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Bleach and biome: Mice studies prove interesting.

It has become customary among our colleagues to discount clinical research performed on mice and only place value on human clinical trials. This has advanced to the point that one of the journals which I occasionally submit articles to now asks that I avoid any citations of animal studies.

Nevertheless, several recent animal studies strike me as being particularly relevant to our clinical practices and worthy of discussion despite the fact that the participants were mice. While the studies are on wildly different topics, their common denominator is that they turn our current understanding of things upside down.

One study suggests that exposure to dilute laundry bleach may protect cancer patients against radiation dermatitis. Two other studies suggest that creating a "leaky gut" is necessary for certain cancer chemotherapy drugs to be effective.

These studies have interesting implications, and it would be a shame to ignore them until human trials confirm their conclusions. Let's start with the bleach one first.

Thomas Leung, a dermatologist at Stanford University, conducted a pair of experiments with mice, bathing them in diluted bleach (hypochlorite). Diluted bleach has been used for years to treat eczema, without anyone's really knowing why it works. One theory was that bleach, being antimicrobial, killed off bacteria that were triggering the skin reaction. While this sounds plausible, the dilutions used were too weak to have antibacterial effect, so Leung looked elsewhere for an explanation. The bleach concentration used to treat eczema, 0.005%, is more dilute than that found in a swimming pool. The authors examined how bleach affects inflammation. Eczema, after all, is inflammation spun out of control.

They looked at nuclear factor-kappaB (NF-kB), as this signaling protein triggers the recruitment of inflammatory cells to sites of infection. Leung's team exposed human skin cells to the bleach dilution used to treat eczema for an hour and reported that this blocked NF-kB signaling. The bleach oxidizes the molecule that activates NF-kB, and by blocking this activator, the bleach completely inhibits the NF-kB inflammatory pathway.

This is more than a little relevant. NF-kB is kind of the common denominator of all bad things; it "regulates cellular responses to inflammation and aging, and alterations in NF-kB signaling underlie the pathogenesis of multiple human diseases."

The researchers then tried this dilute bleach solution in mice that were then exposed to radiation to see if it changed the expected burnlike irritation which this treatment normally causes. They also tested bleach on healthy old mice with aging skin.

In the radiation experiment, the mice were placed in either a dilute bleach bath or a water bath for 30 minutes daily for 10 days prior to radiation treatment. The radiation burns on these "bleached" mice were milder and healed faster than those on the mice that had only been exposed to water baths.

Similar benefits were seen in the old mice. Daily bleach baths "... increased skin cell production resulting in thicker, younger-looking skin than old mice that took plain water baths. In addition, they had lower expression of two genes classically associated with ageing. The effect was short lived, however. The rejuvenated skin returned to its elderly look after about two weeks because the action of bleach on NF-kB is mild, and diminishes with time." (1), (2)

This simple treatment could provide a means to reduce radiation dermatitis. Skin reactions can delay treatment and reduce effectiveness. Preventing them could have a positive impact on long-term statistics. While Leung experimented on mice, not humans, what is the risk in our patients' trying this? Sure, it may not work; but it seems unlikely to hurt, as people spend more time in swimming pools without ill effect.

It is not just reducing radiation dermatitis wherein bleach could play a role in cancer treatment. NF-kB "plays a critical role in cancer development and progression" and is a "a key pathway in activation of immune responses" and this "activation may also affect the cancer's response to therapy, making it less susceptive to radio and chemo treatment." (3) Many of the supplements that we encourage our cancer patients to take lower NF-kB. These include green tea, curcumin, quercetin, Nigella sativa, resveratrol and other polyphenols. (4-11) A daily bleach dip could help cancer patients in ways other than simply reducing injury from radiation therapy.

This study questions our near worship of antioxidants; bleach, after all, is the poster child of oxidizing chemicals. Many will find the very idea that an oxidant has beneficial action difficult to accept. This is backwards. Bleach should hurt, not help.

While this may make little sense to some of us, it made perfect sense to Edward Calabrese, the University of Massachusetts toxicologist who researches hormesis. You may recall that he spoke at the AANP conference at Keystone, Colorado, in the summer of 2013.

In toxicology, hormesis refers to the phenomenon exhibited by some substances in which a graph of their toxic effects takes on a J- or U-shaped curve. Low doses may produce the opposite effect of higher doses. Think of the law of similars in homeopathy but leaving out the infinitesimal dilutions. Concentrated bleach will burn the dickens out of your skin, but in small amounts will protect and heal it. The skin cells respond to the bleach, even in low doses, by turning on adaptive mechanisms to protect themselves from damage, and these same mechanisms once triggered protect against the oxidative damage caused by the radiation treatments.

When I shared this article with Calabrese, he responded, "It looks like yet another example of preconditioning hormesis. I suspect that if it would be studied in a detailed dose-response fashion, it would reveal the classic biphasic dose response."

Understanding hormesis may be key to our understanding many of the therapies that we regularly employ in practice. Plant biologists tell us that many of the phytochemicals which we value are actually produced by the plants to serve as protective toxins. Curcumin, resveratrol, quercetin, and the like are actually insecticides, antifungals, and neurotoxins that the plants make to ward off predators and infectious microrganisms. We take advantage of their hormetic actions. Exposure to these agents triggers an adaptive response in the human body, recruiting resources to neutralize potential injury.

Equally surprising to me as this bleach business is the role that the intestinal biome may play in cancer treatment. Two papers in Science (November 22, 2013) suggested that bacteria living in our intestines play an active role in the action of at least three chemotherapy treatments used by cancer patients. The papers actually suggest that (in mice) gut bacteria are necessary for chemotherapy to work. Cancer patients are often given antibiotics, and this may reduce the benefit of their subsequent chemotherapy.

Laurence Zitvogel is behind one paper. She reported that the chemotherapy drug cyclophosphamide requires translocation of intestinal bacteria out of the gut and into the spleen. In the spleen, these bacteria trigger Th17/Th1 production. Germ-free or antibiotic-treated mice have a weaker response to cyclophosphamide. (12) In the second paper, Dzutsev et al. suggest that gut bacteria are necessary for platinum drugs to work. Pretreatment of mice with antibiotics lessens this drug's action against implanted tumors. (13)

Patients given cyclophosphamide frequently develop digestive problems, and closer examination reveals that the drug has increased small intestine permeability, what we would call "leaky gut." This leakiness allows bacteria, in particular several kinds of gram-positive bacteria, to translocate and settle in the spleen and lymph tissue of treated mice. This translocation is key to the drug's potency. The bacteria trigger immature T cells to turn into Th17 cells, some of which then transform into memory cells, allowing a prolonged immune response against the tumor. In mice that were either bred to be germ free or treated with antibiotics that eliminate gram-positive bacteria, cyclophosphamide worked poorly; it no longer increased Th17 cells and treatment no longer shrank implanted tumors.

Dzutsev's team also treated cancer-implanted mice, first testing an immunotherapy treatment and then oxaliplatin. Pretreating mice with antibiotics to eliminate any microbial populations again limited the effectiveness of the chemotherapy treatments. The mice ceased production of tumor necrosis factor and the tumors did not shrink.

They next tested oxaliplatin. This drug increases reactive oxygen species (ROS), which leads to cancer cell apoptosis. In a study of mice implanted with various cancers, the researchers treated half with antibiotics before administering chemo. Within 3 weeks, 80% of the antibiotic treated mice had died. The mice not given antibiotics that still had normal intestinal flora fared far better; 80% were still alive.

In mice, at least, it appears that intestinal bacteria are necessary for certain types of chemotherapy to work. The researchers seem shocked to the extent that gut flora are necessary. Domino Trincheiri, one of the authors, is quoted: "We suspected that platinum therapy may involve some immune pathway on which the gut microbiota could have a modulating effect, but we were surprised by the extent to which inflammatory cell reactive oxygen species production was strictly dependent on the presence of gut microbiota."

These two studies certainly should bring caution to the routine, prophylactic, and almost cavalier use of antibiotics before or during chemotherapy, in particular with oxaliplatin or cyclophosphamide. These studies should also bring caution to our routine use of probiotics or therapies that reduce intestinal permeability. The specific types of bacteria that these researchers suspect are important in triggering these immune responses are not found in probiotic supplements. The probiotic products in common use are designed to lower immune responses, to calm the immune system; they lower TNF expression. Perhaps we should be using "nastier" bacteria, of the sort that we associate with triggering immune reactions?

If a "leaky gut" is necessary for these chemotherapy drugs to work, certain therapies that we have thought useful in the past may need to be evaluated afresh. Using L-glutamine and melatonin, which both help prevent or heal leaky gut, may impede the anticancer action of these drugs. (14)

On the other hand, supplements or treatments that increase intestinal permeability or worsen leaky gut, such as piperine or fasting, might help increase the cytotoxic effect of chemotherapy. (15), (16) This is totally the opposite of what we have tried to do. Up until now, reducing gut permeability and bacterial translocation has been the goal. (17) (Carbohydrate feeding, by the way, decreases bacterial translocation.) (18)

Many chemotherapy drugs cause bacterial migration, so perhaps this issue extends beyond oxaliplatin and cyclophosphamide. (19)

Bleach is good and probiotics are bad. If this doesn't give you pause, you are not paying attention. These are important ideas with potentially significant implications for our clinical practices. Granted that the studies were done on mice, and humans do not always copy what mice do; that is, human studies do not confirm the findings in studies on mice. Yet these studies may warn us of things to come, and we would be negligent to ignore their results.

Notes

(1.) Botelho A. Vastly diluted bleach may have protective effect on skin. New Scientist. 15 November 2013;18:28.

(2.) Leung TH, Zhang LF, Wang J, Ning S, Knox Si, Kim SK. Topical hypochlorite ameliorates NF-KB-mediated skin diseases in mice. I Clin Invest. 2013 Dec 2;123(12):5361-70. Full text: 10. I 172/JCI70895.

(3.) Berkovich L, Ron I, Earon G, Abu-Ghanem 5, Rimmon A, Lev-Ari S. The role of medicinal herbs with anti-inflammatory properties in prevention and treatment of cancer. jAnicle in Hebrew.] Harefuah. 2012 Nov;151(11):629-632,654.

(4.) Syed DN, Afaq F, Kweon MH, et al. Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. Oncogene. 2007 Feb 1;26(5):673-82.

(5.) Meng Z, Yan C, Deng Q, Gao DF, Niu XL. Curcumin inhibits LPS-induced inflammation in rat vascular smooth muscle cells in vitro via R05-relative TLR4-mAPK/NF-KB pathways. Acta Pharmacol Sin. 2013 May 6.

(6.) Capini C, Jaturanpinyo M, Chang HI, et al. Antigen-specific suppression of inflammatory arthritis using liposomes. I Immunol. 2009 Mar 15;182(6):3556-3565

(7.) Weng Z, Zhang B, Asadi S, et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One, 2012;7(3):e33805.

(8.) Yin Y, Li W, Son YO, et al. Quercitrin protects skin from UVB-induced oxidative damage. Toxicol App! Pharmacol. 2013 Jun 1;269(2):89-99.

(9.) Byun EB, Yang MS, Choi HG, et al. Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression. Biochern Biophys Res Commun. 2013 Feb 22;431(4):698-705. doi: 10.1016/j. bbrc.2013.01.056.

(10.) Vaillancourt F, Silva P, Shi Q, Fahmi H, Fernandes JC, Benderdour MI. Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis. Cell Biochem. 2011 Jan;112(1):107-117. doi: 10.1002/jcb.22884.

(11.) Zhu X, Liu Q, Wang NA, et al. Activation of Sirt1 by resveratrol inhibits TNF-ct induced inflammation in fibroblasts. PLoS One. 2011;6(11):e27081 doi:10.1371/ journal.pone.0027081.

(12.) Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013 Nov 22;342(6161):971-976. doi:10.1126/science.1240537.

(13.) lida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013 Nov 22;342(61611:967-970. doi:10.1126/ science.1240527.

(14.) SOzen 5, Topuz 0, Uzun AS, CetinkOnar 5, Das K. Prevention of bacterial translocation using glutamine and melatonin in small bowel ischemia and reperfusion in rats. Ann hal Chit. 2012 Mar-Apr;133(2):143-148.

(15.) Khajuria A, Thusu N, Zutshi U Piperine modulates permeability characteristics of Intestine by Inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomedicine. 2002 Apr:9(3):224-231.

(16.) Bark T, Katouli M, Svenberg T, Ljungqvist 0. Food deprivation increases bacterial translocation after non-lethal haemorrhage in rats. Eur I Surg. 1995 Feb;161(21:67-71.

(17.) J Bouritius H, van Hoorn DC, Oosting A, et al. Bacterial translocation is reduced by a specific nutritional combination in mice with chemotherapy-induced neutropenia. I Nutr. 2011 Jul;141(7):1292-1298.

(18.) Bouritius H, van Hoom DC, Oosting A, et al. Carbohydrate supplementation before operation retains intestinal barrier function and lowers bacterial translocation in a rat model of major abdominal surgery. Parenter Enteral Nutr. 2008 May-Jun;32(3):247-253.

(19.) Russo F, Linsalata M, Clemente C, D'Attoma B, Orlando A, Campanella G, Giotta F, et al. The effects of fluorouracil, epirubicin, and cyclophosphamide (FEC60) on the intestinal barrier function and gut peptides in breast cancer patients: an observational study. BMC Cancer. 2013 Feb 4;13:56. doi:10.1186/1471-2407-13-56.

by Jacob Schor, ND, FABNO

Jacob Schor, ND, FABNO, has practiced as a naturopathic physician in Denver, Colorado, with his wife, Rena Bloom, ND, since they graduated from National College of Naturopathic Medicine in 1991. He was humbled in 2008 when presented with the Vis Award by the American Association of Naturopathic Physicians (AANP). He has had the honor of serving the members of the Oncology Association of Naturopathic Physicians as a board member and currently as president. Dr. Schor began a term on the AANP's board of directors in January 2012. He is a frequent contributor to, and associate editor of, the Natural Medicine Journal.
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