Tolle Totum
Melanie Keller, ND
Michael D. Erdman, MBBS
Although the origins of irritable bowel syndrome (IBS) were once thought to be mostly psychogenic, we now know that the pathogenesis of IBS is multifactorial. This paradigm shift may be due in part to the fact that small intestinal bacterial overgrowth (SIBO) produces many IBS-type symptoms. It has been estimated that compared to 1-40% of controls, 4-78% of patients with IBS have SIBO.1 Such wide variations in these groups might be due to population differences, criteria for IBS diagnosis, and, especially, methods for diagnosing SIBO.1
IBS is considered an immune-related functional bowel disease, which can be discriminated from inflammatory bowel disease using anti-CdtB and anti-vinculin second-generation biomarker testing.2 Positive antibody response in these tests is associated with a history of bacterial poisoning and warrants investigation of other unidentified microbes that could potentially play roles in the pathophysiology of functional gastrointestinal (GI) disorders.2
One of the important factors to consider when evaluating immune-related functional bowel disorders is sex hormones, as they have an influence on regulatory mechanisms of the brain-gut axis that can be involved in IBS pathophysiology.3 Sex hormones may help explain how IBS influences alterations in gut motility, visceral sensitivity, mucosal barrier function, and immune activation.3 Moreover, it is increasingly recognized that sex differences exist in the stress response of the HPA axis and the autonomic nervous system.3 Also recognized are stress-induced neuroimmune interactions, as well as interactions between estrogen and both corticotropin-releasing factor (CRF) signaling systems and serotonin.3
Endocrine-disrupting chemicals (EDCs), such as glyphosate, have been shown in animal models to affect gut motility.4 A possible response to EDC exposure is increased production of sex hormone-binding globulin (SHBG), reduced stimulation of androgens, and a shift toward estrogen dominance.5 The following discussion concerns a patient with complex and chronic symptoms, and illustrates the sometimes complicated interplay between sex hormones and the gastrointestinal microbiome. Over the course of a decade, the patient was evaluated and cared for by various practitioners including myself.
Patient Case
Presenting Concerns
In 2016, a 38-year-old female presented to my clinic with a 6-year history of persistent eructations, regurgitation, flatulence, bloating, abdominal distention, constipation, and pains in the back, stomach, and intestine. The eructations were constant throughout the day, with regurgitation occurring immediately after eating certain foods. She also reported significant distress, including feelings of anxiety and depression due to the severity of her symptoms and an awareness of functional and cognitive decline.
Her GI symptoms began during a 2006 trip to Peru, 10 years prior, where she was hospitalized for acute gastroenteritis and treated for suspected parasites. Her acute symptoms resolved, but she developed persisting GI symptoms as a result.
Initial Evaluation
Between 2008 and 2011, the patient’s GI symptoms were managed at Mayo Clinic. She was also referred to a psychologist. In 2012, Mayo Clinic diagnosed SIBO in the patient via upper endoscopy and quantitative jejunal aspirate culture, the gold standard for diagnosing SIBO. Of note, lactulose breath testing at that time had been negative, and functional stool testing had been unremarkable. The upper endoscopy also indicated chemical injury and bile reflux. She was treated with ciprofloxacin and instructed to eat a low-FODMAP diet. This initially relieved her symptoms; however, as time passed, her GI symptoms returned and her tolerance of foods diminished significantly, to the point of restricting her diet to 10-20 foods. While she continued to search for the optimal diet, she developed a tendency toward orthorexia.
Mayo Clinic also checked the patient’s serum prolactin, which measured high, at 65.9 ng/mL (RR: 2-29 ng/mL). The prolactinemia was investigated with a brain MRI, which revealed a left-slanted pituitary gland. The patient was treated with oral contraceptives.
Between 2012 and 2014, she worked with a nutritionist. The patient was able to manage her GI symptoms with botanical antimicrobials and a SIBO diet, and was able to reintroduce foods without issue.
In 2014, while on her honeymoon, she experienced a setback in her symptoms after consuming sugary alcoholic drinks. She returned to Mayo Clinic, which performed another endoscopy with duodenal aspirate and culture. This time, results were negative for SIBO. Nonetheless, she resumed a low-FODMAP diet and took varied botanical antimicrobials, but with limited effect.
In early 2016, she was diagnosed with rumination syndrome by Mayo Clinic, given breathing exercises, and referred to a psychologist.
Six months later, she consulted a Functional Medicine physician who ran an in-office lactulose breath test that confirmed SIBO.
My Involvement
She consulted me later that year, although not yet as a patient. I ran first-generation testing for anti-CdtB and anti-vinculin antibodies. Results were inconclusive, warranting further evaluation of the underlying cause. I also recommended that she discontinue her multiple probiotics.
One year later, in 2017, she established care with me as a patient. A Heidelberg pH test demonstrated normal baseline stomach acidity but an overall tendency toward hyperchlorhydria, as evidenced by alkaline challenges during the test. Gastrin and antinuclear and parietal cell antibodies were all normal, and intrinsic factor was at the high end of the reference range (RR: 0.0-1.1; patient result = 1.1).
Additional laboratory workup included blood chemistry, CBC, and an endocrine assessment. Pertinent findings included elevated liver enzymes, a macrocytic anemia, low serum calcium, elevated SHBG (274.2 nmol/L), elevated AM serum cortisol (28.5 nmol/L), and low serum estradiol (<5 pg/mL).
I also ran a urinary Industrial Toxicant assessment, which showed elevations in glyphosate and a couple of gasoline additives: 2-hydroxyisobutyric acid (2HIB) and N-acetyl(3,4-dihydroxybutyl)cysteine (NADB); these measured at nearly double the reference range.
This appeared to be a complex case of recurrent SIBO and GI motility disorder, as suggested by her imbalanced stomach pH and the fact that her SIBO was unresponsive to treatment long-term. Although the patient had previously responded well to antibiotics and a low-FODMAP diet, by the time of my involvement 2 years later, this approach was producing minimal improvement.
Considering the multitude of her food restrictions and the need to support the almost certain micronutrient deficiencies, incorporation of a modified elemental diet (tolerated foods along with a proprietary elemental formula) seemed warranted.
Following the first Heidelberg pH test, I recommended an OTC sodium/potassium bicarbonate solution, to be taken pre- and post-prandially for 2 weeks. Since the migrating motor complex (MMC) originates mostly in the stomach (approximately 25% is initiated in the duodenum or proximal jejunum)6 and gastric emptying is more possible when stomach pH reaches 5, the purpose of the bicarbonate solution was to modulate stomach pH. Intramuscular methylcobalamin (2500 µg) was also administered (daily for 2 weeks, then weekly), given the macrocytic anemia and borderline-high intrinsic factor (RR: 0.0-1.1; patient result = 1.1).
The patient was eventually advised to expand her diet, with no specific guidelines, so as to prevent any further orthorexia tendencies. She was able to tolerate the dietary expansion, and over time the alkaline aid was transitioned to post-prandial and bedtime dosings as well.
One month after starting the bicarbonate solution, she reported marked improvements in the frequency and intensity of abdominal pain, flatulence, bloating, abdominal distention, and constipation. She also reported moderate improvement in the frequency and intensity of the eructations. Bowel movements had initially improved from Bristol stool form scale 1-2, to Bristol stool form scale 3. With the introduction of ox bile 2 weeks after addressing pH, there was further improvement, to Bristol stool form scale 4.
On follow-up a few months later, the patient reported diarrhea from use of the ox bile, so it was tapered down – from 625 mg per meal to 125 mg per meal. We discontinued the methylcobalamin injections.
A SIBO breath test was mildly positive for both hydrogen-producing bacteria and methane-producing archaea. However, the patient’s persistent eructations, regurgitation of all foods immediately after eating, and severe upper abdominal pains that radiated to the back, together suggested a pathological process that was not typical of a straightforward, fermentation-type SIBO. Comprehensive stool analysis was inconclusive for a fungal overgrowth of the large bowel, and parasitology was negative.
Hormonal Considerations
The patient’s persistent eructations and immediate regurgitation of food raised my suspicion of hormonal factors as a potential contributor. Oral contraceptives tend to increase SHBG. This can result in an androgen deficiency, since SHBG preferentially binds testosterone over estrogen.7 Estrogens increase SHBG, whereas androgens decrease it. Based on my clinical impression, and with the support of the Mayo Clinic team, the patient discontinued her hormonal birth control. Treatment with a testosterone derivative in a low-dose, compassionate-use manner was initiated in order to lower the SHBG concentration. During this therapeutic intervention, amenorrhea was noted.
Following 6 weeks of testosterone supplementation, the patient’s AM cortisol, estradiol, and SHBG level had all normalized. At the same time, her eosinophil count rose from an undetectable level to significantly positive. I felt that the eosinophilia (absolute and percent) warranted a referral to Dr Michael Erdman for a repeat Heidelberg pH test, as well as a referral to gastroenterologist, Dr Farshid Sam Rahbar, for a repeat endoscopy with duodenal aspirate and biopsy.
The results of the repeat Heidelberg pH test were identical to those of the first Heidelberg (ie, normal baseline stomach acidity and a tendency toward hyperchlorhydria, as revealed during alkali challenges). However, this Heidelberg test also showed spontaneous rises in the pH tracer – a finding associated with bile reflux.
The eosinophilia and suspected bile reflux heightened the suspicion of a possible underlying cryptic infection. Endoscopy revealed a large amount of juice present in the stomach that was mixing with bile. Biopsies of the stomach were positive for foveolar hyperplasia, a finding commonly seen with bile gastritis. Duodenal aspirate PCR analysis was positive for Trichuris trichiura – a finding that contrasted with the negative parasitology on comprehensive stool analysis.
The Trichuris trichiura infection was treated with albendazole, 200 mg (2 tablets/day X 3 days). This was followed 2 weeks later with ivermectin, 3 mg (2 tablets/day X 3 days). This first round of treatment resulted in a 60% improvement in the frequency of abdominal pain and flatulence; however, eructations and regurgitation were still present. The same protocol was repeated 1 month later, with similar results. Approximately 6 weeks later, following a 2-week course of rifaxamin for the SIBO, a third albendazole-ivermectin protocol was carried out, and the patient’s eructations and regurgitations resolved.
Discussion
The medical literature documents a connection between exposure to EDCs (acting as estrogens in the body) and the development of certain disease states. Glyphosate, for example, has been found in vitro to interrupt the spontaneous motor activity of the intestine.4 In animal studies, glyphosate has been detected in the highest amount in the small intestine shortly after oral exposure, and has been shown to impair gastrointestinal motilityat concentrations said to be a non-toxic to humans.4
Estrogen dominance has been linked with autoimmunity.5 Dr Edward Lichten has found that short-term treatment with low-dose anabolic steroids, which lowers SHBG and increases the Free Androgen Index (FAI), results in improvements in the signs, symptoms, and recovery in difficult-to-treat and rapid-relapse SIBO cases.5 Improvement may be gradual and may require varying lengths of treatment, depending on levels of SHBG, age, disease state(s), autoimmunity, malnutrition, and any other factors pertinent to the individual. Yet, even with an optimal FAI, there may not be resolution of symptoms of disease, as was demonstrated in this case.
Interestingly, the patient’s eosinophilia only became apparent when the FAI was normalized. Is it possible that the elevated SHBG potentially masked an eosinophil response to parasites?
It has been hypothesized that hyperestrogenism, resulting from both endogenous and exogenous estrogen (EDC) exposure, can encourage helminth infection and gut microbiome imbalances.6 Parasite infection (eg, onchocerciasis, or “river blindness”) may also be encouraged by the gram-negative bacterium Wolbachia, which can inhabit parasitic worms and enhance both their fertility and infectivity. In a case study, a patient with recalcitrant SIBO was found to have a low FAI and autoimmunity.6 Many severe SIBO cases have also been shown to resolve with anabolic therapy.8 Current allopathic treatment of onchocerciasis includes albendazole and ivermectin (targeting the larvae) and doxycycline (targeting the Wolbachia). This treatment, along with androgen supplementation, has been shown to promote a more androgenic milieu, which may in turn favorably alter GI microbial balance and bring about symptom relief in patients with recalcitrant SIBO.5
This case report demonstrates the multifactorial complexities that a naturopathic doctor can face with the chronically ill patient with recurrent SIBO, parasite infection, and hormone imbalances. A synergistic crossover of care with a gastroenterology team specializing in duodenal aspirate and PCR analysis can be very helpful in such cases, in particular when one has good reasons to suspect an underlying cryptic infection.
References:
- Ghoshal UC, Shukla R, Ghoshal U. Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome: A Bridge between Functional Organic Dichotomy. Gut Liver. 2017;11(2):196-208.
- Morales W, Rezaie A, Barlow G, Pimentel M. Second-Generation Biomarker Testing for Irritable Bowel Syndrome Using Plasma Anti-CdtB and Anti-Vinculin Levels. Dig Dis Sci. 2019 May 31. doi: 10.1007/s10620-019-05684-6. [Epub ahead of print]
- Mulak A, Taché Y, Larauche M. Sex hormones in the modulation of irritable bowel syndrome. World J Gastroenterol. 2014;20(10):2433-2448.
- Chłopecka M, Mendel M, Dziekan N, Karlik W. Glyphosate affects the spontaneous motoric activity of intestine at very low doses – in vitro study. Pestic Biochem Physiol. 2014;113:25-30.
- Lichten E. Are the estrogenic hormonal effects of environmental toxins affecting small intestinal bacterial and microfilaria overgrowth? Med Hypotheses. 2017;109:90-94.
- Boron WF, Boulpiep EL. Medical Physiology: A Cellular and Molecular Approach. Updated 2nd Edition. Philadelphia, PA: Saunders; 2012
- Burke CW, Anderson DC. Sex-hormone-binding globulin is an oestrogen amplifier. Nature. 1972;240(5375):38-40.
- Lichten E. SIBO. [Unpublished article in submission] Cited in: Lichten E. Are the estrogenic hormonal effects of environmental toxins affecting small intestinal bacterial and microfilaria overgrowth? Med Hypotheses. 2017;109:90-94.
Melanie Keller, ND, specializes in the treatment of IBS, SIBO, and other associated chronic health conditions. She is passionate about epigenetic and nutrigenomic influences that may contribute to gut motility dysfunction and an imbalanced gut microbiome. Dr Keller is an alumna of National University of Natural Medicine (NUNM) and was a founding physician in the development of their SIBO Center and SIBO Symposium(s). She is currently practicing in Los Angeles, CA, and online.
Michael D. Erdman, MBBS, is the senior medical officer at Los Angeles Integrative Gastroenterology & Nutrition. Dr Erdman is a UK-trained physician; he graduated from King’s College London School of Medicine in 2011 and completed the South Thames Foundation School training program in 2013. Following a 3-year stretch working in NHS hospitals throughout the Greater London area, Dr Erdman’s passion for functional medicine led him to join Dr Farshid Sam Rahbar, MD, at the Los Angeles Integrative Gastroenterology & Nutrition. Dr Erdman prides himself on a holistic-minded “whole person” approach to understanding the root cause of functional bowel disorders.
