Estrogen Toxicity and its Interrelationships with SIBO, GI Dysfunction and Chemical Sensitivity

Are you suffering with SIBO?   feel as if you've tried everything and it persists or revisits nonetheless?  In this article, I provide some current research and biochemical evidence that may impact our understanding of SIBO and how it can be more easily and permanently resolved. Its relationship with hormone toxicity is becoming more widely understood, and in clinical practice I am seeing increasing evidence of a direct relationship.

SIBO (small intestinal bacterial overgrowth) is defined as an increase in the number of bacteria, and/or changes in the types of bacteria present in the small bowel, which should be sterile under normal conditions. In most patients, SIBO is not caused by a single type of bacteria, but is an overgrowth of  various types of bacteria that should normally be found only in the colon.  While the majority of treatments have historically been strictly antibacterial in nature, there is much more recent exploration of other approaches which include considerations/complications with oral contraceptives, stress and cortisol release, and layering with other pathogens such as candida.  Our question is how this type of overgrowth may be caused by, or have connections with, malfunctions in hormone metabolism and detoxification.  The theory being explored is that the interaction of estrogens and toxic compounds of similar structure in the gut are a causative factor in SIBO.

Estrogen and the Cytochrome P450 Enzymes

Let's take a look at the CYP enzyme functions relative to estrogens and related compounds. Human CYPs are primarily membrane-associated proteins located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. Cytochrome P450 enzymes are present in most tissues of the body.  They metabolize thousands of endogenous (such as bilirubin) and exogenous (such as drugs, petrochemicals) chemicals and also play important roles in hormone synthesis and methylation (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism.

The understanding of genetic mutations and expressons of individual genetic weaknesses is growing exponentially since the mapping of the human genome.  A constantly growing body of evidence indicates that epigenetic factors are most important in the consideration of genetic expression.  In my practice, I see increasing numbers of mutations in the CYP genes which are needed for proper activation of the P450 enzymes.  Toxicity, as well as lifestyle stressors and pathogenic influences are likely major causes for these mutations to be expressed more frequently.  Associations with PCOS, endometriosis, breast abnormalities, and cancer have all been researched and documented around CYP dysfunction, especially with regards to the environmental toxins which mimic estrogen.  (1)

Oxidative Stress, Cytokines and GI Clearing

In a 2014 study of SIBO sufferers, it was concluded that increases in cytokines and decreases in antioxidants result in oxidative stress, causing impaired GI motility responses which lead to SIBO (1).  There were significant correlations between SIBO and the proper regulation of immune pathways IL-6, 8 & 10,  TNF-alpha, as well as results of lipid peroxidation and glutathione depletion. (2)

  • IL-6, 8 & 10, as well as TNF-alpha are key regulatory cytokines in the body whose functions include pro and anti-inflammatory activities critical to immune modulation.
  • In lipid peroxidation, free radicals steal electrons from lipids in the body and create cell damage.
  • Glutathione is a necessary antioxidant for the removal of heavy molecule toxins in the body.

Of great interest in this article and investigation are the end products of lipid peroxidation which are aldehydes (malondialdehyde & 4-hydroxynonenal).  Aldehydes are phenolic compounds, as are a whole host of things including harmful xenobiotics, petrochemicals, perfumes,  many foods including all of the browning fruits, berries, coffee, chocolate, alcohol, and quite importantly, hormones! (3) When the body is bombarded with excesses of any substance, toxin, or pathogen, there is a risk of developing sensitivity and/or a type of immune reactivity response.  Phenolics are everywhere - and normally, would not create a problem in and of themselves - but our environment is now rife swith dangerous ones which are very harmful and difficult to detoxify.

An additional factor in this particular challenge is that all of these compounds can begin to compete for the same receptor sites. ER-alpha and ER-beta receptor proteins are located in the brain, bones, kidneys, intestinal mucosa, endometrium, hypothalamus, ovarian cells, prostate and endothelium - all areas where hormone activity is being regulated.  When our bodies become overloaded with all varieties of phenolics (from gasoline to PAHs and estrogens) failing to detoxify properly, there can be aberrant hormone metabolism coupled with high levels of toxicity in the gut.  The failure to complete all 3 stages of detoxification including glucoronidation/excretion comes into play in this scenario.  It is safe to say that many people are suffering inadequate evolution of phase III detoxification, in particular, given the overwhelm of toxins in our current environment. This all potentially creates a case of mistaken identity, with dangerous chemicals that mimic necessary hormones & latch on to their receptor sites causing  the brain & pituitary gland to function as if there is a deficit, due to low levels on receptor sites. Excess estrogen production in response to this false "deficit" message, as well as failure of proper reception and detoxification create a recipe for toxic soup in the body. The gut is particularly vulnerable in this scenario.

Also of note, phenolic compounds are capable of "stacking", a beneficial chemical characteristic of molecules with aromaticity. These interactions are important in nucleobase stacking within DNA and RNA molecules, protein folding, template-directed synthesis,  and molecular recognition. (3) It is important for the body to be able to properly recognize and place the compounds in order for this characteristic to be expressed.

Gonadal Hormones and Motility

Estrogens play a significant role in the physiology and pathology of the gastrointestinal (GI) tract,  including the regulation of motor and sensory function.  SIBO has been considered a secondary condition that develops in the setting of altered intestinal anatomy, slowed intestinal motility, or aberrant gastrointestinal function.  The role of gonadal hormones in symptomatology and pathophysiology of IBS/SIBO is being increasingly recognized based upon the female predominance as well as the correlation between IBS symptoms and hormonal status during menstrual cycle phases, pregnancy or menopause.  The ratio of women to men with SIBO symptoms and diagnoses is currently understood to be 2:1.

As stated in a 2014 article in the World Journal of Gastroenterology by authors Mulak, Tache & Larauche:

"Sex hormones may influence peripheral and central regulatory mechanisms contributing to the alterations in visceral sensitivity, motility, permeability, and immune activation of intestinal mucosa. A new concept of “microgenderome” is emerging based on the observations that the gender bias present in numerous diseases may be reinforced by the commensal microbiota of the host." (4)
The authors of this important article also emphasize that clinical  findings support the modulatory actions of gonadal hormones exerted at different levels of the brain-gut-microbiota axis in Irritable Bowel Syndrome (IBS).

In addition to this new understanding of hormone-impacted GI modulation, let's consider that  compromises in the CYP enzyme functions in the body may also include specific CYP's (such as 101, 107A1, 102A1, 119) which are found in some intestinal bacteria and play roles in combating infection, as well as in biotransformation of xenobiotic compounds.  Fecal bacteria can perform hydrolytic, reductive and oxidative reactions of estrogens and androgens.

This biotransformation of xenobiotic conpounds is potentially a very important link in the question of hormone toxicity and its involvement in SIBO.  Some xenobiotics are resistant to degradation. For example, they may be synthetic organochlorides such as plastics and pesticides, or naturally occurring organic chemicals such as polyaromatic hydrocarbons (PAHs) and some fractions of crude oil and coal. However, it is believed that microorganisms are capable of degrading almost all the different complex and resistant xenobiotics found on the earth.  This, however, depends upon the proper balance of microorganisms!

Case Studies in SIBO and Estrogen Toxicity

Let's examine a couple of real cases of combined SIBO and hormone toxicity. Both women are still experiencing menstrual cycles.

Case #1 is a woman with a history of SIBO, unsuccessfully treated.  Diagnosed with the  lactulose breath test with positive elevated hydrogen and combined hydrogen/methane levels, the Dutch hormone test was administered to ascertain her hormonal status.  (Unlike most hormone assessments, the Dutch test gives insight into the balances of healthy vs. dangerous estrogens, as well as the level of metabolites moving down the protective CYP pathway and the amount of protected metabolites being adequately methylated.  It is a groundbreaking test.)

This client presented with the following hormone complications:  menopausal levels of progesterone alongside normal E1, E2, and E3 levels; elevated 4-OH-E1 (a very toxic, cancer-causing estrogen) with low 2-OH-E1 and 2-methoxy-E1 (indicating improper CYP action and methylation of estrogens).  The client was also very sensitive to many of the phenol-based foods and to perfumes/scents of various sorts. Her therapeutic protocol consisted of ellagic acid, Biocidin with proteolytic enzymes,  and N-acetyl cysteine (NAC) initially.  This protocol was followed with gut repair including a polysaccharide formula and restoration of her microbiome with soil-based probiotics.  We also applied the use of multi phenolic homeopathic formulas in order to desensitize the client from this type of immune reactivity. To date, 2 years later, there has been no recurrence of SIBO.

 

Case #2 is a woman presenting with severe premenstrual syndrome, back pain & recurrent infections.  Not previously diagnosed with SIBO, she had repetitive immune problems with chronically elevated monocytes and had used oral birth control for 15 years. Risks for inflammatory bowel disease with oral contraceptives have been studied and reported (5).  A positive lactulose test confirmed SIBO, and Dutch test findings were as follows:  normal E1 & E2 with low menopausal-level progesterones; 4-OH-E1 drastically elevated beyond the top end of the range; and 2-methoxy-E1 at less than 1/5 of 2-OH-E1 (ideal ratio is 1:2).  The client was medically assessed and found to have fibroid tumors and ovarian cysts.  No direct antibiotic treatment was given to this client for the SIBO, but supportive protocols for hormone regulation and detoxification were applied, inclusive of Chaste Tree, DIM, glycine, TMG, DMG, calcium d-glucarate , P5P and zinc plus coffee enemas twice weekly. This client was fortunate to recover completely from SIBO, chemical & hormone sensitivies/toxicities.

Resolving SIBO and Estrogen Toxicity Naturally and Effectively

In some severe cases of SIBO, medical treatment with specific antibiotic applications (rifaximin) is helpful and possibly necessary. In both case studies shared above, it was not necessary to utilize this treatment although both clients were curious about the usefulness for their conditions.  It was also not necessary to implement restricted diets with no starches which is a very common approach in the treatment of SIBO.  Many people in the health field now believe that these restricted diets actually cause the bacteria to be less available/accessible for treatment when not given a certain amount of what feeds them.  (Hibernation and survival mode are practiced if they are not healthy/thriving themselves.)  At True Nature, I practice the nutritional format of Metabolic Typing® combined with ecological nutrition, and believe that every person will require an individualized diet for stabilization and proper healing.  This is a cornerstone of working with a client with SIBO.

In some cases, natural antibacterials will help support healing while toxicity is also being addressed.  These can include berberines, rainforest herbs, garlic, and oregano.

In all successfully resolved cases, I have utilized natural substances for the support of CYP enzyme optimization, hormone detoxification, and liver support.  These may include DIM (diindolymethane), calcium d-glucarate, N-acetyl cysteine, nettles, trimethylglycine, ellagic acid, glutathione, antioxidants, P5P, zinc, B12, and numerous other therapeutic agents.

Going Forward with Intelligent Investigation

The main questions to be asked by you around these particular links with SIBO and estrogen metabolism are:

  • What is my status with SIBO?
  • What treatment options do I wish to consider for SIBO relief?
  • What is my status with hormone metabolism and methylation?
  • What other toxin overload and/or sensitivities might I be dealing with?
  • What treatment options are best for my detoxification needs?
  • What is the status of my microbiome?

As the layers of the onion are peeled back and each area of dysfunction is addressed individually and successfully, the likelihood of long-term complications with SIBO are greatly reduced.  I believe that resolution of this increasing and challenging condition will be achieved much more easily through consideration of the links with hormone metabolism and balanced methylation of  both hormones and phenolic compounds.  To date, this has been the reality with existing clients and case studies.
Moving forward with clients and case studies, I will continue to observe and report on findings related to estrogen as a cause vs. a downstream effect and impacts of the microbiota upon conjugated estrogens.

 

Sources

(1) Evanthia Diamanti-Kandarakis, Jean-Pierre Bourgignon, Linda C. Giudice, Russ Hauser, Gail S. Prins, Ana M. Solo, R. Thomas Zoeller, Andrea C. Gore, Endocrine-Disruptive Chemicals:  An Endocrine Society Scientific, June 2009, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726844/

(2) Rava SV, Sharma S, Kaur J, Prasad KK, Sinha SK, Kochhar R, Malik A, Morva RK, Relationship of cytokines, oxidative stress & GI motility with bacterial overgrowth in ulcerative colitis patients, August 2014, https://www.ncbi.nlm.nih.gov/pubmed/24456736

(3) https://en.wikipedia.org/wiki/Phenols

(4) Agata Mulak, Yvette Tachi & Muriel Laurauche, Sex hormones in the modulation of irritable bowel syndrome, March 2014, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949254/

(5) Comish JA, Tan E, Simillis C, Teare J, Tekkis PP, The risk of oral contraceptives in the etiology of inflammatory bowel disease: A meta analysis, September 2008, https://www.ncbi.nlm.nih.gov/pubmed/?term=18684177

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842473/