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Are the estrogenic hormonal effects of environmental toxins affecting small intestinal bacterial and microfilaria overgrowth?
Accepted Manuscript Are the Estrogenic Hormonal Effects of Environmental Toxins affecting Small Intestinal Bacterial and Microfilaria Overgrowth? Edward Lichten PII: DOI: Reference:
S0306-9877(17)30521-2 https://doi.org/10.1016/j.mehy.2017.09.022 YMEHY 8688
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
18 May 2017 6 September 2017 24 September 2017
Please cite this article as: E. Lichten, Are the Estrogenic Hormonal Effects of Environmental Toxins affecting Small Intestinal Bacterial and Microfilaria Overgrowth?, Medical Hypotheses (2017), doi: https://doi.org/10.1016/j.mehy. 2017.09.022
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Are the Estrogenic Hormonal Effects of Environmental Toxins affecting Small Intestinal Bacterial and Microfilaria Overgrowth?
(EL) Edward Lichten, M.D. Assistant Clinical Professor, Wayne State College of Medicine, Department of Obstetrics and Gynecology Corresponding and responsible author Edward Lichten, M.D. 555 S. Old Woodward Avenue Suite #700 Birmingham, Michigan 48009 Telephone: (248) 593.9999 Fax: (248) 593.9037 Email: [email protected] . No source of financial support
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ABSTRACT: The important role of microfilaria (worms) in human and animal disease remains an area of key disagreement between the naturopathic and allopathic physicians. While microfilaria infections are rampart in undeveloped countries, they rarely rise to identification as a cause of disease in Western countries. New research studies in the diagnosis and treatment of SIBO (Small Intestinal Bacterial Overgrowth) and (IBD) Inflammatory Bowel Diseases of ulcerative colitis, Crohn’s Disease and microcytic colitis may make both sides equally correct. A study of rifaximin failures in SIBO positive individuals finds biomarkers of decreased Free Androgen Index (FAI), high incidence of autoimmune disease and elevated Sex Hormone Binding Globulin (SHBG). The author hypothesizes that the underlying pathophysiology is increased exposure to Endocrine Disrupting Chemicals (EDCs) which hormonally act as xeno-estrogens. These xeno-estrogens increase the host production of SHBG, reduce pituitary stimulation of androgen product and result in a shift to estrogen dominance. Estrogen dominance is associated with autoimmune diseases and catabolic states. Treatment with a mixture of anabolic steroids that raises the FAI and lowers SHBG results in dramatic improvement in the signs and symptoms and recovery of the vast percentage of severe SIBO sufferers the author has treated. Similar results have been seen in severe pre-surgical cases of IBD whom fail all pharmaceutical interventions. Based on the recent recognition of the biological importance of Wolbachia in the occurrence of major diseases in the underdeveloped countries such as onchocerciasis, and the sexual nature of Wolbachia’s role in helminths reproduction, the author hypothesizes that the EDCs are shifting the host’s hormonal milieu in a more estrogenic direction and increasing reproduction of helminths changing the gastrointestinal microbiota. Present allopathic treatment of onchocerciasis utilizes albendazole and avermectin as therapy against the microfilaria larvae and doxycycline as bactericidal for Wolbachia. The allopathic treatments are unacceptable for pregnancy and children. Both naturopathic and allopathic treatments share a common focus on the suppression of the underlying bacterium Wolbachia infestation. The author hypothesizes that treatment of these two very different gastrointestinal diseases involves first establishing a normal, anabolic hormonal milieu and concurrently controlling an underlying yet unrecognized microfilaria overgrowth through naturopathic and allopathic treatments prescribed to the host. A case report of one such critically ill individual is noted. A thorough case controlled observation
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of symptoms matched with biological culture colony count and concentration of microfilaria in disease before and after the aforementioned anabolic treatment may answer the hypothesis.
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Introduction/ Background: Microfilaria1 refers to a “pre-larvae or advanced embryo” stage that exists prior to the first larva stage of certain parasitic nematodes/helminiths of the family Onchocercidae. While the adults live in a tissue or circulatory system of vertebrates (animals), the microfilariae are released into the blood stream where they migrate to just below the skin. Intact microfilaria can be sucked up intact into the mosquito (arthropod) with the bite, and subsequently enter the mosquito’s circulation. Here they mature to the first stage larvae. This vector continues with the mosquito biting another vertebrate animal. In the tissue-dwelling species, the eggs hatch in the uterus of the female and unsheathed microfilariae are released. In most blood-dwelling species, the microfilariae release embryonic eggs that are sheathed in the envelope of the egg. They are ‘hatched’ or ex-sheathed in the arthropod vector. In some species of Onchocercidae, the release of microfilariae by the adult female is periodic—occurring at a particular time of the day or night to increase chance of being picked up by the blood-feeding arthropod vector. The Wolbachia is a more primitive bacterial life-form than the parasitic nematode. The nematodes (parasitic worms) not only contain significant amounts of Wolbachia, but also the nematodes through transovarially transmission moves the bacteria from the adult female uterus to the offspring.2 The discoverers have identified the potential importance of these bacteria: (1). Bacteria-derived molecules should be considered as having an immunological and pathological role in filarial disease, as the nematodes are able to survive in immune competent hosts and (a.) Wolbachia2 manipulate of mast cell-mediated vasodilation to enhance infectivity of vector-borne larvae. (b.) Wolbachia2 is the principal driver of innate and adaptive Th1 inflammatory immunity which contributes to disease and enhanced infectivity. (c.) Wolbachia inserts a genome fragment into the host X chromosome necessary for female nematode fertility.3 The failure to do so leaves the nematode a male that grows and dies without reproducing. (2). As the Wolbachia bacteria are needed by the host nematode, they represent a target for therapy. It has been well known for more than 30 years that tetracycline, which kills intracellular bacteria, such as Wolbachia, also kills the nematodes Brugia pahangi and Litomosoides sigmodontis4. When doxycycline and ivermectin were used together, doxycycline(DOXY) dose: 10 mg/kg/day and ivermectin(IVM): 6 microgram/kg orally weekly, the resultant loss of both Wolbachia and nematoid DNA were similar to those of control worms, suggesting a loss of both Wolbachia and nematodes. Electron microscopy of nematodes recovered from the IVM/DOXY 4
combination group showed complete loss of immunohistochemistry for Wolchachia was negative5.
uterine
content
in
females
and
(3). The Wolbachia bacteria is necessary for the reproduction of the Onchocerca. Death and clearance of the Wolbachia after tetracycline treatment causes reproductive abnormalities in worms and affects worm’s embryogenesis, resulting in sterility6. Five prescription medications have been clinically tested for treatment of Onchocerciasis. 1. Anti-rickettsia: erythromycin and doxycycline. Chloramphenicol is less effective. 2. Anti-parasitic: ivermectin, abendazole and diethylcarbamazine (4). WALADin benzimidazoles modulate the function of prophobilinogen synthases orthologs. These medications have emerged as species-selective PBGS inhibitors against Wolbachia endobacteria of filarial worms. However, the medications may result in inhibition or stimulation of Pseudomonas aeruginosa depending on facts and pH.7 This implies that Wolbachia is linked to survival/ proliferation of Pseudomonas and other bacteria as well. Pseudomonas is implicated in the water of individuals at high risk for inflammatory bowel disease. 8 (5). While tetracycline as anti-Wolbachia therapy delivers safe macrofilaricidal activity and superior therapeutic outcomes compared to all standard antifilarial treatments, this therapy is contraindicated in children under 8 years of age and pregnancy.9 Therefore, the primary goal of the anti-Wolbachia consortium is to find drugs and regimens that reduce the period of treatment from weeks to 7 days or less and find drugs which would be safe in exclude target populations (children and pregnancy).9 Therefore, the goal of any treatment that destroys the Wolbachia or shifts the gender-preference from female to male of the Onchocerca proves to reduce the number of Onchocerca and improve the vertebral host health status akin to the present treatment for Onchocerca, river blindness. The potential drop in the concentration of the microfilaria in the microbiota by changing to a more androgenic milieu potentially changes the makeup of the gastro-intestinal microbiota and may correlate to symptom relief. Turner10 reported in a double-blind, in randomized field trial of 6 weeks of group (1) doxycycline 200mg/day alone or in combination with ivermectin 150mcg/kg/day or (group 2) placebo or ivermectin alone at four months. The combination treatment of doxycycline/ ivermectin had lower levels of microfilaridermia and high frequency of amicrofilaridermia compared with ivermectin or doxycycline only groups. At 12 months, 89% of the doxycycline/ ivermectin group and 67% of the doxycycline only group were amicrofilaridermic, compared with 21% of the ivermectin only group. 10 Of strong note, O. volvulus were completely depleted of Wolbachia and all embryonic stages in utero in the doxycycline group 10 and the sterilization was unaffected by ivermectin.10 5
Gayen11 in a placebo controlled field trial established that the combination of doxycycline/ (DOXY) (200mg/day) and albendazole (ABZ): 400mg/day provided the best efficacy by totally eliminating the circulating microfilaria (in 42% cases) on day 365 with (99.85%, P <.05) suppression; better than DOXY (69%, P<.05) and ABZ (89% P<.05). Gayen concluded “a 30day course of doxycycline and ABZ in combination is a safe and well-tolerated treatment for lymphatic filariasis with significant activity against microfilaremia”. 11 Tafatatha12 noted that doubling the standard dosage of ivermectin (IVM) and albendazole (ABZ) did not improve clearance rate of microfilaria based on count/ml. 12 Kar13 noted the higher and or more frequent dosing with ABZ with a fixed 300mg dose of diethylcarbazine resulted in only marginally greater clearance of lymphatic filariasis. 13 Kramer14 noted that in dogs with lung pathology from Dirofilaria immitis, that the combination of doxycycline/ DOXY (20mg/kg per os daily) with ivermectin/ IVM (6mcg/kg per os) for 24 weeks resulted in less severe arterial lesions and virtual absence of thrombi after intramuscular injection of melarsomine dihydrochloride at week 12. 14
SIBO Observation In light of known and published information comes a quandary of gastro-intestinal symptoms labelled Small Intestinal Bacterial Overgrowth Syndrome. 15 The symptom complex includes bloating, diarrhea, malabsorption, weight loss and malnutrition. Some diagnostic studies have confirmed a high concentration of colon bacteria in the small bowel/ jejunum. Some breathe testing of hydrogen/ methane after lactulose and glucose may be positive in a significant percentage of sufferers. The prognosis can be quite serious. The patients may appear suffering from extremely mal-nutrition and cachexia. Under normal physiological circumstances, there are several endogenous defense mechanisms for preventing bacterial overgrowth: gastric acid secretion, intestinal motility, intact ileocecal valve, immunoglobulins within intestinal secretion and bacteriostatic properties of pancreatic and biliary secretion. Human intestinal microbiota creates a complex polymicrobial ecology. This is characterized by its high population density, wide diversity and complexity of interaction. Any imbalance of this complex intestinal microbiome, both qualitative and quantitative, might have serious health consequence for a macro-organism, including small intestinal bacterial overgrowth syndrome (SIBO). SIBO is defined as an increase in the number and/or alteration in the type of bacteria in the upper gastrointestinal tract. There are several endogenous defense mechanisms for preventing bacterial overgrowth: gastric acid secretion, intestinal motility, intact ileo-caecal valve, immunoglobulins within intestinal secretion and bacteriostatic properties of pancreatic and 6
biliary secretion. Etiology of SIBO is usually complex, associated with disorders of protective antibacterial mechanisms (e.g. achlorhydria, pancreatic exocrine insufficiency, immunodeficiency syndromes), anatomical abnormalities (e.g. small intestinal obstruction, diverticula, fistulae, surgical blind loop, previous ileo-caecal resections) and/or motility disorders (e.g. scleroderma, autonomic neuropathy in diabetes mellitus, post-radiation enteropathy, small intestinal pseudo-obstruction). In some patients, more than one factor may be involved. Symptoms related to SIBO are bloating, diarrhea, malabsorption, weight loss and malnutrition. The gold standard for diagnosing SIBO is still microbial investigation of jejunal aspirates. Noninvasive hydrogen and methane breath tests are most commonly used for the diagnosis of SIBO using glucose or lactulose. Therapy for SIBO must be complex, addressing all causes, symptoms and complications, and fully individualized. It should include treatment of the underlying disease, nutritional support and cyclical gastro-intestinal selective antibiotics. Prognosis is usually serious, determined mostly by the underlying disease that led to S.I.B.O.28/16
This bacterial overgrowth has been confirmed in 45% of individuals with Crohn’s disease 17 and 17.8% of those with ulcerative colitis. The hydrogen/methane testing correlates with delayed orocecal transit time. In a second study, 26.5% of Crohn’s disease patients were considered SIBO.18 positive based on breath analysis testing. Percentage of methane positive IBD patients (2.9%) was significantly lower as compared to methane positive controls (24.4%) 18. Testing for ‘leaky-gut’ are inconclusive. For all practical purposes, therefore, the etiology of S.I.B.O.’s bacterial overgrowth is unknown. A mainstay of the treatment of Small Intestinal Bacterial Overgrowth19 (SIBO) has been the use of the aforementioned macrolide antibiotics and Rifampin/ Xifaxin®. The use of the antibiotic has resulted in reduction of methane production as noted in the Hydrogen/ Methane Breathe Analysis Test and reduction of symptoms, albeit temporarily, are noted. The high degree of treatment failures after 3 or more months is disheartening to both the patients who may repeat treatment time after time and the physician left without treatment options. Rifampin was suggested as an alternative for doxycycline for treating Wolbachia in children, albeit, less effective.20 However, rifampin does not improve clearance of Wolbachia over oytetracycline.19 Nor does ciprofloxin19. Rifamfin may in fact interfere with male-killing of Wolbachia.21 The complete minimum inhibitory concentration (mic) of 32 antibiotics to Wolbachia shows only doxycycline/ tetracycline and erythromycins to be most biologically active.22
Evaluation of the Hypothesis: Empirical Data: Case Report responding to Anti-helminth/ Nematode Treatment 7
SB is a 38-year old woman who presented with severe SIBO and fibromyalgia that left her unable to work and minimally able to care for herself and her family. She failed to respond to the aforementioned naturopathic products. Laboratory evaluation showed reduced FAI, positive tests for SIBO, autoimmune antibodies, and failure to respond to repeated treatments with rifaximin and other antibiotics. She was desperate to try alternative therapies. She reported initially no improvement with naturopathic products, but did show improvement initially to the nandrolone and stanozolol weekly injections. Then the medication lost effectiveness. After doubling and then quadrupling the nandrolone/ stanozolol injections to get relief from the severe SIBO symptoms, she had to discontinue the medications because of hirsutism and side-effects. She then developed tan stools and extreme abdominal pain. Naturopathic preparations including ox bile, digestive enzymes, and a litany of supplements were to no avail. The gastro-intestinal physicians at the major hospital in Boston were unable to make a diagnosis or initiate treatment. Her gallbladder X-ray, ultrasound and CT were normal. The author and naturopathic physicians made the diagnosis of severe pernicious anemia and initiated treatment with 5000 mcg of methyl-cobalamin intramuscularly every other day with dramatic improvement. Secondarily, as the tan stools persisted, they assumed ascending cholangitis and started a course of doxycycline and albendazole considering a microfiliaria infection of the gallbladder as the cause of the tan stools. The patient starting naturopathic Allimed™ and Neem Plus™. With this treatment, the patient has recovered. Ongoing treatment includes resuming the low dose nandrolone/ stanozolol weekly, praziquantel for unproven liver flukes, and the doxycycline and albendazole as microfilaridemic. Case Reports: SIBO Failures Respond to Anabolic Therapy The author reports23 in an unpublished peer-reviewed journal submission the successful management of 14 of 18 of the most severe SIBO cases with a novel mixture of anabolic steroids. These patients had failed Rifaximin® and naturopathic treatment with allicin/ Allimend® and Neem® Plus. He also reports that both pre-surgical Crohn’s and Ulcerative Colitis adult male and female patients24 responded miraculously to using the same combination of anabolic steroids: nandrolone and stanozolol. Lichten proposes that this hormonal combination raises the biomarker levels of the Free Androgen Index (FAI) 24. It does so by first, raising serum androgens and strongly saturates the cellular Androgen Receptor (A-R). Based on the greater affinity of nandrolone than estrogens for the A-R, Lichten rationalizes that xenoestrogens from the environmental are thereby denied access to the cell and thereafter the nucleus. This would prevent the xeno-estrogens from propagating abnormal mRNA and DNA, block their abnormal protein production and reduce the autoimmune reactions these abnormal proteins induce. Autoimmunity is inherent in both SIBO23 and Inflammatory Bowel Disease.24 The physiology of raising the FAI with the nandrolone/ stanozolol combination is as follows: Nandrolone has greater than 30-times affinity for the A-R as does any bio-identical or xeno8
estrogen, therefore, nandrolone should keep the xeno-estrogens out of the cell. Stanozolol reverses the estrogen induced production of Sex Hormone Binding Globulin, thereby, reducing SHBG. Elevated SHBG is an oestrgoen amplifier 25; reducing SHBG will amplify anabolic effects. This serves to amplify the nandrolone effectiveness in both the A-R and as an anabolic hormone. Up to a 100-fold increase in FAI was noted in the 2014 endometriosis case report 26 where a most extreme disease state was reversed.
The Hypothesis Theory: Will shifting to a more Anabolic Milieu change the Microbiota and Reduce Symptoms of Gastrointestinal Disease? Current thinking puts bacteria at the center of two prominent gastrointestinal diseases: Helicobacter pylori- peptic ulcer, and methane producing bacteria- Small Intestinal Bacterial overgrowth (SIBO). The addition of anabolic steroids in a manner to normalize the Free Androgen Index (FAI) correlates with symptomatic improvement in at least SIBO. Only one report in the medical literature has shown an improvement in Crohn’s Disease with added back testosterone. No one has connected that xeno-estrogenic effects of environmental toxins could be causing a relative testosterone/anabolic deficiency in gastro-intestinal disease. No one has looked at how changes in the hormonal milieu might affect the microfilaria in the gastrointestinal tract. This is important because the use of antibiotics is resulting in increased antibiotic resistance and greater than 30 percent treatment failures leaving patient suffers with SIBO and potentially H. Plyori without treatment options.
Consequences of the Hypothesis and Discussion: This hypothesis and observational cases disrupts the commonly held belief that bacteria are the cause of gastro-intestinal diseases and propagate autoimmune and related disease. These observations support the concept that endocrine disrupting chemicals (EDCs), environmental toxins in fact cause a change in the microbiota that could lead to bacterial overgrowth, autoimmune and related diffuse diseases such as SIBO and IBD. The aforementioned discussion clearly shows that the antibiotics prescribed for methane producing bacteria of SIBO, rifaximin and a multitude of others, are not effective for treating the symptoms, the observed hormonal disruption, and changes in transit time that are components of these disease complexes. The host needs to stay anabolic to maintain the tight junction of enterocytes, the transit time must be maintained, and pathologic biota need to remain in the colon and not ascend to the small bowel. All these conditions are necessary for the gastro-intestinal tract to maintain homeostasis. Should the shift from an androgenic to estrogen milieu occur because of increased exposure to EDCs, 9
the Wolbachia/ microfilaria infections are hypothesized to increase, and they may be the unrecognized causative agents for SIBO and other gastrointestinal disease states. The use of rifaximin presumed to treat methane producing bacteria is misdirected leading to delays in treatment and unnecessary expensive. After diagnosing and correcting the disruption of the hormonal milieu and the secondary autoimmune disease states in these patients with gastrointestinal distress, then and only then can these patients be evaluated naturopathic first and antibiotic intervention lastly for SIBO. The author hypothesizes that a more comprehensive and less expensive program for normalizing the microbiota would be first addressing by the aforementioned agents of systemic causation: normalizing the hormonal milieu. The addition of symptomatic treatment with naturopathic products could be dispensed concurrently. Then, if necessary, the physician could choose agents selective against Wolbachia27, rather than the presumed methane producing Small Intestinal Bacterial Overgrowth, SIBO bacteria. Pimentel’s28 original choice of the antibiotic, erythromycin in 50mg doses four times per day to improve transit time, seems most logical, and most safe for children and pregnancy and inexpensive. The use of the naturopathic product Allicum®, the garlic extract, needs additional testing to determine if it has a minimum inhibitory concentration (mic) against Wolbachia. It might be equally effective as doxycycline or erythromycin. As a new anti-Wolbachia regimen is needed that is safe for children under 8 years of age and in pregnancy, Allicum® may very well serve this purpose. Together, naturopath and allopath physicians may begin a new treatment direction for diseases starting with SIBO and IBD. Lichten’s report of reversing the worse cases of Crohn’s Disease 24, Ulcerative Colitis24, and in fact, SIBO23 raises many questions unanswered to date. Is this a paradigm shift in understanding a unifying concept of EDCs hormonal role in the cause of inflammatory and autoimmune diseases? If the stated hypothesis is proven true, and the proposed anabolic regimen does block xenoestrogens, then the allopathic direction of medical treatment should shift to the use of anabolic hormonal therapy instead of antibiotics for gastrointestinal bacterial SIBO disease. The author sees validity in the naturopathic orientation to parasites as cause of disease becomes ‘res ipsa loquitur’ [common law: it speaks for itself]- the truth. Used concurrently, the anabolic regimen and naturopathic products improves the healing potential of the host.
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13. Kar SK, Dwibedi B, Kerketa AS, Maharana A, Panda SS, Mohanty PC, Horton J, Ramachandran CP. A randomized controlled trial of increased dose and frequency of albendazole with standard dose DEC for treatment of Wuchereria bancrofti microfilaremics in Odisha, India.PLoSNegl TropDis 2015 Mar 17; 9(3):e0003583. D0o: 10.1371/journal (missing information) 14. Kramer L, Grandi G, Passeri B, Gianelli P, GenchiM, Dzimianski T, Supakordej P, Mansour AM, Supakorndej N, McCall SD, McCall JW. Evaluation of lung pathology in Dirofilaria immitis-experimentally infected dogs treated with doxycycline or a combination of doxycycline and ivermectin before administration of melarsomine diydrochloride. Vet Parasitol 2011 Mar 22; 176(4): 357-60. Do.10.1016/j.vetpar.2011.01.021. Epub 2011 Jan 19. 15. Bures J, Cyrany J, Kohoutova D, Förstl M, Rejchrt S, Kvetina J, Vorisek V, Kopacova M. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol. 2010 Jun 28;16(24):2978-90 16. Bures J, et.al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol 2010 Jun 28; 16(24): 2978-90 PMID0572300 17. Rana SV, Sharma S, Malik A, Kaur J, Prasad KK, Sinha SK, Singh K Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease. Dig Dis Sci. 2013 Sep;58(9):2594-8. doi: 10.1007/s10620-013-2694-x. Epub 2013 May 7. 18. Greco A, Caviglia GP, Brignolo P, Ribaldone DG, Reggiani S, Sguazzini C, Smedile A, Pellicano R, Resegotti A, Astegiano M, Bresso F. Glucose breath test and Crohn's disease: Diagnosis of small intestinal bacterial overgrowth and evaluation of therapeutic response. Scand J Gastroenterol. 2015;50(11):1376-81. doi: 10.3109/00365521.2015.1050691. Epub 2015 May 19. 19. Specht S, Mand S, Marfo-Debrekyei Y, Debrah AY, Konadu P, Adjei O, Büttner DW, Hoerauf A. Efficacy of 2- and 4-week rifampicin treatment on the Wolbachia of Onchocerca volvulus. Parasitol Res. 2008 Nov;103(6):1303-9. doi: 10.1007/s00436-0081133-y. Epub 2008 Aug 5. 20. Bah GS, Ward EL, Srivastava A, Trees AJ, Tanya VN, Makepeace BL. Efficacy of threeweek oxytetracycline or rifampin monotherapy compared with a combination regimen against the filarial nematode Onchocerca ochengi Antimicrob Agents Chemother. 2014;58(2):801-10. doi: 10.1128/AAC.01995-13. Epub 2013 Nov 18. 21. Sungpradit S, Chatsuwan T, Nuchprayoon S. Susceptibility of Wolbachia, an endosymbiont of Brugia malayi microfilariae, to doxycycline determined by quantitative PCR assay. Southeast Asian J Trop Med Public Health. 2012 Jul;43(4):841-50. 22. Charlat S, Davies N, Roderick GK, Hurst GD. Disrupting the timing of Wolbachiainduced male-killing. Biol Lett. 2007 Apr 22;3(2):154-6. 23. Lichten E. SIBO Unpublished Article in submission. 24. Lichten E. IBD Unpublished Article in submission. 25. Burke CW, Anderson DC. SHBG is an Oestrogen Amplifier. 1972 Nov 3; 240(5375):3840. PMID: 4120573 26. Lichten EM. Novel Medical Protocol Offers Alternative to Total Abdominal Hysterectomy With Bilateral Salpingo-oophorectomy and Hemicolectomy in Stage VI Endometriosis. Obstetrics & Gynecology: May 2014doi: 10.1097/01.AOG.0000447086. 18352.4f Tuesday, April 29, 2014: PDF Only 12
27. Fenollar F, Maurin M, Raoult D. Wolbachia pipientis growth kinetics and susceptibilities to 13 antibiotics determined by immunofluorescence staining and real-time PCR. Antimicrob Agents Chemother. 2003 May;47(5):1665-71 28. Pimentel M, Morales W, Lezcano S, Sun-Chuan D, Low K, Yang J. Low-dose nocturnal tegaserod or erythromycin delays symptom recurrence after treatment of irritable bowel syndrome based on presumed bacterial overgrowth. Gastroenterol Hepatol (N Y). 2009 Jun;5(6):435-42.PMID:20574504
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S0306-9877(17)30521-2 https://doi.org/10.1016/j.mehy.2017.09.022 YMEHY 8688
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
18 May 2017 6 September 2017 24 September 2017
Please cite this article as: E. Lichten, Are the Estrogenic Hormonal Effects of Environmental Toxins affecting Small Intestinal Bacterial and Microfilaria Overgrowth?, Medical Hypotheses (2017), doi: https://doi.org/10.1016/j.mehy. 2017.09.022
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Are the Estrogenic Hormonal Effects of Environmental Toxins affecting Small Intestinal Bacterial and Microfilaria Overgrowth?
(EL) Edward Lichten, M.D. Assistant Clinical Professor, Wayne State College of Medicine, Department of Obstetrics and Gynecology Corresponding and responsible author Edward Lichten, M.D. 555 S. Old Woodward Avenue Suite #700 Birmingham, Michigan 48009 Telephone: (248) 593.9999 Fax: (248) 593.9037 Email: [email protected] . No source of financial support
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ABSTRACT: The important role of microfilaria (worms) in human and animal disease remains an area of key disagreement between the naturopathic and allopathic physicians. While microfilaria infections are rampart in undeveloped countries, they rarely rise to identification as a cause of disease in Western countries. New research studies in the diagnosis and treatment of SIBO (Small Intestinal Bacterial Overgrowth) and (IBD) Inflammatory Bowel Diseases of ulcerative colitis, Crohn’s Disease and microcytic colitis may make both sides equally correct. A study of rifaximin failures in SIBO positive individuals finds biomarkers of decreased Free Androgen Index (FAI), high incidence of autoimmune disease and elevated Sex Hormone Binding Globulin (SHBG). The author hypothesizes that the underlying pathophysiology is increased exposure to Endocrine Disrupting Chemicals (EDCs) which hormonally act as xeno-estrogens. These xeno-estrogens increase the host production of SHBG, reduce pituitary stimulation of androgen product and result in a shift to estrogen dominance. Estrogen dominance is associated with autoimmune diseases and catabolic states. Treatment with a mixture of anabolic steroids that raises the FAI and lowers SHBG results in dramatic improvement in the signs and symptoms and recovery of the vast percentage of severe SIBO sufferers the author has treated. Similar results have been seen in severe pre-surgical cases of IBD whom fail all pharmaceutical interventions. Based on the recent recognition of the biological importance of Wolbachia in the occurrence of major diseases in the underdeveloped countries such as onchocerciasis, and the sexual nature of Wolbachia’s role in helminths reproduction, the author hypothesizes that the EDCs are shifting the host’s hormonal milieu in a more estrogenic direction and increasing reproduction of helminths changing the gastrointestinal microbiota. Present allopathic treatment of onchocerciasis utilizes albendazole and avermectin as therapy against the microfilaria larvae and doxycycline as bactericidal for Wolbachia. The allopathic treatments are unacceptable for pregnancy and children. Both naturopathic and allopathic treatments share a common focus on the suppression of the underlying bacterium Wolbachia infestation. The author hypothesizes that treatment of these two very different gastrointestinal diseases involves first establishing a normal, anabolic hormonal milieu and concurrently controlling an underlying yet unrecognized microfilaria overgrowth through naturopathic and allopathic treatments prescribed to the host. A case report of one such critically ill individual is noted. A thorough case controlled observation
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of symptoms matched with biological culture colony count and concentration of microfilaria in disease before and after the aforementioned anabolic treatment may answer the hypothesis.
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Introduction/ Background: Microfilaria1 refers to a “pre-larvae or advanced embryo” stage that exists prior to the first larva stage of certain parasitic nematodes/helminiths of the family Onchocercidae. While the adults live in a tissue or circulatory system of vertebrates (animals), the microfilariae are released into the blood stream where they migrate to just below the skin. Intact microfilaria can be sucked up intact into the mosquito (arthropod) with the bite, and subsequently enter the mosquito’s circulation. Here they mature to the first stage larvae. This vector continues with the mosquito biting another vertebrate animal. In the tissue-dwelling species, the eggs hatch in the uterus of the female and unsheathed microfilariae are released. In most blood-dwelling species, the microfilariae release embryonic eggs that are sheathed in the envelope of the egg. They are ‘hatched’ or ex-sheathed in the arthropod vector. In some species of Onchocercidae, the release of microfilariae by the adult female is periodic—occurring at a particular time of the day or night to increase chance of being picked up by the blood-feeding arthropod vector. The Wolbachia is a more primitive bacterial life-form than the parasitic nematode. The nematodes (parasitic worms) not only contain significant amounts of Wolbachia, but also the nematodes through transovarially transmission moves the bacteria from the adult female uterus to the offspring.2 The discoverers have identified the potential importance of these bacteria: (1). Bacteria-derived molecules should be considered as having an immunological and pathological role in filarial disease, as the nematodes are able to survive in immune competent hosts and (a.) Wolbachia2 manipulate of mast cell-mediated vasodilation to enhance infectivity of vector-borne larvae. (b.) Wolbachia2 is the principal driver of innate and adaptive Th1 inflammatory immunity which contributes to disease and enhanced infectivity. (c.) Wolbachia inserts a genome fragment into the host X chromosome necessary for female nematode fertility.3 The failure to do so leaves the nematode a male that grows and dies without reproducing. (2). As the Wolbachia bacteria are needed by the host nematode, they represent a target for therapy. It has been well known for more than 30 years that tetracycline, which kills intracellular bacteria, such as Wolbachia, also kills the nematodes Brugia pahangi and Litomosoides sigmodontis4. When doxycycline and ivermectin were used together, doxycycline(DOXY) dose: 10 mg/kg/day and ivermectin(IVM): 6 microgram/kg orally weekly, the resultant loss of both Wolbachia and nematoid DNA were similar to those of control worms, suggesting a loss of both Wolbachia and nematodes. Electron microscopy of nematodes recovered from the IVM/DOXY 4
combination group showed complete loss of immunohistochemistry for Wolchachia was negative5.
uterine
content
in
females
and
(3). The Wolbachia bacteria is necessary for the reproduction of the Onchocerca. Death and clearance of the Wolbachia after tetracycline treatment causes reproductive abnormalities in worms and affects worm’s embryogenesis, resulting in sterility6. Five prescription medications have been clinically tested for treatment of Onchocerciasis. 1. Anti-rickettsia: erythromycin and doxycycline. Chloramphenicol is less effective. 2. Anti-parasitic: ivermectin, abendazole and diethylcarbamazine (4). WALADin benzimidazoles modulate the function of prophobilinogen synthases orthologs. These medications have emerged as species-selective PBGS inhibitors against Wolbachia endobacteria of filarial worms. However, the medications may result in inhibition or stimulation of Pseudomonas aeruginosa depending on facts and pH.7 This implies that Wolbachia is linked to survival/ proliferation of Pseudomonas and other bacteria as well. Pseudomonas is implicated in the water of individuals at high risk for inflammatory bowel disease. 8 (5). While tetracycline as anti-Wolbachia therapy delivers safe macrofilaricidal activity and superior therapeutic outcomes compared to all standard antifilarial treatments, this therapy is contraindicated in children under 8 years of age and pregnancy.9 Therefore, the primary goal of the anti-Wolbachia consortium is to find drugs and regimens that reduce the period of treatment from weeks to 7 days or less and find drugs which would be safe in exclude target populations (children and pregnancy).9 Therefore, the goal of any treatment that destroys the Wolbachia or shifts the gender-preference from female to male of the Onchocerca proves to reduce the number of Onchocerca and improve the vertebral host health status akin to the present treatment for Onchocerca, river blindness. The potential drop in the concentration of the microfilaria in the microbiota by changing to a more androgenic milieu potentially changes the makeup of the gastro-intestinal microbiota and may correlate to symptom relief. Turner10 reported in a double-blind, in randomized field trial of 6 weeks of group (1) doxycycline 200mg/day alone or in combination with ivermectin 150mcg/kg/day or (group 2) placebo or ivermectin alone at four months. The combination treatment of doxycycline/ ivermectin had lower levels of microfilaridermia and high frequency of amicrofilaridermia compared with ivermectin or doxycycline only groups. At 12 months, 89% of the doxycycline/ ivermectin group and 67% of the doxycycline only group were amicrofilaridermic, compared with 21% of the ivermectin only group. 10 Of strong note, O. volvulus were completely depleted of Wolbachia and all embryonic stages in utero in the doxycycline group 10 and the sterilization was unaffected by ivermectin.10 5
Gayen11 in a placebo controlled field trial established that the combination of doxycycline/ (DOXY) (200mg/day) and albendazole (ABZ): 400mg/day provided the best efficacy by totally eliminating the circulating microfilaria (in 42% cases) on day 365 with (99.85%, P <.05) suppression; better than DOXY (69%, P<.05) and ABZ (89% P<.05). Gayen concluded “a 30day course of doxycycline and ABZ in combination is a safe and well-tolerated treatment for lymphatic filariasis with significant activity against microfilaremia”. 11 Tafatatha12 noted that doubling the standard dosage of ivermectin (IVM) and albendazole (ABZ) did not improve clearance rate of microfilaria based on count/ml. 12 Kar13 noted the higher and or more frequent dosing with ABZ with a fixed 300mg dose of diethylcarbazine resulted in only marginally greater clearance of lymphatic filariasis. 13 Kramer14 noted that in dogs with lung pathology from Dirofilaria immitis, that the combination of doxycycline/ DOXY (20mg/kg per os daily) with ivermectin/ IVM (6mcg/kg per os) for 24 weeks resulted in less severe arterial lesions and virtual absence of thrombi after intramuscular injection of melarsomine dihydrochloride at week 12. 14
SIBO Observation In light of known and published information comes a quandary of gastro-intestinal symptoms labelled Small Intestinal Bacterial Overgrowth Syndrome. 15 The symptom complex includes bloating, diarrhea, malabsorption, weight loss and malnutrition. Some diagnostic studies have confirmed a high concentration of colon bacteria in the small bowel/ jejunum. Some breathe testing of hydrogen/ methane after lactulose and glucose may be positive in a significant percentage of sufferers. The prognosis can be quite serious. The patients may appear suffering from extremely mal-nutrition and cachexia. Under normal physiological circumstances, there are several endogenous defense mechanisms for preventing bacterial overgrowth: gastric acid secretion, intestinal motility, intact ileocecal valve, immunoglobulins within intestinal secretion and bacteriostatic properties of pancreatic and biliary secretion. Human intestinal microbiota creates a complex polymicrobial ecology. This is characterized by its high population density, wide diversity and complexity of interaction. Any imbalance of this complex intestinal microbiome, both qualitative and quantitative, might have serious health consequence for a macro-organism, including small intestinal bacterial overgrowth syndrome (SIBO). SIBO is defined as an increase in the number and/or alteration in the type of bacteria in the upper gastrointestinal tract. There are several endogenous defense mechanisms for preventing bacterial overgrowth: gastric acid secretion, intestinal motility, intact ileo-caecal valve, immunoglobulins within intestinal secretion and bacteriostatic properties of pancreatic and 6
biliary secretion. Etiology of SIBO is usually complex, associated with disorders of protective antibacterial mechanisms (e.g. achlorhydria, pancreatic exocrine insufficiency, immunodeficiency syndromes), anatomical abnormalities (e.g. small intestinal obstruction, diverticula, fistulae, surgical blind loop, previous ileo-caecal resections) and/or motility disorders (e.g. scleroderma, autonomic neuropathy in diabetes mellitus, post-radiation enteropathy, small intestinal pseudo-obstruction). In some patients, more than one factor may be involved. Symptoms related to SIBO are bloating, diarrhea, malabsorption, weight loss and malnutrition. The gold standard for diagnosing SIBO is still microbial investigation of jejunal aspirates. Noninvasive hydrogen and methane breath tests are most commonly used for the diagnosis of SIBO using glucose or lactulose. Therapy for SIBO must be complex, addressing all causes, symptoms and complications, and fully individualized. It should include treatment of the underlying disease, nutritional support and cyclical gastro-intestinal selective antibiotics. Prognosis is usually serious, determined mostly by the underlying disease that led to S.I.B.O.28/16
This bacterial overgrowth has been confirmed in 45% of individuals with Crohn’s disease 17 and 17.8% of those with ulcerative colitis. The hydrogen/methane testing correlates with delayed orocecal transit time. In a second study, 26.5% of Crohn’s disease patients were considered SIBO.18 positive based on breath analysis testing. Percentage of methane positive IBD patients (2.9%) was significantly lower as compared to methane positive controls (24.4%) 18. Testing for ‘leaky-gut’ are inconclusive. For all practical purposes, therefore, the etiology of S.I.B.O.’s bacterial overgrowth is unknown. A mainstay of the treatment of Small Intestinal Bacterial Overgrowth19 (SIBO) has been the use of the aforementioned macrolide antibiotics and Rifampin/ Xifaxin®. The use of the antibiotic has resulted in reduction of methane production as noted in the Hydrogen/ Methane Breathe Analysis Test and reduction of symptoms, albeit temporarily, are noted. The high degree of treatment failures after 3 or more months is disheartening to both the patients who may repeat treatment time after time and the physician left without treatment options. Rifampin was suggested as an alternative for doxycycline for treating Wolbachia in children, albeit, less effective.20 However, rifampin does not improve clearance of Wolbachia over oytetracycline.19 Nor does ciprofloxin19. Rifamfin may in fact interfere with male-killing of Wolbachia.21 The complete minimum inhibitory concentration (mic) of 32 antibiotics to Wolbachia shows only doxycycline/ tetracycline and erythromycins to be most biologically active.22
Evaluation of the Hypothesis: Empirical Data: Case Report responding to Anti-helminth/ Nematode Treatment 7
SB is a 38-year old woman who presented with severe SIBO and fibromyalgia that left her unable to work and minimally able to care for herself and her family. She failed to respond to the aforementioned naturopathic products. Laboratory evaluation showed reduced FAI, positive tests for SIBO, autoimmune antibodies, and failure to respond to repeated treatments with rifaximin and other antibiotics. She was desperate to try alternative therapies. She reported initially no improvement with naturopathic products, but did show improvement initially to the nandrolone and stanozolol weekly injections. Then the medication lost effectiveness. After doubling and then quadrupling the nandrolone/ stanozolol injections to get relief from the severe SIBO symptoms, she had to discontinue the medications because of hirsutism and side-effects. She then developed tan stools and extreme abdominal pain. Naturopathic preparations including ox bile, digestive enzymes, and a litany of supplements were to no avail. The gastro-intestinal physicians at the major hospital in Boston were unable to make a diagnosis or initiate treatment. Her gallbladder X-ray, ultrasound and CT were normal. The author and naturopathic physicians made the diagnosis of severe pernicious anemia and initiated treatment with 5000 mcg of methyl-cobalamin intramuscularly every other day with dramatic improvement. Secondarily, as the tan stools persisted, they assumed ascending cholangitis and started a course of doxycycline and albendazole considering a microfiliaria infection of the gallbladder as the cause of the tan stools. The patient starting naturopathic Allimed™ and Neem Plus™. With this treatment, the patient has recovered. Ongoing treatment includes resuming the low dose nandrolone/ stanozolol weekly, praziquantel for unproven liver flukes, and the doxycycline and albendazole as microfilaridemic. Case Reports: SIBO Failures Respond to Anabolic Therapy The author reports23 in an unpublished peer-reviewed journal submission the successful management of 14 of 18 of the most severe SIBO cases with a novel mixture of anabolic steroids. These patients had failed Rifaximin® and naturopathic treatment with allicin/ Allimend® and Neem® Plus. He also reports that both pre-surgical Crohn’s and Ulcerative Colitis adult male and female patients24 responded miraculously to using the same combination of anabolic steroids: nandrolone and stanozolol. Lichten proposes that this hormonal combination raises the biomarker levels of the Free Androgen Index (FAI) 24. It does so by first, raising serum androgens and strongly saturates the cellular Androgen Receptor (A-R). Based on the greater affinity of nandrolone than estrogens for the A-R, Lichten rationalizes that xenoestrogens from the environmental are thereby denied access to the cell and thereafter the nucleus. This would prevent the xeno-estrogens from propagating abnormal mRNA and DNA, block their abnormal protein production and reduce the autoimmune reactions these abnormal proteins induce. Autoimmunity is inherent in both SIBO23 and Inflammatory Bowel Disease.24 The physiology of raising the FAI with the nandrolone/ stanozolol combination is as follows: Nandrolone has greater than 30-times affinity for the A-R as does any bio-identical or xeno8
estrogen, therefore, nandrolone should keep the xeno-estrogens out of the cell. Stanozolol reverses the estrogen induced production of Sex Hormone Binding Globulin, thereby, reducing SHBG. Elevated SHBG is an oestrgoen amplifier 25; reducing SHBG will amplify anabolic effects. This serves to amplify the nandrolone effectiveness in both the A-R and as an anabolic hormone. Up to a 100-fold increase in FAI was noted in the 2014 endometriosis case report 26 where a most extreme disease state was reversed.
The Hypothesis Theory: Will shifting to a more Anabolic Milieu change the Microbiota and Reduce Symptoms of Gastrointestinal Disease? Current thinking puts bacteria at the center of two prominent gastrointestinal diseases: Helicobacter pylori- peptic ulcer, and methane producing bacteria- Small Intestinal Bacterial overgrowth (SIBO). The addition of anabolic steroids in a manner to normalize the Free Androgen Index (FAI) correlates with symptomatic improvement in at least SIBO. Only one report in the medical literature has shown an improvement in Crohn’s Disease with added back testosterone. No one has connected that xeno-estrogenic effects of environmental toxins could be causing a relative testosterone/anabolic deficiency in gastro-intestinal disease. No one has looked at how changes in the hormonal milieu might affect the microfilaria in the gastrointestinal tract. This is important because the use of antibiotics is resulting in increased antibiotic resistance and greater than 30 percent treatment failures leaving patient suffers with SIBO and potentially H. Plyori without treatment options.
Consequences of the Hypothesis and Discussion: This hypothesis and observational cases disrupts the commonly held belief that bacteria are the cause of gastro-intestinal diseases and propagate autoimmune and related disease. These observations support the concept that endocrine disrupting chemicals (EDCs), environmental toxins in fact cause a change in the microbiota that could lead to bacterial overgrowth, autoimmune and related diffuse diseases such as SIBO and IBD. The aforementioned discussion clearly shows that the antibiotics prescribed for methane producing bacteria of SIBO, rifaximin and a multitude of others, are not effective for treating the symptoms, the observed hormonal disruption, and changes in transit time that are components of these disease complexes. The host needs to stay anabolic to maintain the tight junction of enterocytes, the transit time must be maintained, and pathologic biota need to remain in the colon and not ascend to the small bowel. All these conditions are necessary for the gastro-intestinal tract to maintain homeostasis. Should the shift from an androgenic to estrogen milieu occur because of increased exposure to EDCs, 9
the Wolbachia/ microfilaria infections are hypothesized to increase, and they may be the unrecognized causative agents for SIBO and other gastrointestinal disease states. The use of rifaximin presumed to treat methane producing bacteria is misdirected leading to delays in treatment and unnecessary expensive. After diagnosing and correcting the disruption of the hormonal milieu and the secondary autoimmune disease states in these patients with gastrointestinal distress, then and only then can these patients be evaluated naturopathic first and antibiotic intervention lastly for SIBO. The author hypothesizes that a more comprehensive and less expensive program for normalizing the microbiota would be first addressing by the aforementioned agents of systemic causation: normalizing the hormonal milieu. The addition of symptomatic treatment with naturopathic products could be dispensed concurrently. Then, if necessary, the physician could choose agents selective against Wolbachia27, rather than the presumed methane producing Small Intestinal Bacterial Overgrowth, SIBO bacteria. Pimentel’s28 original choice of the antibiotic, erythromycin in 50mg doses four times per day to improve transit time, seems most logical, and most safe for children and pregnancy and inexpensive. The use of the naturopathic product Allicum®, the garlic extract, needs additional testing to determine if it has a minimum inhibitory concentration (mic) against Wolbachia. It might be equally effective as doxycycline or erythromycin. As a new anti-Wolbachia regimen is needed that is safe for children under 8 years of age and in pregnancy, Allicum® may very well serve this purpose. Together, naturopath and allopath physicians may begin a new treatment direction for diseases starting with SIBO and IBD. Lichten’s report of reversing the worse cases of Crohn’s Disease 24, Ulcerative Colitis24, and in fact, SIBO23 raises many questions unanswered to date. Is this a paradigm shift in understanding a unifying concept of EDCs hormonal role in the cause of inflammatory and autoimmune diseases? If the stated hypothesis is proven true, and the proposed anabolic regimen does block xenoestrogens, then the allopathic direction of medical treatment should shift to the use of anabolic hormonal therapy instead of antibiotics for gastrointestinal bacterial SIBO disease. The author sees validity in the naturopathic orientation to parasites as cause of disease becomes ‘res ipsa loquitur’ [common law: it speaks for itself]- the truth. Used concurrently, the anabolic regimen and naturopathic products improves the healing potential of the host.
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