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“Identifying Helicobacter pylori’s role in digestive and systemic disease”.
Dave HompesM.Sc.
Background
• I’ve been researching H. pylori since 2007.
• I had it myself (twice) - first time in Egypt in 2004.
• Never felt the same afterwards.
• Period of stress in 2007 brought all symptoms back.
• Stool antigen test showed H. pylori, B. hominis, Aspergillus.
• Cortisol upside down, B6, Mg, Zn deficiencies.
• 30-days, felt much better.
• 6 months, completely back to old self.
Background (cont.)
• PubMed: MASSIVE amount of information
– Helicobacter: 41,000 entries
– Pylori: 90,000 entries
• I want to give you the most clinically relevant info.
• I’m not including many references on the slides.
– I’ll send you a list and a PDF pack
Aims of this session
• Evidence-based summary of associations between H. pylori and digestive and systemic diseases.
• A basic understanding of the underlying mechanisms behind H. pylori’s role in systemic disease.
• Host/human and microbe/H. pylori interactions, including H. pylori strains and biofilms.
• Advantages of PCR stool testing.
• Stomach cleanse ideas.
What is H. pylori?
• Spiral shaped bacterium
• Gram negative
• Identified in 1982 by Marshall
– Corkscrew (active) phase
– Coccoidal (inactive) phase
• Corkscrew shape enables it to bury into stomach lining.
• Causes irritation, immune response, cytokines.
• End result is acute or chronic inflammation.
What is H. pylori?
http://www.sciencedirect.com/science/article/pii/S2319417016000160
What is H. pylori?
https://en.wikipedia.org/wiki/Helicobacter_pylori#/media/File:Ulcer-causing_Bacterium_(H.Pylori)_Crossing_Mucus_Layer_of_Stomach.jpg
H. pylori diseases
• Chronic gastritis.
• 80% peptic ulcers.
• 95% duodenal ulcers.
• Atrophic gastritis.
• Stomach cancer
– Class I carcinogen.
– 4 to 6x risk; risk may be strain-associated. http://www.nobelprize.org/nobel_prizes/medi
cine/laureates/2005/press.html
Classic H. pylori symptoms
• Heartburn
• Gnawing pain in chest
• Bloating
• Belching
• Halitosis
• Constipation
• Diarrhoea
• Some associations with IBS and IBD
Many factors need to be considered
• H. PYLORI:
– Precise location of the infection
– Duration of infection• Childhood?
– H. pylori strain• There are many!
– Co-infections• E.g. Candida
• HUMAN:
– Genetic polymorphisms (human)
– The patient’s stress level
– Diet, food intolerance • How many times do
symptoms clear up when foods are changed?
– Nutritional status
– Stomach acid levels, etc.
– Metaphysical
Many factors need to be considered
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753193/figure/F2/
Predisposing human polymorphisms
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1539101/
Location of the infection
Testerman TL et al . H. pylori pathogenesis, diagnosis, and treatment
Location of the infection
https://www.researchgate.net/figure/6938890_fig4_FIG-4-Acid-secretion-and-the-associated-pattern-of-gastritis-play-an-important-role-in
Location of the infection
https://www.spandidos-publications.com/ijo/42/1/5
Environmental risk factors
• Assessment of Risk Factors of Helicobacter Pylori Infection and Peptic Ulcer Disease.
• “Lower SES, consumption of restaurant food, meat, non-filtered water, and smoking are risk factors for H. pylori.”
• J Glob Infect Dis. 2013 Apr-Jun; 5(2): 60–67.
Stress levels in the patient
• Psychological stress enhances the colonization of the stomach by Helicobacter pylori in the BALB/c mouse.
• “We found that the H. pylori colonization in the stomach of psychologically stressed mice was significantly greater than in the control mice, and histological examination showed that the gastric mucosal injury in the stressed mice was more extensive than in the control mice.”
• Stress. 2009 Nov;12(6):478-85. doi: 10.3109/10253890802642188.
Stress levels in the patient
“Microbial endocrinology shows that, through their long coexistence with animals and plants,
microorganisms have evolved sensors for detecting eukaryotic hormones, which the microbe uses to
determine that they are within proximity of a suitable host and to optimally time the expression of genes
needed for host colonisation.”
Hindawi Publishing Corporation ScientificaVolume 2013, Article ID 361073, 15 pages http://dx.doi.org/10.1155/2013/361073
Stress levels in the patient
• Neurotransmitters have a profound effect on the microbiome.
• Noradrenaline (stress) enhances H. pylori growth.
• N. C. Doherty, A. Tobias, S. Watson, and J. C. Atherton, “The effect of the human gut-signalling hormone, norepinephrine, on the growth of the gastric pathogen Helicobacter pylori,” Helicobacter, vol. 14, no. 3, pp. 223–230, 2009.
Stress in the patient
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2011, 62, 6, 591-599
Stress in the patient
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2011, 62, 6, 591-599
Don’t blame H. pylori for all ulcers
• Long-term stress and Helicobacter pylori infection independently induce gastric mucosal lesions in C57BL/6 mice.
• “The present study showed that long-term stress can induce gastric mucosal inflammation and erosions, and this effect may occur independently of H. pylori infection.”
• Scand J Gastroenterol. 2002 Nov;37(11):1259-64.
Don’t blame H. pylori for all ulcers
• Psychological stress increases peptic ulcer risk irrespective of H. pyloriinfection, NSAID use.
• “Psychological stress increased risk for peptic ulcer regardless of Helicobacter pylori infection status or use of NSAID drugs, according to data from a prospective study of a population-based cohort in Denmark.”
• Levenstein S, et al. Clin Gastroenterol Hepatol. 2015;doi:10.1016/j.cgh.2014.07.052; March 6, 2015
H. pylori strains
• CagA – cytotoxin–associated gene A
• VacA – vacuolating toxin A
• BabA and SabA – Lewis antigen binding
• OipA – outer inflammatory protein
• DupA – duodenal ulcer-producing
• HP-NAP – neutrophil activating protein
• GGT – gamma-glutamyl transpeptidase– Increased inflammatory cytokines, Th1 and Th17 responses,
oxidative stress; HP-NAP may be beneficial in allergies by creating shift to Th1.
H. pylori strains
“It is important to note that the presence of cagAusually coincides with the presence of other virulence factors, including vacA, babA and oipA. Thus, H. pylori
pathogenesis is multifactorial and cannot be boiled down to one gene.”
Testerman TL et al . H. pylori pathogenesis, diagnosis, and treatment
H. pylori strains
https://www.spandidos-publications.com/ijo/42/1/5
H. pylori strains
http://www.steadyhealth.com/articles/h-pylori-latest-discoveries-and-treatment-options
H. pylori strains
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753193/figure/F1/
H. pylori strains
Figure 2 Effects of Helicobacter pylori on host cells. Helicobacter pylori virulence factors can lead to apoptosis, vacuolization, disruption of barrier function (leading to nutrient leakage),
de-differentiation, and carcinogenesis.
H. Pylori strain testing
• Importance of H. pylori strain ID can’t be overstated.
• Molecular testing (GI-MAP) trumps other tests.
• CagA and VacA ID as well as antibiotic resistance.
• Any CagA or VacA presence on the GI-MAP test should be addressed, taking into consideration the antibiotic resistance information.
What about H. pylori & “extragastrointestinal”
disorders?
Non-classic H. pylori presentation
• Low sex drive
• Menstrual issues
• Low energy
• Muscle aches/pains
• Anxiety / depression
• Sleep problems
• Skin, nail hair symptoms
• [Weight gain/loss]
The evidence-based list I had in 2008
• Anaemia• Bronchitis • Colitis • Colorectal Cancer • Crohn’s Disease • Halitosis • Heart Disease • High Blood Pressure • High Cholesterol / lipid Imbalances • Homocysteine elevation• Hypochlorhydria (low stomach acid) • Gallstones • Insulin Resistance • Liver Disease
• Lung Cancer• Migraines• Osteoporosis• Pancreatitis• Parkinson’s Disease • Raynaud’s Syndrome • Rosacea • Sperm Health / Male Fertility • Thyroid (autoimmune) • Type I Diabetes • Urticaria• Vitamin and Mineral Deficiency • Vomiting during Pregnancy Weight gain
/ obesity
Non-classic H. pylori presentation
“H. pylori… non-digestive abnormal condition and/or diseases, such as… metabolic syndrome, atherosclerosis and CVD, which have lots of prior studies… autoimmune thyroid disease, urticaria, atopy & asthma; … diseases, such as chronic obstructive pulmonary disease (COPD),
migraine, anemia and hyperemesis gravidarum.”
Non-classic H. pylori presentation
“H. pylori is increasingly being associated with extragastric diseases. H. pylori is widely accepted as a
cause of iron deficiency anemia and idiopathic thrombocytopenia, but the jury is still out on other
diseases. In most cases, H. pylori is believed to be one of several causes, meaning that H. pylori eradication will
only benefit a subset of patients.”
Non-classic H. pylori presentation
“Since the discovery that gastric mucosa could be colonized by bacteria, evidence of greater than 50
extragastric manifestations has been reported, linking H. pylori infection and the development of diseases
associated with cardiology, dermatology, endocrinology, obstetrics and gynecology, hematology, pneumology, neurology, odontology, ophthalmology,
otorhinolaryngology, and pediatrics.”
Helicobacter pylori and Hematologic Diseases German Campuzano-Maya.
http://dx.doi.org/10.5772/62971
H. pylori & CVD
H. pylori & CVD
Possible mechanisms
1. Specific location of bacteria
2. Gut-brain axis
3. Systemic inflammation
4. Microbiome perturbation
5. LPS (H. pylori is gram negative) and leaky gut
6. Nutrient deficiencies
– B12, iron, vitamin C are 100% confirmed; likely others
7. Stress response
– HPA, HPT, HPG axes
1. Specific location of bacteria
Testerman TL et al . H. pylori pathogenesis, diagnosis, and treatment
Specific location of bacteria
“H. pylori DNA has been amplified from atherosclerotic plaques and the oral cavity for years, but the
significance in these locations is still debated. Many have questioned whether H. pylori truly colonizes those
sites. For example, macrophages might have phagocytized H. pylori in the stomach and later traveled
to atherosclerotic plaques.”
Testerman TL et al . H. pylori pathogenesis, diagnosis, and treatment
2. Gut-Brain Axis
“The bidirectional relationship between H. pylori infection and the brain-gut axis influences both the contagion process and the host’s neuroendocrine-
immunological reaction to it, resulting in alterations in cognitive functions, food intake and appetite,
immunological response, and modification of symptom
sensitivity thresholds.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017036/
Gut-Brain Axis
“Furthermore, disturbances in the upper and lower digestive tract permeability, motility and secretion can
occur, mainly as a form of irritable bowel syndrome. Many of these abnormalities disappear following H.
pylori eradication.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017036/
3. Systemic inflammation
“Biologically, H. pylori infection to gastric tissue can induce inflammatory cytokines, such as c- reactive
protein (CRP), IL-series including IL1, IL6, IL18, etc, and TNF-α, which leads to systemic inflammation.”
Testerman TL et al . H. pylori pathogenesis, diagnosis, and treatment
Systemic inflammation
“Hp, by inducing several inflammatory mediators such as tumor necrosis factor-α and interleukin (IL)-6, may
contribute to blood-brain barrier (ΒΒΒ) disruption leading to brain neurodegenerative diseases.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585404/
4. Microbiome perturbation
“Moreover, H. pylori infection led to significantly different population structures in both the gastric and
intestinal microbiota. These studies indicate that H. pylori influences the microbiota and host immune
responses not only locally in the stomach, but distantly as well, affecting important target organs.”
Cell Rep. 2016 February 16; 14(6): 1395–1407. doi:10.1016/j.celrep.2016.01.017.
Microbiome perturbation
“Our preliminary stool metagenomics study shows that eradication of H. pylori caused perturbation of the gut
microbiome and may indirectly affect the health of human. Clinicians should be aware of the effect of
broad spectrum antibiotics in H. pylori eradication and be cautious in the clinical management of H. pylori,
particularly in immunocompromised patients.”
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151893
5. Endotoxin / LPS
“Lipopolysaccharides from H. pylori link to the activation of Toll-like receptors (TLRs), expressed mainly
in macrophages and dendritic cells, which results in energy harvesting, fat accumulation and consequently
insulin resistance.”
Testerman TL et al . H. pylori pathogenesis, diagnosis, and treatment
6. Nutrient deficiencies
• The literature shows categorically that H. pylori can cause iron deficiency anemia and B12 deficiency in patients of all ages.
Helicobacter pylori and Hematologic Diseases German Campuzano-Maya. http://dx.doi.org/10.5772/62971
Nutrient deficiencies
“There is evidence linking H. pylori to the aetiology of otherwise unexplained iron-deficiency anaemia,
idiopathic thrombocytopenic purpura (ITP) and vitamin B12 deficiency. In these disorders, H. pylori should be
sought and eradicated.”
http://gut.bmj.com/content/61/5/646.full
Nutrient deficiencies
• IDA symptoms:
– Fatigue
– Weakness
– Palor
– Headache
– Hair loss
– Glossitis, mouth ulcers
– Tinnitus
– Palpitations
• CYP450 need haeme
• B12 deficiency symptoms:
– Weakness
– Fatigue
– Palpitations
– Shortness of breath
– Palor
– GI complaints
– Nerve & muscle issues
– Vision loss
– Depression, memory loss, or behavioral changes
Nutrient deficiencies
• H. pylori causes low stomach acid in many people.
• Implications for zinc, magnesium, folates
• Vit C appears to decline in H. pylori infection Fat soluble antioxidants (A and E) are typically lower in H. pylori.
• Research is appearing on vitamin D and H. pylori.
– Measure homocysteine in H. pylori patients and you will see high levels most of the time.
Methylation and detoxification
7. HPA axis
“Compelling data has been amassed indicating that soluble factors, or cytokines, emanating from the immune system can have profound effects on the
neuroendocrine system, in particular the hypothalamic-pituitary-adrenal (HPA) axis.”
https://www.ncbi.nlm.nih.gov/pubmed/26476562
HPA axis
“Endotoxin is considered to be a systemic (immunological) stressor eliciting a prolonged
activation of the HPA axis. The HPA-axis response after an endotoxin challenge is mainly due to released
cytokines (IL-1, IL-6 and TNF-alpha) from stimulated peripheral immune cells, which in turn stimulate
different levels of the HPA axis.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1224723/
HPA axis, neurotransmission
https://www.hindawi.com/journals/grp/2016/7150959/fig2/
HPA Axis, neurotransmission
http://gut.bmj.com/content/47/6/861.full
HPA Axis, neurotransmission
Infertility, pregnancy
World J Gastroenterol 2014 January 21; 20(3): 654-664
“Doctor, how could H. pylori NOT cause symptoms all
around my body?”
H. pylori testing
• Conventional testing:
– Endoscopy/biopsy: invasive but can spot serious issues and hernias).
– Blood test: ok initially but useless as a retest.
– Breath test: H. pylori is not the only organism that influences the result.
– Stool antigen: non-invasive and can be done commercially
– None of these have strain identification.
PCR for H. pylori
• Most people, including doctors, don’t know about PCR.
• Yet is it used in the research setting most of the time.
• The paper opposite is a good one to have to hand if clients ask.
PCR for H. pylori
“The choice among these tests depends on the cost and availability, clinical setting, prevalence of H. pylori
infection in the population and most importantly, the performance of the test itself.”
QATAR MEDICAL JOURNAL. VOL. 2014 / ART. 1
PCR for H. pylori
“Real-time PCR is efficacious for H. pylori detection and genotypic resistance-guided quadruple therapy has a high efficacy in treating functional dyspepsia with H.
pylori infection.”
http://www.ncbi.nlm.nih.gov/pubmed/25629566
PCR for H. pylori
“Simple extraction methods are available to efficiently extract DNA from human stools and nested-PCR
targeting the 23S rRNA gene have proven to be highly sensitive for the detection of H. pylori. Detection of clarithromycin susceptibility/resistance is important
clinically and the mutation of the 23S rRNA gene responsible for resistance can also be detected using stool. This method can be modified for other clinical
samples such as gastric juice or biopsy material.”http://www.ncbi.nlm.nih.gov/pubmed/23104297
PCR for H. pylori
“Our newly developed nested PCR assay is at least as sensitive as histology and may be useful for H. pylori
detection in patients unfit for endoscopic examination.”
http://www.ncbi.nlm.nih.gov/pubmed/23104297
PCR for H. pylori
“PCR techniques can be used to detect H. pylori DNA most reliably in biopsy samples, but saliva and feces
have also been used. PCR sensitivity nearing 100% and specificity of 100% can be obtained. Contamination
from improperly cleaned endoscopes may create false positive results. False negative results may occur due to
PCR inhibitors within gastric tissue or feces. Wide acceptance of PCR techniques in the clinical setting is
limited and PCR is primarily used in research settings.”
Testerman TL et al . H. pylori pathogenesis, diagnosis, and treatment
PCR for H. pylori
“PCR is a DNA amplification that uses the rapid production of a target DNA sequence to identify H. pylori. It is capable of identifying H. pylori strains in biopsies with chronic gastritis and non-identifiable bacteria. PCR can be
performed on samples obtained by invasive and non-invasive methods using samples obtained of saliva,
gastric juice, and stools. It is simple to perform and can provide additional genotypic information about the strain
and antibiotic susceptibilities. PCR could be complete in 3–4 hours, and it is capable to detect the point mutations
attributed to the development of clarithromycin resistance.”
PCR for H. pylori
“In the past, drawbacks with DNA analysis have been its incredible sensitivity and potential for non- specific binding.
Because of the tremendous sensitivity of DNA analysis, other methods detected microbes that were not actually present in high numbers at the time of stool collection and which may
not have been clinically relevant. Cross-reactivity can also be a problem with DNA analysis lending to issues with specificity. With the GI-MAP method, probes are attached to different
beads in such a way that non-specific binding is nearly eliminated, lowering false positive rates that have been
associated with previous DNA methods.”
Diagnostic Solutions White Paper
Standard H. pylori treatment
Antibiotic resistance
• Clarithromycin resistance is 70% globally.
• Resistance to other antibiotics varies.
• The literature suggests that after 2 failures, strain and resistance should be investigated
• The GI-MAP does this for us before any treatment!
Biofilms
• Biofilms can develop on biotic and abiotic surfaces.
• Planktonic state > attaches to surfaces (sessile).
• Evasion of immune defenses.
• Antibiotics cannot penetrate.
• Prolongs infection.
• Dispersal cycle.
– Candida, Pseudomonas and many others can develop biofilms.
Biofilms
Biofilms
“H. pylori was first found to demonstrate an ability to form in vitro biofilms in the early and late 1990s with solid evidence of this ability reported by Stark et al in
1999. More recent reports on the ability of H. pylori to form biofilms within in vitro and in vivo environments,
specifically the gastric mucosa, have now been demonstrated.”
World J Gastrointest Pathophysiol 2014 August 15; 5(3): 122-132
Structuring a “stomach cleanse”
• Herbal and nutritional protocols can be run before or after antibiotics.
– 7-10 days of biofilm busters first?
• I typically do not have people taking meds and herbs at the same time (too many potential interactions).
• Probiotics can be taken to lessen side effects and improve triple/quadruple therapy efficacy.
Structuring a “stomach cleanse”
• Anti H. pylori foods:– Garlic– Coconut oil (lauric acid)– Olive oil (phenols)– Pine nut oil (?)– Berries (esp. cranberry)– Red wine (?)– Ginger, turmeric, cayenne/chilli– Green tea– Propolis– Manuka honey– Probiotic foods– Broccoli, especially sprouts
• Other crucifers due to sulforaphane content
Structuring a “stomach cleanse”
• Anti H-pylori supplements:– NAC (biofilm)– Other biofilm disruptors (e.g. silver, enzymes)– Mastic gum– Garlic– DGL– Black seed oil– Propolis– Curcumin– Resveratrol– Berberine– Bismuth– Oregano oil– Chinese, Mexican, Iranian, Amazonian herbs
Structuring a “stomach cleanse”
• Things to consider with the literature:
– In vitro or in vivo?
– Inhibition versus killing effect
– Animal or human models
– What actually works in the real world, with real people?
Case study #1
• Female, 38
• Gastritis, GERD
• Anxiety
• Weight loss
• History of H. pylori
– Stool test also showed high Candida albicans and other dysbiotic bacteria (incl. Pseudmonas).
– No improvement with any functional medicine protocol (emotional issues currently being addressed)
Case Study #2
• Female, 30
• Multiple symptoms –complex history
• Klebsiella and Morganella (rare) detected– All symptoms gone in 90-
days using stomach cleanse and general antimicrobials / probiotics.
Case Study #3
• Female, 29
• Extreme fatigue
• GI issues
• Muscle pain
– All symptoms gone in 90-days on GF, DF diet; increased protein, stomach cleanse.
Case Study #3
Case study #4
• Female, 49
• Fatigue, depression
• Hopelessness
• GI problems
• Candida also on test
– All symptoms gone in 60-days using stomach cleanse, fungal cleanse and increased protein intake.
Thanks and questions!
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