestines is referred to as the “brain-gut interaction” or the “gut-brain axis,” named by the Intestinal Microbiology Society, and hydrogen-producing gut bacteria may play a central role in this relationship.
It has been reported that (1) microbiomes, (2) oxidative stress, (3) inflammation, and (4) mitochondrial dysfunction are closely related to mental disorders. While the exact functions of hydrogen are not mentioned explicitly in these reports, it is easy to imagine that hydrogen plays a central role in the treatment of these diseases, considering that hydrogen produced by gut bacteria, or the “microbiome,” mechanistically reduce “oxidative stress” in various parts of the body, including the brain, to suppress both “mitochondrial dysfunction” and “inflammation.”
| Hydrogen May Bring a Healthy Longevity|| |
People who lack hydrogen-producing bacteria in their intestines can supply hydrogen to their bodies by inhaling hydrogen gas or by drinking hydrogen water. Hydrogen-producing bacteria not only produce hydrogen, but also produce energy through the decomposition of hydrogen using hydrogenase. Hydrogen-producing bacteria are also able to conserve energy by decomposing hydrogen with carbon dioxide to produce acetate and methane, or by reducing sulfate with hydrogen to generate hydrogen sulfide. As such, supplying hydrogen through these methods can in fact increase the number of hydrogen-producing bacteria in the body.
In a joint study with the Osaka University School of Medicine, it was revealed that the administration of hydrogen water to sepsis-induced mice models for 7 days suppressed bacterial translocation that was causing sepsis and also increased the number of Bacteroides in the intestine. The increasing number of hydrogen-producing bacteria consequently increases hydrogen production in the intestines and contributes to the maintenance of health.
Since a correlation between the concentration of hydrogen in exhaled air and the amount of hydrogen produced by hydrogen-producing bacteria has been reported in the past, the concentration of hydrogen in exhaled air can be used as a useful indicator of hydrocarbons metabolized by intestinal bacteria. It has been reported in the past that the concentration of hydrogen in Japanese people over 100 years of age is much higher than those of the elderly diabetics with an average age of 79 years. Although the concentration of hydrogen in exhaled air is affected not only by the number of hydrogen-producing bacteria in the intestinal but also the diet, the hydrogen produced by bacteria in the body may contribute to longer life spans by preventing oxidative stress. In the future, hydrogen may even contribute to immortality over healthy longevities. Hydrogen may be supplied via the inhalation of hydrogen gas without relying on hydrogen-producing bacteria. Although many people are skeptical about the medical benefits of hydrogen, it can help to improve people’s health. Hence, hydrogen-producing bacteria can be seen as “super-beneficial bacteria.”
We would like to thank Ms. Yoko Satoh and Mr. Mine Susumu (MiZ Company Limited) for their excellent advice upon writing this manuscript.
YI and FS designed and wrote the manuscript; SH, BS, HY, and YT supported this study by giving advice and revising the manuscript. All authors read and approved the final manuscript.
Conflicts of interest
YI, HY, SH, BS, and FS are employees of MiZ Company limited. The authors declare no conflicts of interest.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
| References|| |
Bourlioux P, Koletzko B, Guarner F, Braesco V. The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The Intelligent Intestine,” held in Paris, June 14, 2002. Am J Clin Nutr
Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature
Wolf PG, Biswas A, Morales SE, Greening C, Gaskins HR. H2 metabolism is widespread and diverse among human colonic microbes. Gut Microbes
Hylemon PB, Harris SC, Ridlon JM. Metabolism of hydrogen gases and bile acids in the gut microbiome. FEBS Lett
Ogata H, Nishikawa K, Lubitz W. Hydrogens detected by subatomic resolution protein crystallography in a [NiFe] hydrogenase. Nature
Hirano SI, Ichikawa Y, Kurokawa R, Takefuji Y, Satoh F. A “philosophical molecule,” hydrogen may overcome senescence and intractable diseases. Med Gas Res
Hirano SI, Ichikawa Y, Sato B, Yamamoto H, Takefuji Y, Satoh F. Potential therapeutic applications of hydrogen in chronic inflammatory diseases: possible inhibiting role on mitochondrial stress. Int J Mol Sci
Donaldson GP, Ladinsky MS, Yu KB, et al. Gut microbiota utilize immunoglobulin A for mucosal colonization. Science
Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med
Ostojic SM. Inadequate production of H(2) by gut microbiota and parkinson disease. Trends Endocrinol Metab
Perman JA, Modler S, Olson AC. Role of pH in production of hydrogen from carbohydrates by colonic bacterial flora. Studies in vivo and in vitro. J Clin Invest
Liu C, Kurokawa R, Fujino M, Hirano S, Sato B, Li XK. Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes. Sci Rep
Fukai Y. Molecular hydrogen for medicine: the art of ancient life revived. Singapore: Springer
Saji N, Murotani K, Hisada T, et al. The relationship between the gut microbiome and mild cognitive impairment in patients without dementia: a cross-sectional study conducted in Japan. Sci Rep
Nakajima A, Vogelzang A, Maruya M, et al. IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria. J Exp Med
Naito Y, Takagi T, Inoue R, et al. Gut microbiota differences in elderly subjects between rural city Kyotango and urban city Kyoto: an age-gender-matched study. J Clin Biochem Nutr
Archer SY, Meng S, Shei A, Hodin RA. p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. Proc Natl Acad Sci U S A
Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A
Ostojic SM. Hydrogen-rich water as a modulator of gut microbiota? J Funct Foods
Lewis KN, Rubinstein ND, Buffenstein R. A window into extreme longevity; the circulating metabolomic signature of the naked mole-rat, a mammal that shows negligible senescence. Geroscience
Grimes KM, Barefield DY, Kumar M, et al. The naked mole-rat exhibits an unusual cardiac myofilament protein profile providing new insights into heart function of this naturally subterranean rodent. Pflugers Arch
Orr ME, Garbarino VR, Salinas A, Buffenstein R. Extended postnatal brain development in the longest-lived rodent: prolonged maintenance of neotenous traits in the naked mole-rat brain. Front Neurosci
Debebe T, Holtze S, Morhart M, et al. Analysis of cultivable microbiota and diet intake pattern of the long-lived naked mole-rat. Gut Pathog
Yoritaka A, Abe T, Ohtsuka C, et al. A randomized double-blind multi-center trial of hydrogen water for Parkinson’s disease: protocol and baseline characteristics. BMC Neurol
Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science
Chen JB, Kong XF, Lv YY, et al. “Real world survey” of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients. Med Gas Res
Appanna VD. Dysbiosis, probiotics, and prebiotics: in diseases and health. Hum Microbes Power Within
Dixon BJ, Tang J, Zhang JH. The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. Med Gas Res
Wurm P, Spindelboeck W, Krause R, et al. Antibiotic-associated apoptotic enterocolitis in the absence of a defined pathogen: the role of intestinal microbiota depletion. Crit Care Med
Yoshida N, Emoto T, Yamashita T, et al. Bacteroides vulgatus and bacteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis. Circulation
Simrén M, Barbara G, Flint HJ, et al. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut
Ojima M, Motooka D, Shimizu K, et al. Metagenomic analysis reveals dynamic changes of whole gut microbiota in the acute phase of intensive care unit patients. Dig Dis Sci
Shimizu K, Ogura H, Goto M, et al. Altered gut flora and environment in patients with severe SIRS. J Trauma
Hasegawa S, Goto S, Tsuji H, et al. Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson’s disease. PLoS One
Vaahtovuo J, Munukka E, Korkeamäki M, Luukkainen R, Toivanen P. Fecal microbiota in early rheumatoid arthritis. J Rheumatol. 2008;35:1500-1505.
Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science
Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia
Shiozaki A, Yoneda S, Yoneda N, et al. Intestinal microbiota is different in women with preterm birth: results from terminal restriction fragment length polymorphism analysis. PLoS One
Ohkusa T, Koido S. Intestinal microbiota and ulcerative colitis. J Infect Chemother
Huang Y, Shi X, Li Z, et al. Possible association of Firmicutes in the gut microbiota of patients with major depressive disorder. Neuropsychiatr Dis Treat
Suzuki A, Ito M, Hamaguchi T, et al. Quantification of hydrogen production by intestinal bacteria that are specifically dysregulated in Parkinson’s disease. PLoS One
Suzuki Y, Sano M, Hayashida K, Ohsawa I, Ohta S, Fukuda K. Are the effects of alpha-glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Lett
Seksik P, Rigottier-Gois L, Gramet G, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon. Gut
Kajiya M, Sato K, Silva MJ, et al. Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochem Biophys Res Commun
Keshavarzian A, Engen P, Bonvegna S, Cilia R. The gut microbiome in Parkinson’s disease: A culprit or a bystander? Prog Brain Res
Kaplan BJ, Rucklidge JJ, Romijn A, McLeod K. The emerging field of nutritional mental health: inflammation, the microbiome, oxidative stress, and mitochondrial function. Clin Psychol Sci
Kurokawa R, Seo T, Sato B, Hirano S, Sato F. Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation. Med Gas Res
Ikeda M, Shimizu K, Ogura H, et al. Hydrogen-rich saline regulates intestinal barrier dysfunction, dysbiosis, and bacterial translocation in a murine model of sepsis. Shock
Aoki Y. Increased concentrations of breath hydrogen gas originated from intestinal bacteria may be related to peopleâs longevity in Japan. Paper presented at: 9th
Edition of International Conference on Preventive Medicine & Public Health; London. 2018.