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ionized alkaline water reduces HEMODIALYSIS-induced oxidative stress in END-STAGE RENAL DISEASE patients

 

Abstract

BACKGROUND:

Increased oxidative stress in end-stage renal disease (ESRD) patients may oxidize macromolecules and consequently lead to cardiovascular events during chronic hemodialysis. Electrolyzed reduced water (ERW) with reactive oxygen species (ROS) scavenging ability may have a potential effect on reduction of hemodialysis-induced oxidative stress in ESRD patients.

METHODS:

We developed a chemiluminescence emission spectrum and high-performance liquid chromatography analysis to assess the effect of ERW replacement on plasma ROS (H2O2 and HOCl) scavenging activity and oxidized lipid or protein production in ESRD patients undergoing hemodialysis. Oxidized markers, dityrosine, methylguanidine, and phosphatidylcholine hydroperoxide, and inflammatory markers, interleukin 6 (IL-6), and C-reactive protein (CRP) were determined.

RESULTS:

Although hemodialysis efficiently removes dityrosine and creatinine, hemodialysis increased oxidative stress, including phosphatidylcholine hydroperoxide, and methylguanidine. Hemodialysis reduced the plasma ROS scavenging activity, as shown by the augmented reference H2O2 and HOCl counts (Rh2o2 and Rhocl, respectively) and decreased antioxidative activity (expressed as total antioxidant status in this study). ERW administration diminished hemodialysis-enhanced Rh2o2 and Rhocl, minimized oxidized and inflammatory markers (CRP and IL-6), and partly restored total antioxidant status during 1-month treatment.

CONCLUSION:

This study demonstrates that hemodialysis with ERW administration may efficiently increase the H2O2- and HOCl-dependent antioxidant defense and reduce H2O2- and HOCl-induced oxidative stress.

 2003 Aug;64(2):704-14.
Reduced hemodialysis-induced oxidative stress in end-stage renal disease patients by electrolyzed reduced water.

Author information

1
Department of Family Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.

Studies and observations on the HEALTH effects of drinking electrolyzed-reduced alkaline water ( ionized)

B. Rubik Institute for Frontier Science, Oakland, California, USA

Abstract

Studies and observations on the health effects of drinking electrolyzed-reduced alkaline(ionized ) water Municipal drinking water, prefiltered and treated by partial electrolysis, followed by collecting the cathodic water that is alkaline (pH 8.5 to 9.5), shows a high negative oxidative reductive potential (ORP) (-150 to -250 mV) compared to untreated tap water (+150 mV) as well as smaller molecular clusters.

A growing body of literature indicates beneficial effects from drinking this electrolyszed (ionized) alkaline water by patients with diabetes and kidney disease, with improved outcomes and fewer medical complications. Additional studies suggest that this water increases the activity of a key detoxifying enzyme in the body, superoxide dismutase, which is central to protecting against free radical damage both in aging and chronic degenerative disease. Recent published studies on the health benefits of this drinking (alkaline ionized/electrolyzed reduced ) water are summarized. Evidence from live blood analysis from a case study suggests that drinking reduced alkaline water reduces blood cell stickiness, aggregation, and early clotting. Results suggest that long term consumption of this water slows the effects of aging and may improve the peripheral circulation; serve as an adjunct therapy for diabetes and kidney disorders; and help prevent cardiovascular and other chronic diseases.

1 Introduction

Water, which constitutes over 70% of the human body, is involved in virtually every function of life. It is an essential but often underrated necessity that is involved in most biochemical reactions; a constituent of the bodily fluids – blood, lymph, cerebrospinal fluid, saliva and other digestive fluids; joint lubrication; detoxification; and maintaining the blood pressure. Yet it is far more than just a constituent. A new science of water is emerging in which the structure and dynamics of water is much more complex than was previously thought. Water is a complex dynamic liquid sensitive and responsive to its environment. We are now in the midst of a paradigm shift in which liquid water is seen as an active agent rather than a passive constituent or universal solvent of life. For example, water and living systems are equally sensitive to a single quantum of magnetic flux [1]. Water shows long-range ordering features around cell membranes, where is it more like an epitaxial liquid crystal with distinct properties in those regions that radically distinguish it from bulk water [2] while chemically still remaining H2O. It used to be thought that water was passive, “dancing to the tune of biomolecules”, but now, water is considered the “matrix of life.” The greatest physiological change with aging is not within our biomolecules, but in the loss of water from the body. The body of a young infant consists of over 80% water, but that of a person over 70 years old is typically comprised of less than 60% water. There are many concerns about drinking water quality worldwide today. Many people choose to drink commercially bottled water for various reasons, but its healthfulness is questionable. Some device manufacturers claim that water treated by a vortex, electromagnetic fields, or other physical means to “energize” it, is more healthful than untreated waters and may also slow the aging process. In this paper, we review published evidence for the impact on health of drinking a particular type of water called “electrolyzed-reduced”(ionized alkaline) water and show observations from the blood.

2 Background and literature review

Alkaline mineral water with a relatively high negative oxidative reductive potential (ORP = -150 to -300 millivolts) and a pH over 8.0 is characteristic of natural mountain streams and certain deep wells. Aside from these natural sources, where can one find water with these properties? If this natural water were to be bottled, it would lose its high negative ORP and may react with plastic bottles that contain phthalates, toxic carcinogens. Nonetheless, one can generate water with these properties at point-of-use by using a device called a water ionizer. This is a commercially available water treatment system for the home that first filters the water through a multi-stage water filter to remove chlorine, chloramine, and other contaminants, and then performs partial electrolysis of the filtered water over platinum-coated titanium electrodes with a DC electric field. This yields 2 fractions: oxidized acidic water from the anode, and reduced alkaline water from the cathode. The reduced alkaline water appears to match most closely natural mountain spring water at the source in its physical properties and taste. This water is the subject of this paper. It has been called by various names: reduced, electrolyzed-reduced, and alkaline ionized water, to name a few. In this paper, we refer to it as ERW, “electrolyzed-reduced water.” The ERW fraction retains the alkaline ionic minerals from the tap water, including calcium and magnesium, which are important minerals for health, has a high negative ORP, an alkaline pH, a low level of dissolved oxygen, and is microstructured, with 5 to 6 molecules of water per cluster. It also has a lower surface tension than the starting tap water, which makes it a better solvent and may improve hydration.

Most of the studies on ERW have been conducted in Japan, Korea, and China. Not all of the research reports have been translated into English. Peer-reviewed studies from various laboratories worldwide show that ERW “electrolyzed-reduced” water aka (ionized alkaline) water , with its high negative ORP, scavenges free radical chemical species, protecting from oxidative damage. This, along with its alkalinity and microstructure, yield numerous health benefits. In addition, clinical reports, with or without controlled studies supporting them, further suggest that ERW produces declines in blood sugar levels in diabetic patients; improvements in peripheral circulation in diabetic gangrene; improvements in intestinal flora; declines in uric acid levels in patients with gout; improvements in liver function tests in hepatic disorders; improvements in gastroduodenal ulcer with prevention of recurrences; improved hydration and fluid replacement; and improvements in blood pressure in the case of either hypertension or hypotension. Here we summarize some of the key findings from the peer-reviewed literature on humans and other biological systems.

2.1 Active reducing agent and protection against oxidative stress

Shirahata et al. studied the properties of ERW “electrolyzed-reduced” water aka (ionized alkaline) water and reported that it showed a superoxide dismutase-like activity in protecting against oxidative damage, alleviating oxidative damage of DNA molecules and other species in vitro [3]. This antioxidant effect of ERW “electrolyzed-reduced” water aka (ionized alkaline) water has been verified [4]. The nature of the reducing species (antioxidant) in ERW “electrolyzed-reduced” water aka (ionized alkaline) water has been proposed to be active hydrogen and/or molecular hydrogen, but it is NOT the same as ordinary hydrogen gas and remains unresolved [5, 6]. One group reports that ERW contains both atomic and molecular hydrogen [7]. ERW “electrolyzed-reduced” water aka (ionized alkaline) water prevented oxidative cleavage of proteins and also stimulated the activity of free radical scavenger, ascorbic acid(vitamin C) [8]. Rats, upon drinking ERW “electrolyzed-reduced” water aka (ionized alkaline) water for just one week, showed significantly reduced amounts of peroxidized lipid in their urine, suggesting reduced oxidative stress in the rats [9]. These studies document that ERW has strong antioxidant activity. Antioxidant activity is important to protect cells and biomolecules from the toxic effects of oxidative damage associated with reactive oxygen species such as superoxide radicals that are associated with the biochemistry of inflammation and implicated as underlying factors in chronic disease.

2.2 Prolonged lifespan in nematodes and mice

It is well accepted that oxidative damaged mice compared to control mice fed tap water [10]. Landis and Tower showed that enhanced activity of superoxide dismutase, as has been demonstrated by various investigators using ERW, can reduce oxidative damage and extend life span [11]. A study on ERW used in the aqueous medium of the nematode (worm), C. Elegans in laboratory cultures showed that it significantly extended its lifespan, which has been interpreted to be at least in part due to the reactive oxygen species (ROS)-scavenging action of ERW [12].

2.3 Studies on kidney disease and use of hemodialysis

In end-stage kidney-diseased patients on dialysis, ERW “electrolyzed-reduced” water aka (ionized alkaline) water appears to have a beneficial effect on reduction of hemodialysis-induced oxidative stress. Huang et al. studied the reactive oxygen species in the plasma of these patients and found that ERW “electrolyzed-reduced” water aka (ionized alkaline) water diminished hemodialysis-enhanced peroxide levels, and minimized oxidized and inflammatory markers (C-reactive protein and interleukin-6) after 1 month of drinking ERW “electrolyzed-reduced” water aka (ionized alkaline) water . These findings suggest that cardiovascular complications (stroke and heart attack) in these kidney dialysis patients might be prevented by ERW [13].

Another study investigated use of ERW directly in the hemodialysis process of 8 kidney patients, and found that the viability of patients’ polymorphonuclear leukocytes was better preserved [14].

2.4 Studies on diabetes and blood glucose levels

Reactive oxygen species (ROS), such as superoxide and other free radical oxygen species, are known to cause reduction of glucose update by inhibiting the insulin-signaling pathway in cultured cells. Therefore, the scavenging of ROS is important to the control of diabetes. ERW scavenged intracellular ROS and stimulated glucose uptake in the presence or absence of insulin in rat L6 skeletal muscle cells and mouse 3T3/L1 adipocytes. This insulin-like activity of ERW was inhibited by wortmannin, a specific inhibitor of PI-3 kinase, a key molecule in insulin signalling pathways. ERW protected insulin responsive cells from sugar toxicity and improved the damaged sugar tolerance of type II diabetes model mice. This suggests that ERW may improve the status of those with insulin-independent diabetes mellitus [15]. Oxidative stress is produced under diabetic conditions and involved in progression of pancreatic beta-cell dysfunction. ERW in diabetic mice improved islet beta-cell function, resulting in increased release of circulating insulin and improved insulin sensitivity in both type I and type II diabetes [16, 17]. In a study on Otsuka Long-Evans Tokushima Fatty (OLETF) rats, ERW given to one group showed significantly lower blood glucose levels than controls given tap water. Moreover, blood levels of triglycerides and total cholesterol also decreased in the rats fed ERW [18].

A study on 411 type II diabetes patients whose average age was 71.5 years, who drank natural reduced water from the Nordenau Spring in Germany, up to 2 liters per day over 6 days, showed that 186 (45%) responded positively, with reduced blood glucose, improved cholesterol, LDL, HDL, and serum creatinine levels. 70.6% of a random sample of 136 of the patients also showed a decrease in blood ROS [19].

Recent bioelectrical impedance analysis studies showed that diabetics have a lower ratio of intracellular water (ICW) to extracellular water (ECW).

336 type II diabetics were recruited in a randomized, double-blind trial. The subjects received 250 ml of ERW or distilled water twice daily for 4 weeks. Results show that ERW consumption improved cell water distribution (ICW/ECW), basal metabolism rate, and cell capacitance during the 4-week period. The authors speculate that the relatively small size of the water molecule clusters in ERW may underlie the beneficial findings of improved cell structure and function [20].

2.5 Stimulation of anaerobic microflora in the human gut

The high negative ORP of ERW favors the growth of key anaerobic bacteria in the human gut that are important for normal intestinal microflora, health of the colon, and optimum nutrition [21]. 2.6 Lack of toxicity in microbes, cells, and animals ERW used up to a concentration of 100% in the Ames Test with Salmonella typhimurium did not show any bacterial mutations, either in the presence or absence of rat liver for exogenous metabolic activation. Similarly, ERW did not induce any chromosome aberrations in Chinese hamster lung fibroblast cells with or without rat liver, for up to 24 hours. Rats administered ERW at a dose of 20 mL/kg/day for 28 days via intragastric infusion did not show any clinical symptoms or toxic changes. These results demonstrate the expected safety for a 60 kg human to drink at least 1.2L/day of ERW [22]. Developing animals are the most sensitive to biological agents and are often used in studies to investigate toxicity. Thus, ERW was given to pregnant and also lactating rats to look for any effects. Development of rat fetuses and offspring were normal, and ERW increased the weight of the animals over controls. ERW was also found to have positive biological effects on postnatal growth. Moreover, postnatal morphological development was also accelerated [23]. No significant difference in milk yield or suckled milk volume was noted. It is suspected that the water-hydrated calcium cations transferred to the fetus through the placenta and to the offspring through the milk, might be the cause of the increased body weight, since calcium plays a key role in skeletal formation [24].

2.7 Inhibition of cancer but not normal cells

It is known that tumor cells produce ROS more abundantly than normal cells. It is also well known that antioxidants can inhibit tumor cell proliferation, which indicates an important role of ROS in mediating the loss of growth control. Human tongue carcinoma cells were shown to be significantly inhibited for either colony formation or colony sizes by ERW in cell cultures without inhibition to normal human tongue epithelial cells. ERW also caused growth inhibition, cell degeneration, and inhibition of invasion to human fibrosarcoma cells HT-1080. These studies suggest that ERW may help prevent tumor progression and invasion [25]. In vitro examination of leukemia cells (HL-60) treated with ERW showed enhanced mitochondrial damage and cell apoptosis. However, normal peripheral blood mononuclear cells showed no cytotoxic effect from ERW [26]. ERW also suppressed the growth rate of cancer cells transplanted into mice, demonstrating anti-cancer effects in vivo.

2.8 Protection of liver from toxic agents

Mice with carbon tetrachloride-induced liver damage given ERW showed significantly lowered serum levels of hepatic enzyme markers and increased activities of superoxide dismutase and other key detoxifying enzymes. The effects of ERW were similar to silymarin, an extract from milk thistle well known for its hepato-protective properties. Results suggest that ERW may be used to protect the liver against toxins that induce oxidative damage [27].

2.9 Conclusions from the literature review

These studies show impressive health benefits in humans and other biological systems from consumption of ERW over a very short time, and without any toxic effects observed. Clearly, ERW is a useful adjunct for treating ROS-associated diseases, including diabetes, kidney disease, cancer, and cardiovascular disease. In addition, due to its anti-aging effects in scavenging oxygen free radicals, ERW appears to be an excellent choice for regular water consumption, although its antioxidant activity is unstable upon storage. Nonetheless, it is easily produced from tap water at point-of-use.

3 Observations from live blood analysis

The blood is the most easily monitored tissue that can show rapid changes that correlate with health and disease. We have observed that persons drinking ERW show exceptionally clean biological terrains as monitored by live blood analysis. Live blood analysis is the visual examination of a small droplet of fresh capillary blood typically taken from the fingertip, put onto a glass slide, and immediately observed under a high-powered light microscope equipped with a dark-field condenser. This method offers a visual perspective of the blood cells and plasma at high magnification enhanced by modern optical techniques. It provides an assessment of the ecology of the blood, the “biological terrain”. Live blood analysis is used clinically to look for the malaria and Lyme disease parasites. Here we discuss it as a tool to assess blood cell stickiness, clumping, and coagulation and clotting processes, which are related to the activation of the inflammatory cascade.

A microphotograph from live blood analysis is shown in Figure 1. This is a photograph of normal healthy blood of a fasted female, age 37. The red blood cells (RBCs) are seen as single, free, round cells. Only a few platelet aggregates are seen in the plasma as grey areas. No RBC stickiness and no other clotting factors are found throughout the blood sample.

Figure 1: Normal healthy blood from female, age 37.

By contrast, Figure 2 shows the blood of a male, 65 years old. This blood is also typical of that found in many elderly persons. The RBCs are sticky and tightly clumped together in rouleau (rolls of coins seen on edge). Fibrin (white threads) is present, indicating that blood coagulation and clotting have been activated. This is the picture of systemic inflammation. Peripheral circulation was also impaired for this subject, because only single RBC can move freely through the smallest capillaries. Poor circulation in the extremities is a common complaint of the elderly.

Figure 2: Unhealthy blood from male, 65, showing blood congestion and clotting.

Following this test, the subject, M, age 65, drank 1 to 1.5 liters/day of ERW from a water ionizer for 6 months but made no other changes in diet or lifestyle. Figure 3 shows the blood from the same person after 6 months. The RBC stickiness, aggregation, and clotting factors are no longer present. It is particularly striking to see this change in an older person’s blood. Although this is a single case presented here, numerous other cases have been observed as well.

4 Conclusions

Chronic inflammation is considered to be one of the main underlying factors of virtually all of the chronic degenerative diseases, including cancer, cardiovascular, and autoimmune diseases. From observing changes in the biological terrain apparently due to consumption of ERW, it appears that ERW may be a useful intervention to mitigate activation of the clotting and inflammatory pathways. Long-term consumption of ERW may improve the blood circulation and possibly help prevent the chronic diseases of our times. Acid-alkaline balance is another key to health and wellness [28]. Metabolism of food leads to acid wastes, yet the biological terrain needs to be alkaline, pH 7.2-7.4. Drinking alkaline water such as ERW can contribute to neutralizing acid waste and maintaining proper pH balance in the body. In conclusion, a growing body of scientific and clinical literature shows increasing support for ERW as a “functional” drinking water that scavenges free radicals, diminishes systemic inflammation, and is a useful adjunct for treating ROS-associated diseases, including diabetes, kidney disease, cancer, and cardiovascular disease. From observations of the blood, it appears to mitigate early blood clotting and systemic inflammation seen as sticky, aggregated RBCs and fibrin. Collectively, this evidence points to ERW alkaline ionized water as a healthy drinking water

References

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[13] Huang, K.C., Lee, K.T., Chien, C.T., Reduced hemodialysis-induced oxidative stress in end-stage renal disease patients by electrolyzed reduced water. Kidney International 64(2), pp. 704-714, 2003.

[14] Nakayama, M., Kabayama, S., Nakano, H., Zhu, W.J., Terawaki, H., Nakayama, K., Katoh, K., Satoh, T., Ito, S. Biological effects of electrolyzed water in hemodialysis. Nephron Clinical Practice 112, pp. 9- 15, 2009.

[15] Oda, M., Kusumota, K., Teruya, T., Hara, T., Maki, t., Kabayama, S., Katakura, Y., Otsubo, K., Morisawa, S., Hayashi, H. Electrolyzed and natural reduced water exhibit insulin-like activity on glucose uptake into muscle cells and adipocytes. Animal Cell Technology: Products from Cells, Cells as Products, Proc of the 16th ESACT Meeting, April 25-29, 1999, eds A. Bernard, B. Griffiths, W. Noe, F. Wurm. Kluwer Academic Publishers: New York, Chapter VII, pp. 425-427, 2002.

[16] Kim, M.J., Kim, H.K. Anti-diabetic effects of electrolyzed reduced water in streptozotocin-induced and genetic diabetic mice. Life Sciences 79, 2288- 91, 2006.

[17] Kim, M.J., Jung, K.H., Uhm, Y.K, Leem, K.H., Kim, H.K. Preservative effect of electrolyzed reduced water on pancreatic beta-cell mass in diabetic db/db mice. Biological and Pharmaceutical Bulletin 30(2), pp. 234-236, 2007.

[18] Jin, D., Ryu, S.H., Kim, H.W., Yang, E.J., Lim, S.J., Ryang, Y.S., Chung, C.H., Park, S.K., Lee, K.J. Anti-diabetic effect of alkaline-reduced water on OLETF rats. Bioscience, Biotechnology, and Biochemistry 70(1), pp. 31- 37, 2006.

[19] Gadek, Z., Hamasaki, T., Shirahata, S., “Nordenau Phenomenon” – application of natural reduced water to therapy. Animal Cell Technology: Basic and Applied Aspects, 15, pp. 265-271, 2009.

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[21] Vorobjeva, N.V., Selective stimulation of the growth of anaerobic microflora in the human intestinal tract by electrolyzed reducing water. Medical Hypotheses 64(3), pp. 543-546, 2005.

[22] Saitoh, Y., Harata, Y., Mizukashi, F., Nakajima, M., Miwa, N. Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon mutagenicity, genotoxicity, and subchronic oral toxicity. Toxicology and Industrial Health 26(4), pp. 203-216, 2010.

[23] Watanabe, T., Effect of alkaline ionized water on reproduction in gestational and lactational rats. Journal of Toxicology Science 20(2), pp. 135-142, 1995.

[24] Watanabe T., Pan, I., Fukuda, Y., Murasugi, E., Kamata, H., Uwatoko, K. Influences of alkaline ionized water on milk yield, body weight of offspring, and perinatal dam in rats. Journal of Toxicology Science 23(5), pp. 365-71, 1998.

[25] Saitoh, Y., Okayasu, H., Xiao, L., Harata, Y., Miwa, N. Neutral pH hydrogen-enriched electrolyzed water achieves tumor-preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncology Research 17, pp. 247-255, 2008.

[26] Tsai, C.F., Hsu, Y.W., Chen, W.K., Ho, Y.C., Lu, F.J. Enhanced induction of mitochondrial damage and apoptosis in human leukemia HL-60 cells due to electrolyzed-reduced water and glutathione. Bioscience, Biotechnology, and Biochemistry 73(2), pp. 280-287, 2009.

[27] Tsai, C.F., Hsu, Y.W., Chen, W.K., Chang, W.H., Yen, C.C., Ho, Y.C., Lu, F.J. Hepatoprotective effect of electrolyzed reduced water against carbon tetrachloride-induced liver damage in mice. Food and Chemical Toxicology 47, pp. 2031-2036, 2009.

[28] Minich, D.M., Bland, J.S. Acid-alkaline balance: role In chronic disease and detoxification. Alternative Therapies 13(4), pp. 62-65, 2007. Water and Society

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Effects of Alkaline ionized Water on IRRITABLE BOWEL SYNDROME with Diarrhea

 A Randomized Double-Blind, Placebo-Controlled Pilot Study

Abstract

Objectives

The purpose of this study was to investigate whether the ingestion of alkaline-reduced water (ARW) is helpful in improving the symptoms of diarrhea-predominant irritable bowel syndrome (IBS).

Methods

Twenty-seven patients (male, 25.9%; mean, 41.7 years old) with diarrhea-predominant IBS were randomly allocated to two groups. For eight weeks, the ARW group (n = 13) ingested at least 2 liters/day of ARW, while the control group (n = 14) ingested placebo water. IBS symptom scores (quality-of-life, abdominal pain/discomfort), stool form, and frequency were assessed before and after treatment via questionnaires.

Results

Eight patients (61.5%) in the ARW group and six patients (42.9%) in the control group indicated that their symptoms had improved in more than four out of the eight weeks of treatment (p = 0.449). The IBS quality-of-life score significantly improved from 57.2 to 30.8 in the ARW group; this improvement was significantly greater than the slight improvement from 48.7 to 42.2 observed in the control group (p = 0.029). The abdominal pain score improved from 1.8 to 0.9 in the ARW group and from 1.8 to 1.1 in the control group, with no significant group difference (p = 0.232).

Conclusions

Drinking ARW for eight weeks improves the quality of life in patients with diarrhea-predominant IBS.

1. Introduction

Irritable bowel syndrome (IBS) is a functional intestinal disorder accompanied by abdominal pain and bowel habit changes, without evidence of an underlying injury. It is a very common disease, occurring in about 11% of people worldwide []. According to the Korean National Health Insurance System database, 5.1% of men and 6.9% of women were diagnosed with IBS []. IBS is one of the most common illnesses in primary care, with a repeated cycle of deterioration and relief over the years. Improving symptoms through appropriate treatment is important; IBS lowers the quality of life and increases medical costs []. Patients with IBS also suffer from anxiety, major depressive disorder, and chronic fatigue syndrome []. However, the cause and mechanisms underlying the various symptoms are not entirely understood. Many hypotheses have been proposed, including small bowel bacterial overgrowth syndrome, genetic factors, food hypersensitivities, gastrointestinal motility disorders, gut-brain axis alterations, hypersensitivity of the intestine, and psychosocial factors []. Recent studies indicate that the intestinal microbiota is one of the important factors affecting the onset of IBS [].

Various drugs have been used to improve symptoms, including antacids, antispasmodics, and drugs that stimulate gastrointestinal motility (prokinetic agents). However, with a lack of convincing evidence for a pathophysiological basis, conventional therapies have not achieved complete symptom improvement. Therefore, several alternative therapeutic methods, including dietary changes, probiotics, and other medications, have been proposed []. Furthermore, mineral water with various electrolyte compositions has been utilized in the treatment of functional gastrointestinal diseases; mineral water supplements have been reported to improve functional dyspepsia associated with IBS by controlling gastric acid output and intestinal transit time []. In addition, carbonated water not only attenuates the hunger but also improves dyspeptic symptoms and heartburn []. Drinking sulfur-rich mineral water for more than three weeks was found to be effective in treating constipation by increasing frequency of bowel movements []. Bicarbonate-containing alkaline-reduced water (ARW) has also been hypothesized to affect various digestive functions. Although animal studies have provided evidence that ARW is effective in treating functional bowel disease, human studies are lacking []. Therefore, the purpose of this randomized double-blind pilot study was to evaluate the effect of ARW ingestion on diarrhea-predominant IBS.

2. Methods

2.1. Ethical Approval

This study was conducted in accordance with the ethical principles for medical research involving human subjects in the Declaration of Helsinki. This study was approved by the Seoul National University Bundang Hospital Medical Ethics Committee (IRB number: E-1405/250-002) and aspires to protect the lives, health, privacy, and dignity of the research participants. Thus, the purpose and characteristics of the clinical trial were fully explained to the participants. Only patients who voluntarily signed an informed consent were included, and patients were allowed to stop participating at any time during the trial. All results obtained in this clinical study are confidential.

2.2. Study Population

Men and women aged 18–75 years who met Rome III criteria [] for diarrhea-predominant IBS, had no underlying disease of the colon on a sigmoidoscopy or colonoscopy performed within 5 years prior to screening, and could understand and respond to the symptom questionnaires were included. Rome III criteria for IBS involve recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months with two or more of the following: improvement with defecation, onset associated with a change in stool frequency, or onset associated with a change in stool form []. Diarrhea-predominant IBS involves loose or watery stools in more than 25% of bowel movements and hard or lumpy stool in less than 25% of bowel movements.

The following were excluded: patients with a psychiatric history; patients with untreated malignant tumors; patients with severe liver or kidney disease (AST, ALT levels 3-fold greater than the normal upper limit, and serum creatinine levels 1.5-fold greater than the normal upper limit); patients with severe heart failure; patients with acute gastrointestinal tract infection within the last 3 months. In addition, patients who were taking medications during the study period that could affect the results were also excluded. This included drugs that might influence IBS symptoms, such as antispasmodics, laxatives, prokinetics, anticholinergics, antianxiety drugs, antidepressants, analgesics, thyroid hormone, antibiotics, and steroids.

It is difficult to predict the therapeutic response rate between the test group and the control group since similar studies related to ARW have not existed before. This is a small-scale preliminary pilot study to investigate feasibility, adverse events, and improvement before a full-scale research project. This study was planned with 30 participants per group, which is the minimum number of participants recommended in a pilot study []. Given an estimated dropout rate of 15%, at least 35 people per group were planned to be enrolled.

2.3. Randomization and Allocation

Patients who were diagnosed with diarrhea-predominant IBS by Rome III criteria were equally allocated to experimental and control groups. Randomization was performed using a 1 : 1 computerized block randomization with a predetermined random code. Because both the investigator and the patients were blinded, a research coordinator performed the random assignment. The research coordinator did not provide information on randomization to the patients and researchers until the end of the study. Neither the participants nor the researchers could distinguish group assignments.

2.4. Study Design

A flowchart of the study design is provided in Figure 1. Patients completed screening tests (blood, urinalysis, colonoscopy, and a past medical history questionnaire) 1–3 weeks before participating in the study. Laboratory evaluation included assessments of liver function (albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels), kidney function (creatinine and blood urea nitrogen levels), electrolytes (sodium, potassium, chloride, calcium, and inorganic phosphorus levels), and the complete blood count (CBC).

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Schedule of patients participating in the study.

Baseline questionnaires on the IBS quality of life, abdominal pain/discomfort, stool form, and stool frequency were completed at the start of the study. The IBS quality-of-life questionnaire is an indicator of abdominal discomfort and consists of 34 items (each recorded as 1–5 points: 1: not at all, 2: slightly, 3: moderately, 4: quite a bit, and 5: extremely) []. Symptom scores for abdominal pain/discomfort were rated on a scale of 0–4 (0: asymptomatic, 1: mild, 2: moderate, 3: severe, and 4: very severe) and were based on the worst level of the day. Abdominal discomfort was defined as an uncomfortable sensation not described as pain. Stool form was assessed using the Bristol stool scale, which is a diagnostic tool designed to classify the form of human feces into seven categories. In general, types 1 and 2 (hard or lumpy stool) indicate constipation, and types 5–7 (soft or watery stool) indicate diarrhea []. In addition, the number of bowel movements was recorded daily.

The experimental group ingested ARW from an installed test device, while the control group ingested placebo water from a sham device. Both groups were instructed to ingest more than 2 liters per day for eight weeks. Participants visited the hospital every two weeks and completed self-administered questionnaires on compliance, adverse effects, the amount ingested, symptom scores (abdominal pain/discomfort), stool form, and the number of daily bowel movements. Questionnaires on the IBS quality of life were completed only at the end of the eighth week. If adverse events occurred during the trial period, participants were instructed to stop the medication immediately and visit an outpatient clinic.

The primary outcome was the proportion of participants with adequate symptomatic improvement in more than four weeks of the 8-week treatment period. The secondary outcomes were changes in IBS quality of life, symptom scores (abdominal pain/discomfort), and stool form/frequency.

2.5. Research Equipment

ARW with a pH of 8.5–10.0 was produced using an alkali water ionizer (Kim Young Kwi alkali water ionizer, KYK33000). Placebo water was prepared using a sham device (model name: sham KYK33000), which was not able to generate ARW, but had the same appearance as that of the test apparatus. The devices were installed at the patient’s home and patients were allowed to drink water as needed.

2.6. Statistical Analyses

Statistical analyses were performed using SPSS for Windows (ver. 22.0, IBM Corporation, Chicago, IL, USA) and STATA software (ver. 14.0, STATA Corporation, College Station, TX, USA). Group differences were evaluated using Student’s t-test for continuous variables and the Chi-square or Fisher’s exact test for categorical variables. Group differences in treatment-related changes in variables related to IBS (abdominal pain/frequency, stool form, and frequency of bowel movements) were evaluated using a linear mixed model with an interaction term between group and time (before and after treatment). Changes in the IBS quality-of-life score were evaluated using the paired t-test. Two-sided p values less than 0.05 were considered statistically significant.

3. Results

3.1. Baseline Characteristics

Only 29 were enrolled in the study and 2 dropped out during the study; because the patients were burdened with drinking more than 2 liters of water a day for a long time, we failed to enroll the intended 70 patients. Finally, 13 patients in the ARW group and 14 patients in the control group completed the study (Figure 2). There were no significant group differences in baseline characteristics (Table 1). Ten out of thirteen (76.9%) patients in the ARW group and ten out of fourteen (71.4%) patients in the control group were women. The mean age in the ARW group was slightly higher compared to that of the control group, but without statistical significance (43.3 versus 40.1, p = 0.584). At the beginning of the study, IBS symptom scores (quality-of-life, abdominal pain/discomfort), Bristol stool form, and stool frequency were not significantly different between the two groups. In addition, the consumption of water was similar in the two groups (ARW group: 2,124 ± 900 ml/day; control group: 2,052 ± 648 ml/day, p = 0.834).

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CONSORT flow diagram of patient recruitment.

Table 1

Characteristics of baseline demographics of patients.

Alkaline-reduced water group
(n = 13)
Control group
(n = 14)
p value
Female, n (%) 10 (76.9%) 10 (71.4%) 0.745
Mean age ± SD (years) 43.3 ± 14.4 40.1 ± 15.7 0.584
Initial symptom scores
 Quality-of-life score 57.2 ± 28.0 48.7 ± 26.4 0.428
 Abdominal pain 1.8 ± 0.9 1.8 ± 0.8 0.983
 Abdominal discomfort 1.8 ± 0.8 2.1 ± 0.8 0.362
 Stool form (BSFS) 5.3 ± 0.5 5.3 ± 1.4 0.939
 Stool frequency/day 2.6 ± 1.2 1.9 ± 1.0 0.130
Amount of water (ml/day) 2,124 ± 900 2,052 ± 648 0.834

SD: standard deviation; BSFS: Bristol stool form scale.

3.2. Primary Outcome Measure

Table 2 shows the number of responders (a favorable symptom improvement in more than four weeks of the eight-week treatment period) and nonresponders in each group. Although the proportion of patients responding to the treatment was higher in the ARW group (8/13, 61.5%) than in the control group (6/14, 42.9%), the difference was not statistically significant (Fisher’s exact test, p = 0.449).

Table 2

Proportion of responders who showed symptomatic improvement after treatment (primary outcome measure).

Alkaline-reduced water group (n = 13) Control group (n = 14) p value
Responder, n (%) 8 (61.5%) 6 (42.9%) 0.449
Nonresponder, n (%) 5 (38.5%) 8 (57.1%)

3.3. Secondary Outcome Measures

After eight weeks of treatment, the IBS quality-of-life score had improved from 57.2 to 30.8 points in the ARW group and from 48.7 to 42.2 in the control group (Table 3), with a significant group difference (Figure 3(a)p = 0.029). The abdominal pain score improved from 1.8 to 0.9 in the ARW group and from 1.8 to 1.1 in the control group, without a statistically significant group difference (Figure 3(b)p = 0.232). Abdominal discomfort, stool form, and stool frequency were somewhat improved in the ARW group; however, there were no significant group differences (Figures 3(c)3(e)).

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Graph of change before and after treatment of IBS. (a) Quality-of-life score. (b) Abdominal pain score. (c) Abdominal discomfort score. (d) Bristol stool form scale. (e) Stool frequency per day.

Table 3

Symptom scores of patients before and after treatment (secondary outcome measures).

Alkaline-reduced water group (n = 13) Control group
(n = 14)
p value
Quality-of-life score Week 0 57.2 ± 28.0 48.7 ± 26.4 0.428
Week 8 30.8 ± 24.9 42.2 ± 36.3 0.353

Abdominal pain Week 0 1.8 ± 0.9 1.8 ± 0.8 0.983
Week 2 1.6 ± 1.0 1.7 ± 0.8 0.796
Week 4 1.0 ± 0.9 1.4 ± 0.8 0.324
Week 6 0.8 ± 0.8 1.3 ± 0.7 0.123
Week 8 0.9 ± 0.8 1.1 ± 0.6 0.480

Abdominal discomfort Week 0 1.8 ± 0.8 2.1 ± 0.8 0.362
Week 2 1.9 ± 1.1 1.9 ± 0.7 0.964
Week 4 1.4 ± 1.2 1.6 ± 0.8 0.688
Week 6 1.0 ± 0.7 1.5 ± 0.8 0.113
Week 8 1.2 ± 0.9 1.3 ± 0.7 0.777

Stool form (BSFS) Week 0 5.3 ± 0.5 5.3 ± 1.4 0.939
Week 2 4.9 ± 0.8 5.1 ± 0.8 0.546
Week 4 4.5 ± 0.8 4.6 ± 1.0 0.791
Week 6 4.5 ± 0.8 4.4 ± 1.3 0.747
Week 8 4.7 ± 0.9 4.4 ± 1.0 0.313

Stool frequency/day Week 0 2.6 ± 1.2 1.9 ± 1.0 0.130
Week 2 2.5 ± 1.1 1.8 ± 0.7 0.073
Week 4 2.1 ± 0.9 1.7 ± 0.7 0.198
Week 6 2.0 ± 0.8 1.7 ± 0.9 0.349
Week 8 2.1 ± 0.9 1.7 ± 0.7 0.213

Week 0: the time of randomization; BSFS: Bristol stool form scale.

3.4. Adverse Effects

One of the patients in the control group visited the emergency room due to vomiting and abdominal pain during the second week of the study, but improved with conservative treatment. There were no specific adverse effects associated with ARW ingestion during the eight weeks of the trial.

4. Discussion

IBS is one of the most common gastrointestinal disorders in the general population []. In addition, because the effects of medications are often temporary, patients may increase the dose of the medication or take several medications, resulting in the occurrence of side effects. Thus, interest in alternative therapies that do not have side effects (even after long-term use) is growing []. Numerous animal studies have investigated the ability of controlling the electrolyte balance or acidity of the drinking water to treat functional gastrointestinal disorders. For example, animal studies have shown ARW to be effective in treating gastritis because it permanently denatures pepsin []. In addition, an animal study demonstrated that ingestion of more than 1.5 liters of bicarbonate-alkaline mineral water for 30 days improves dyspeptic symptoms []. It has also been suggested that a regular course of crenotherapy with bicarbonate-alkaline mineral water can be used to treat functional dyspepsia, improving gastrointestinal motility and secretory function by modulating the secretion of peptide hormones and regulating the movement of digestive organs []. These studies support the hypothesis that ARW can effectively treat IBS; however, prior to the present study, there were no supporting human clinical trials. Given this preclinical basis, we aimed to investigate whether ARW ingestion for eight weeks improved the symptoms of IBS.

This randomized controlled, double-blind, placebo-controlled study was designed to determine whether the ingestion of ARW could improve the quality of life, abdominal pain/discomfort, stool form, and stool frequency in diarrhea-predominant IBS. In terms of the primary endpoint, the proportion of responders (IBS patients who had improved symptoms in more than four weeks of the 8-week treatment period) was higher in the ARW group than in the control group, but the group difference was not statistically significant. This is likely due to the small number of patients who completed the trial; however, it is hard to predict an effect size, as no similar studies exist. We believe that a positive result could be obtained in a larger-scale study. In contrast to the primary outcome, a significant group difference was observed in the secondary outcomes. The IBS-related quality-of-life and abdominal pain scores were decreased to a greater extent with ARW ingestion compared to those with the ingestion of placebo water. This is a meaningful result because it demonstrates that it is possible to reduce IBS symptoms simply by ingesting water with a different pH, without taking any other medication. In addition, ARW has few adverse effects; thus, it shows potential in becoming an important complementary therapy for functional bowel disease. However, there were no significant group differences in the stool form and frequency improvements. At the beginning of the study, the frequency of bowel movements in both groups was 2-3 times a day, which is less than that for the definition of diarrhea (more than three times a day). Thus, the patients in both groups mainly had mild diarrhea, which may explain the lack of a significant change in symptom scores with treatment.

The mechanism by which ARW improves IBS symptoms remains unclear. ARW refers to water with a pH of at least 8.4; in contrast, most tap or bottled water has a pH between 6.7 and 7.4 []. ARW is thought to increase the pH level of the stomach given its large amount of bicarbonate ions. Interestingly, just infusing a small amount (0.1 mol/L) of acid into the stomach can aggravate indigestion in most people []. In addition, acidification of the duodenum exacerbates dyspeptic symptoms by inducing proximal gastric relaxation and inhibiting gastric accommodation to a meal []. In one animal study, duodenal acidification-induced gastric hypersensitivity could be the cause of dyspepsia in patients with IBS and serotonin 5-HT3 receptors play a key role []. Furthermore, in patients with pancreatic insufficiency, such as cystic fibrosis, the small intestine is exposed to an acidic environment, resulting in impaired absorption. Rapid neutralization of gastric acid in the proximal portion of the duodenum and tight regulation of the gastrointestinal pH play important roles in maintaining nutrient absorption and function in the intestines []. In addition, mineral water with a unique electrolyte composition may help improve the symptoms of indigestion []. Carbonated water could regulate gastrointestinal motility diseases by stimulating bile flow and pancreatic exocrine secretion. Furthermore, drinking carbonated water for more than 15 days has been shown to improve gallbladder muscle contractions []. The ingestion of water containing a lot of mineral salts has been shown to improve gastric emptying in patients with indigestion []. It is presumed that the various ions contained in mineral water directly or indirectly (via neuroendocrine secretion of vasointestinal peptides) stimulate the smooth muscle involved in gastrointestinal motility. These actions appear to improve the symptoms of IBS by improving intestinal transit time and excretory capacity. These actions are thought to not only reduce the bowel transit time, but also promote gastrointestinal hormone secretion, thereby improving abdominal bloating. We expect that large-scale studies on ARW with various electrolytic compositions will proceed in the future.

Gut microbiota appear to be one of the important factors contributing to the cause and pathophysiology of IBS []. Postinfectious IBS should be suspected when the patient complains of dyspepsia or abdominal discomfort after acute gastroenteritis []. Postinfectious IBS is thought to be due to persistent low-grade inflammation and alteration of gut flora intestinal microorganisms. The composition of gut microbiota is also associated with the pathophysiology of IBS and the host immune response []. Abundance of Cyanobacteria is associated with bloating, satiety, and increased abdominal discomfort. The amount of Proteobacteria is associated with pain threshold []. Therefore, it was suggested that probiotics, antibiotics, and fecal microbiota transplantation might be effective in the treatment of IBS []. Many gastrointestinal disorders, including IBS, are caused by an imbalance of residential microflora of the intestinal tract. Human intestinal microbiota consist of 96–99% anaerobes and 1–4% aerobes. Microorganisms have their own intrinsic reduction potential (Eh) for each species, and aerobic and anaerobic bacteria grow at different oxidation-reduction potentials. Aerobic bacteria require a positive potential of +400 mV and facultative anaerobic bacteria require negative electric potential between −300 and −400 mV. Electrochemically generated reduced water has a negative potential of 0 to −300 mV, while the tap water has a potential of +300 to +450 mV []. By drinking reduced water, it is possible to improve symptoms of functional bowel disease by accelerating the growth of anaerobic bacteria (Lactobacilli andBifidobacteria) and inhibiting the growth of aerobic pathogens.

The present study has some limitations. First, the statistical power was weak because of the small sample size. Second, patients with IBS tend to be somewhat less adherent due to the distrust of conventional therapies and hospitals. Third, although IBS is a highly prevalent disease, there were some difficulties in recruiting patients. Because the participants expressed difficulty in drinking more than 2 liters of water a day, we could not enroll as many patients as intended. In addition, subjects were already taking several medications before participating in the study, so it was not easy to stop them all and treat them with ARW only for 8 weeks. Patients’ compliance should be taken into account when designing large-scale studies on this topic in the future. Fourth, the lifestyle and diet were not controlled except for the medications. These confounding factors may be somewhat offset in the randomization process. Despite these limitations, the main strength of the present study is its randomized, double-blind, placebo-controlled design. Moreover, ARW is a simple and inexpensive treatment that physicians can easily consider in the treatment of IBS. To our knowledge, this is the first study to show whether ARW can improve IBS in humans, irrespective of the mechanism.

In conclusion, the present study suggests that ingestion of ARW can improve the quality of life and reduce abdominal pain in patients with diarrhea-predominant IBS. We hope that this pilot study provides a cornerstone for future large-scale trials on the effectiveness of ARW in the treatment of IBS.

 

Logo of ecam

Evidence-based Complementary and Alternative Medicine : eCAM
Published online 2018 Apr 15. doi:  [10.1155/2018/9147914]
PMCID: PMC5925025
PMID: 29849734
Effects of Alkaline-Reduced Drinking Water on Irritable Bowel Syndrome with Diarrhea: A Randomized Double-Blind, Placebo-Controlled Pilot Study
1Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea
2Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Dong Ho Lee: rk.oc.oohay@nhojlhd
Academic Editor: Senthamil R. Selvan
Received 2017 Nov 3; Revised 2018 Mar 4; Accepted 2018 Mar 6.

Acknowledgments

Statistical analysis support was provided by the Medical Science Research Institute in Seoul National University Bundang Hospital. This study was funded by a grant from Seongnam Industry Promotion Agency’s 2014 Medibio products clinical trial support program.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Dong Woo Shin analyzed the data and drafted the manuscript. Hyuk Yoon and Dong Ho Lee designed the study and revised the manuscript. Hyun Soo Kim, Yoon Jin Choi, Cheol Min Shin, Young Soo Park, and Nayoung Kim critically reviewed the manuscript. Dong Woo Shin and Hyuk Yoon have contributed equally to this work.

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