Hashimoto’s Thyroiditis Caused by H. Pylori Infection

A 54 year old optometrist and mother of three arrived in my office complaining of fatigue, anemia, hypertension, hot flashes, night sweats and insomnia. Her previous doctor had made the diagnosis of Hashimoto’s thyroiditis by virtue of a TPO (thyroid peroxidase antibody) level of greater than 900 IU/ml. Her previous doctor also started her on blood pressure medication for new onset of hypertension. The patient takes iron supplements for iron deficiency anemia. Previous labs showed a high FSH indicating the patient is post-menopausal, and a good candidate for hormone replacement. On physical examination, her tendon reflexes were delayed and she had a mild hand tremor. Blood pressure on anti-hypertensive medication was normal. Our laboratory studies then showed a positive H. Pylori Breath Test indicating active infection in the stomach. (Note: this was missed by the previous doctor.) Thyroid hormone levels showed a mildly elevated TSH of 4.7, with a normal Free T3, T4 and reverse T3.

Header Image: Electron Microscope view of H. pylori organism (dark rectangular struture upper left) with multiple flagella (long spagetti like fillaments). Author :Yutaka Tsutsumi, M.D. Professor Department of Pathology, Fujita Health University School of Medicine, Copyrighted as free use. Courtesy of Wikimedia Commons.(EM has negative staining)

The patient was treated with triple therapy for the H. Pylori infection. In addition, a basket of anti-H. Pylori supplements was given (see below for details) .  Repeat H. Pylori breath test 12 weeks later was negative indicating successful eradication. 12 weeks after the H. Pylori eradication, the patient’s blood pressure returned to normal and the patient was able to discontinue the anti-hypertensive medication. No thyroid medication was given at the present time. However, the patient was treated with myo-inositiol for the mildly elevated TSH. For more on this see Myo-inositol for Hashimmoto’s Thyroiditis.  The patient was then started on natural, bioidentical progesterone cream 50 mg/gram  (half gram applied topically twice a day.) 12 weeks later, repeat labs showed the TSH had come down to 3.1 mIU/L and the TPO antibody had also declined from >900 to 674 IU/ml. The patient reports she is feeling better with resolution of most of her original symptoms.

Above image: Schematic diagram of virulence factors of Helicobacter pylori. Purple Arrow = Body of H.Pylori organism. Black Arrow = Flagella.
Red Arrow = Pili (needle-like structure for injecting toxis into cells, cagA (Cytotoxic A Gene) and IL-8 induction, Host cell growth and apoptosis inhibtion. Orange vacuoles on right =  Effector vacuoles. Notice vacuoles at left (Green Vacuoles containing exotoxins and Blue vacuoles containing proteolytic enzymes). These vacuoles are secreted by the H. Pylori orgnism and may circulate in the blood stream. Author: Y_tambe, GFDL, CC-by-sa, GNU Free Documentation License, Version 1.2. Courtesy of Wikimedia Commons.

What is Causing the Hashimoto’s Autoimmune Thyroid Disease?

The next most logical question is:

What could be the cause of Hashimoto’s Thyroiditis, Hypertension and Iron deficiency anemia? The answer is H.Pylori infection with the virulent strain called the CagA strain ( Cyto-toxin Associated Gene A) which secretes cyto-toxins and inflammatory exosomes which circulate in the blood stream causing endothelial dysfunction, hypertension and accelerated atherosclerotic vascular disease identified by increasing coronary artery calcification on CAT scan, the calcium score. The H. Pylori infection is associated with auto-immune gastritis, and atrophic gastritis which causes iron malabsorption, thus explaining the iron deficiency anemia.

H. Pylori Causes Auto-Immune Thyroid Disease

For decades now, H. Pylori infection has been implicated in the etiology of the two auto-immune thyroid diseases, Hashimoto’s and Graves’ disease. Testing for H. Pylori is key for all auto-immune thyroid patients. This can be done easily with the breathe test developed in 1991 by Drs. Robin Warren and Barry Marshal. These are the two Australian pathologists who received the 2005 Nobel Prize in Medicine for the discovery of H. Pylori as the cause of gastritis, gastric ulcer and gastric cancer.  H. Pylori eradication is the cornerstone of treatment in the autoimmune thyroid patient.

Antibodies Decline After H Pylori Eradication

In 2004, Dr. Giovanni Bertalot studied 5 patients with Hashimoto’s Thyroiditis who were positive for H. Pylori. In all five patients, the anti-TPO and anti-thyroglobukin antibodies declined after H. Pylori eradication with triple therapy. (61)

Above Image : Fig 2 . A list of Autoimmune diseases Associated with H pylori, Courtesy of Dr. Li Wang, 2022. (62)

H. Pylori Implicated in Many Autoimmune Diseases

In 2022, Dr. Li Wang reviewed the medical literature on H. Pylori as possibly acting as a trigger for other auto-immune disease, such as inflammatory bowel disease, autoimmune thyroiditis, type 1 diabetes mellitus, autoimmune liver diseases, rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, Sjogren’s syndrome, chronic urticaria and psoriasis, writing:

The researches have revealed that H. pylori is a potential trigger of gastric autoimmunity, and it may be associated with other autoimmune diseases, both innate and acquired. This paper reviews the current support or opposition about H. pylori as the role of potential triggers of autoimmune diseases, including inflammatory bowel disease, autoimmune thyroiditis, type 1 diabetes mellitus, autoimmune liver diseases, rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, as well as Sjogren’s syndrome, chronic urticaria and psoriasis, and tried to explain the possible mechanisms. (62)

In 2021, Dr. Masoud Youssefi did a systematic review and meta-analysis of Helicobacter Pylori and auto-immune diseases finding association of the more virulent strains (CagA) with systemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis and autoimmune pancreatitis, writing:

The frequency and relationship between H. pylori infection and systemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis, and autoimmune pancreatitis were evaluated using the data from 43 studies involving 5052 patients. According to statistical analysis it is probable that infection with more virulent strains of H. pylori (such as H. pylori cagA positive) can increase the risk of autoimmune diseases. (63)

H. Pylori Eradication

My office uses a second generation improved version of triple therapy (two antibiotics and a PPI antiacid drug) shown in 2007 by Dr. Dino Vaira to achieve a higher eradication rate (89% vs. 77%) compared to the first generation triple therapy protocol. (1-7)

For First Five Days:

Omeprazole 20 mg caps, One PO BID x5 days #10
Amoxicillin 500 mg caps, Two caps PO BID x 5 days #20

For the Second 5 Days:

Omeprazole 20 mg caps, One PO BID x5 days #10
Clarithromycin 500 mg tabs, One tab PO BID x 5 days #10
Tinidazole, (Generic Tindamax) 500 mg Tabs, One tab PO BID X 5 days #10

If the patient is allergic to penicillin derivatives, the Amoxicillin is deleted and replaced with Clarithromycin for the first 5 days.

To Increase the eradication rate even further, we add to the Triple therapy a list of natural treatments:

H. Pylori Natural Treatments with Links to Product on Amazon

InnovixLabs Multi-Strain Probiotic Supplement – for Gut Health, 50 Billion CFU, Probiotics Lactobacillus Acidophilus, Prebiotics and Probiotics, 60 Pills
Take one capsule with meal daily.

Horbaach Mastic Gum 1500mg 120 Capsules | Non-GMO & Gluten Free
Three (3) capsules daily in between meals

Pepto Bismol Chewable Tablets, 48 Count, for Relief of Gas, Anti Diarrhea, Heartburn, Nausea, Upset Stomach, and Indigestion
Two tablets twice a day in between meals

Biotics Research A.D.P. © – Highly Concentrated Oil of Oregano, Optimal Absorption and Delivery. Antioxidant, Supports Microbial Balance
One tablet daily between meals

Conclusion: H. Pylori is not only a gastric pathogen, it is also implicated in auto-immune thyroid disease, hypertension, atherosclerosis, and auto-immune gastric atrophy with malabsorption of iron and B12. The gastric atrophy (or auto-immune gastritis) may impair absorption of thyroxine, making the hypothyroid patient refractory to treatment. The highly virulent strain called CagA causes the most damage, sending out inflammatory exosomes into the circulation which cause vascular and neurological disease, and may be implicated in a host of other auto-immune disease as mentioned above. H. Pylori inflammatory exosomes have been implicated as causing colitis,in the colon downstream to the  gastric infection. Testing for H. Pylori with the Breath Test should be done routinely on every patient, and when positive, the H Pylori infection should be eradicated with second generation triple therapy. Natural supplements with antimicrobial activity against H Pylori should be added to improve eradication rate. If your doctor has not ordered an H. Pylori Breath test, then you need a new doctor.

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Natural Thyroid Toolkit

If you liked this article, you might like my new book, Natural Thyroid Toolkit available on Amazon. If you purchase a book, remember to  leave a favorable review. That would be much appreciated. See the book cover, left image.

Articles with related interest:

Addressing the Auto-Immune component of Thyroid Disease

Myo-inositol for Hashimoto’s Thyroiditis. 

All thyroid articles

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com 

References:

H. Pylori Eradication

1) Vaira, Dino, et al. “Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial.” Annals of internal medicine 146.8 (2007): 556-563.
Results: The eradication rate achieved with the sequential regimen
was significantly greater than that obtained with the standard treat ment in the intention-to-treat analysis (89% vs. 77%; P
0.0134;
difference, 12% [95% CI, 3% to 20%]), t

2) Moshkowitz, M., et al. “One week triple therapy with omeprazole, clarithromycin and tinidazole for Helicobacter pylori: differing efficacy in previously treated and untreated patients.” Alimentary pharmacology & therapeutics 10.6 (1996): 1015-1019.

3) Choi, I. J., et al. “Efficacy of low‐dose clarithromycin triple therapy and tinidazole‐containing triple therapy for Helicobacter pylori eradication.” Alimentary pharmacology & therapeutics 16.1 (2002): 145-151.

4)  Silva, Fernando Marcuz, et al. “Factors affecting Helicobacter pylori eradication using a seven-day triple therapy with a proton pump inhibitor, tinidazole and clarithromycin, in brazilian patients with peptic ulcer.” Revista do Hospital das Clínicas 56 (2001): 11-16.

5) Moayyedi, et al. “The effectiveness of omeprazole, clarithromycin and tinidazole in eradicating Helicobacter pylori in a community screen and treat programme.” Alimentary pharmacology & therapeutics 14.6 (2000): 719-728.

6) Bazzoli, Franco, et al. “Short-term low-dose triple therapy for the eradication of Helicobacter pylori.” European journal of gastroenterology & hepatology 6.9 (1994): 773-778.

7) Calabrese, C., et al. “Pantoprazole, azithromycin and tinidazole: short duration triple therapy for eradication of Helicobacter pylori infection.” Alimentary pharmacology & therapeutics 14.12 (2000): 1613-1617.

H Pylori Associated with Hashimotos and Graves

8) Hou, Yi, et al. “Meta-analysis of the correlation between Helicobacter pylori infection and autoimmune thyroid diseases.” Oncotarget 8.70 (2017): 115691.

H. pylori infection correlated with GD [Graves Disease] and HT [Hashioto’s Thyroiditis], and the eradication of H. pylori infection could reduce thyroid autoantibodies.

https://pubmed.ncbi.nlm.nih.gov/23737311/
9) Aghili, Rokhsareh, et al. “The association of Helicobacter pylori infection with Hashimoto’s thyroiditis.” Acta Medica Iranica (2013): 293-296.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339455/
10) Choi, Yun Mi, et al. “Association between thyroid autoimmunity and Helicobacter pylori infection.” The Korean Journal of Internal Medicine 32.2 (2017): 309.

Results – H. pylori IgG antibodies were found in 2,875 subjects (52.3%), and TPO-Ab were found in 430 (7.8%). Individuals positive for H. pylori Ab were older than those negative for H. pylori Ab (p < 0.01). The proportion of females was significantly higher in the TPO-Ab positive group (41.0% vs. 64.2%, p < 0.01). Prevalence of TPO-Ab positivity was higher in subjects with H. pylori infection (8.6% vs. 7.00%, p = 0.03), and this association was significant after adjusting for age, sex, and body mass index (odds ratio, 1.02; 95% confidence interval, 1.00 to 1.03; p = 0.04).

In our study, prevalence of TPO-Ab positivity is more frequent in subjects with H. pylori infection. Our findings suggest H. pylori infection may play a role in the development of autoimmune thyroiditis.

11) Astl, J., and I. Šterzl. “Activation of Helicobacter pylori causes either autoimmune thyroid diseases or carcinogenesis in the digestive tract.” Physiological Research 64 (2015).

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https://www.nejm.org/doi/full/10.1056/NEJMoa043903
12) Centanni, Marco, et al. “Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis.” New England Journal of Medicine 354.17 (2006): 1787-1795.

Thyroxine absorption impaired by H Pylori/chroonic gastritis, resolves with eradication of H Pylori.

https://pubmed.ncbi.nlm.nih.gov/21435090/
13) Bugdaci, Mehmet Sait, et al. “The role of Helicobacter pylori in patients with hypothyroidism in whom could not be achieved normal thyrotropin levels despite treatment with high doses of thyroxine.” Helicobacter 16.2 (2011): 124-130.
Conclusion: In hypothyroid cases, H. pylori gastritis may be responsible for an inadequate response to the treatment [thyroxine]. H. pylori eradication in the cases receiving high doses of thyroxine has a risk for thyrotoxicosis.

Graves and H Pylori

https://pubmed.ncbi.nlm.nih.gov/21073613/
14) Bassi, Vincenzo, et al. “Identification of a correlation between Helicobacter pylori infection and Graves’ disease.” Helicobacter 15.6 (2010): 558-562.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296983/
15) Bassi, Vincenzo, et al. “Autoimmune thyroid diseases and Helicobacter pylori: the correlation is present only in Graves’s disease.” World Journal of Gastroenterology: WJG 18.10 (2012): 1093.

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hashimotos and Autoimmune gastritis

serum parietal cell (PCA) and/or intrinsic factor (IFA) autoantibodies (2, 3). (pernicious anemia)

16) Cellini, Miriam, et al. “Hashimoto’s thyroiditis and autoimmune gastritis.” Frontiers in endocrinology 8 (2017): 92.
The term “thyrogastric syndrome” defines the association between autoimmune thyroid disease and chronic autoimmune gastritis (CAG), and it was first described in the early 1960s.

The thyrogastric syndrome was initially described in the early 1960s and initially characterized by the presence of thyroid autoantibodies in patients with pernicious anemia, the latter being used as synonymous for atrophic gastritis (1). More recently, the autoimmune gastritis has been better characterized classifying chronic atrophic gastritis, with or without the PA, based on the histological evaluation and the presence of serum parietal cell (PCA) and/or intrinsic factor (IFA) autoantibodies (2, 3). Based on these criteria, the association between autoimmune thyroid disorders and chronic autoimmune gastritis (CAG) has also been reassessed (4, 5) and nowadays is included in the adult form of polyglandular autoimmune syndrome (PAS), characterized by two or more endocrine and non-endocrine autoimmune disorders (6). In particular, Betterle and colleagues have proposed the inclusion of thyrogastric syndrome in the PAS Type 3b, in which Hashimoto’s thyroiditis (HT) occurs also associated with non-endocrine autoimmune gastrointestinal disorders and where it plays a pivotal role (7, 8). This is in keeping with the evidence that chronic autoimmune thyroiditis represents the more prevalent autoimmune disorder worldwide making the frequency of thyrogastric syndrome quite high (4). This notion is supported by the high percentage (12–40%) of positivity of PCA in adult patients with HT (9) which, in turn, is present in approximately 40% of patients with atrophic gastritis (10). Besides the fact that the thyroid and the stomach share some embryological and biochemical features (11), some intriguing similarities have been observed even in the putative pathogenic mechanisms, which characterize the thyrogastric syndrome (12).

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CagA protein and Pathogenicity of H Pylori—-CagA is also known as the first bacterial onco-protein, ranking the H. pylori-mediated adenocarcinoma as the second most deadly cancer type worldwide.

17) Figura, N., et al. “The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders.” Journal of Physiology and Pharmacology 50.5 (1999): 817-826.The overall prevalence of infection by CagA-positive H. pylori was significantly higher in patients with ATD (23/41, or 56.0%) than that in controls (8/33, or 24.2%) (P = 0.006, OR = 3.99, RR = 2.31).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167994/
18) Figura, Natale, et al. “Helicobacter pylori infection and autoimmune thyroid diseases: the role of virulent strains.” Antibiotics 9.1 (2019): 12.
Results: H. pylori infection prevalence was significantly increased in GD (66.6%) and HT (64.4%) patients, vs. 29.4% of controls and 34.0% of AT. CagA seropositivity was significantly more frequent in GD (46.1%) and HT (46.9%) infected patients, vs. infected controls (20%). fT3 and fT4 median values were significantly decreased in infected CagA+ GD patients vs. uninfected GD patients. IL-1β median values were increased in patients respect to controls, independently of the clinical form of AITD. Median values of IL-6, TNF-α and anti-Tg autoantibodies in CagA infected patients were significantly higher than those measured in infected CagA− and uninfected patients and in infected CagA+ controls
Conclusions: Overall H. pylori and CagA+ H. pylori infection were associated with GD and HT, putatively through an increased inflammatory status and molecular mimicry.

https://pubmed.ncbi.nlm.nih.gov/23544831/
19) Shi, Wei-Jia, et al. “Associations of Helicobacter pylori infection and cytotoxin-associated gene A status with autoimmune thyroid diseases: a meta-analysis.” Thyroid 23.10 (2013): 1294-1300.

Helicobacter pylori infection is reportedly associated with extradigestive diseases such as immune thrombocytopenic purpura and coronary heart disease.

Five of the seven articles reported the association of CagA seroprevalence and ATDs. CagA seropositivity significantly increased the risk for ATDs by 2.24-fold [CI 1.06-4.75].

Conclusions: Both the prevalence of H. pylori infection and the seroprevalence of CagA-positive strains are associated with ATDs. These findings suggest that H. pylori infection potentially plays a part in the development of ATDs.

https://pubmed.ncbi.nlm.nih.gov/26796299/
20) Tohidpour, Abolghasem. “CagA-mediated pathogenesis of Helicobacter pylori.” Microbial pathogenesis 93 (2016): 44-55.
Abstract

Helicobacter pylori has been described as the main etiologic agent of gastric cancer, causing a considerable rate of mortality and morbidity in human population across the world. Although the infection mainly begins asymptomatically, but simply develops to peptic ulcer, chronic gastritis, lymphoma of the gastric mucosa and eventually adenocarcinoma. The major pathological feature of H. pylori infection is due to the activity of the cytotoxin-associated gene A (CagA), a 125-140 kDa protein encoded by the cag pathogenicity island (cagPAI). CagA is also known as the first bacterial onco-protein, ranking the H. pylori-mediated adenocarcinoma as the second most deadly cancer type worldwide. Upon cytoplasmic translocation CagA undergoes interacting with numerous proteins in phosphorylation dependent and independent manners within the gastric epithelial cells. The profound effect of CagA on multiple intracellular pathways causes major consequences such as perturbation of intracellular actin trafficking, stimulation of inflammatory responses and disruption of cellular tight junctions. Such activities of CagA further participate in development of the hummingbird phenotype and gastric cancer. This review is sought to provide a structural and functional analysis of the CagA protein with focus on demonstrating the molecular basis of the mechanism of CagA intracellular translocation and its interaction with intracellular targets.

21) Takahashi-Kanemitsu, Atsushi, Christopher T. Knight, and Masanori Hatakeyama. “Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis.” Cellular & molecular immunology 17.1 (2020): 50-63.

22) Ansari, Shamshul, and Yoshio Yamaoka. “Helicobacter pylori virulence factor cytotoxin-associated gene A (CagA)-mediated gastric pathogenicity.” International journal of molecular sciences 21.19 (2020): 7430.

23) Xu, Shaohan, et al. “CagA orchestrates eEF1A1 and PKCδ to induce interleukin-6 expression in Helicobacter pylori-infected gastric epithelial cells.” Gut Pathogens 12 (2020): 1-11.

24) Takahashi-Kanemitsu, Atsushi, et al. “The Helicobacter pylori CagA oncoprotein disrupts Wnt/PCP signaling and promotes hyperproliferation of pyloric gland base cells.” Science Signaling 16.794 (2023): eabp9020.

Hypertension / Atherosclerosis/ CagA+

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104887/
25) Dore, Maria Pina, et al. “Increased risk to develop hypertension and carotid plaques in patients with long-lasting Helicobacter pylori gastritis.” Journal of Clinical Medicine 11.9 (2022): 2282.
Results. A total of 7152 clinical records from patients older than 30 years (63.4% women) were available for the study. Hypertension was present in 2039 (28.5%) patients and the risk was significantly increased in those with long-lasting H. pylori infection after adjusting for age decades, sex, BMI, cigarette smoking, diabetes, and dyslipidemia (OR 1.17, 95% CI 1.02–1.35). In addition, the long-lasting H. pylori infection was an independent risk for carotid plaques (OR 2.15, 95% CI 1.14–4.09). Conclusions. Our retrospective study demonstrated that long-lasting H. pylori infection is an independent risk factor for hypertension and the presence of carotid lesions after adjusting for potential confounders, although further validation our findings is needed from prospective studies.

https://pubmed.ncbi.nlm.nih.gov/37792567/
26) Dore, Maria Pina, et al. “Helicobacter pylori infection and rheumatoid arthritis as risk enhancers’ factors for atherosclerotic cardiovascular diseases.” Helicobacter 28.6 (2023): e13025.
atherosclerotic cardiovascular diseases (aCVDs),long-lasting infection (LLHp)
Results: Among 4821 records (mean age 52.1 ± 16.7 years; 66.0% female), H. pylori infection was detected in 2262 patients, and more specifically, a LLHp infection was present in 1043 (21.6%). Three-hundred-three (6.3%) patients were diagnosed with aCVD, and 208 (4.3%) with RA. In patients with aCVD (cases), the LLHp infection (33.3% vs. 20.8%, p < 0.0001) and RA (12.2% vs. 3.8%, p < 0.0001) were more frequent in cases compared with controls (patients without aCVD). After adjusting for traditional aCVD risk factors, ORs significantly increased for LLHp infection (1.57; 95% CI 1.20-2.06) and RA (2.63; 95% CI 1.72-4.02).

Interestingly, the LLHp infection in patients with RA showed an overall addictive effect on the risk for aCVD (7.89; 95% CI 4.29-14.53).

Conclusions: According to our findings, patients with RA should benefit from being screened and eventually treated for H. pylori infection.

https://pubmed.ncbi.nlm.nih.gov/35378540/
27) Yue, Limin, et al. “Relationship between Helicobacter pylori and Incident Hypertension as well as Blood Pressure: A Systematic Review and Meta-Analysis.” Digestive diseases (Basel, Switzerland) 41.1 (2023): 124-137.

Conclusion: This meta-analysis suggested that H. pylori infection increased the risk of hypertension. This may provide a new strategy for hypertension prevention.

https://www.scielo.br/j/abc/a/mnZP3ZV8s9fH5vRNXnh8x9t/?lang=en
28) Huang, Mengyun, et al. “Association between Helicobacter pylori infection and systemic arterial hypertension: a meta-analysis.” Arquivos Brasileiros de Cardiologia 117 (2021): 626-636.
A total of 17 studies involving 6,376 cases of hypertension and 10,850 controls were enrolled. H. pylori infection rate in hypertension patients and controls were 64.9% and 56.3%, respectively. A significantly positive association was shown between H. pylori infection and hypertension with an overall OR of 2.07 (95% CI: 1.46–2.94; p < 0.05).
This meta-analysis indicated that H. pylori infection is positively associated with hypertension.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10049385/
29) Sundqvist, Martin O., et al. “Helicobacter pylori virulence factor cytotoxin-associated gene A (CagA) induces vascular calcification in coronary artery smooth muscle cells.” International Journal of Molecular Sciences 24.6 (2023): 5392.

In vitro study using coronary artery smooth muscle cells (CASMCs)

In conclusion, this is the first study to show that CagA induces pro-inflammatory and pro-calcific effects on CASMCs [coronary artery smooth muscle cells] through which H. pylori may induce vascular calcification and contribute to cardiovascular disease.

Helicobacter pylori (H. pylori) has been associated with cardiovascular diseases. The pro-inflammatory H. pylori virulence factor cytotoxin-associated gene A (CagA) has been detected in serum exosomes of H. pylori-infected subjects and may exert systemic effects throughout the cardiovascular system. The role of H. pylori and CagA in vascular calcification was hitherto unknown. The aim of this study was to determine the vascular effects of CagA through human coronary artery smooth muscle cell (CASMC) osteogenic and pro-inflammatory effector gene expression as well as interleukin 1β secretion and cellular calcification. CagA upregulated bone morphogenic protein 2 (BMP-2) associated with an osteogenic CASMC phenotype switch and induced increased cellular calcification. Furthermore, a pro-inflammatory response was observed. These results support that H. pylori may contribute to vascular calcification through CagA rendering CASMCs osteogenic and inducing calcification.

Recently, one study revealed that CagA could be detected in exosomes in systemic circulation of H. pylori-infected patients. Furthermore, following induced CagA expression, gastric epithelial cells secrete CagA-containing exosomes [23], indicating that this pro-inflammatory virulence factor could reach distal organs through systemic circulation.

However, one study detected CagA in the vasa vasorum of human aortic sections from CagA-positive patients using immunohistochemical staining [34], which further indicates that systemic occurrence of CagA is possible and relevant in patients. In vivo mouse models using CagA-containing outer membrane vesicles of H. pylori as treatment accelerated atherosclerosis when administrated intra-gastrically [35].

30) Xia, Xiujuan, et al. “CagA+ Helicobacter pylori, not CagA–Helicobacter pylori, infection impairs endothelial function through exosomes-mediated ROS formation.” Frontiers in Cardiovascular Medicine 9 (2022): 881372.

https://pubmed.ncbi.nlm.nih.gov/35716599/
31) Tahmina, Kamrunnesa, et al. “Transgenically expressed Helicobacter pylori CagA in vascular endothelial cells accelerates arteriosclerosis in mice.” Biochemical and Biophysical Research Communications 618 (2022): 79-85.

Arteriosclerosis is intimately associated with cardiovascular diseases. Recently, evidence accumulated that infection with Helicobacter pylori cagA-positive strains, which causes gastritis, peptic ulceration, and gastric cancer, is also involved in the development of arteriosclerosis.

The cagA-encoded CagA protein is injected into the attached gastric epithelial cells via the type IV secretion system. We previously showed that CagA-containing exosomes are secreted from CagA-injected gastric epithelial cells and enter the systemic blood circulation, delivering CagA into endothelial cells. In the present study, transgenic mice were established in which CagA was selectively expressed in endothelial cells by Cre-loxP system. Treatment of the mice with a high-fat diet revealed that atherogenic lesions were induced in mice expressing CagA in vascular endothelial cells but not in CagA-nonexpressing mice.
To investigate the effects of CagA on endothelial cells, we also established conditional CagA-expressing human vascular endothelial cells using the Tet-on system. Upon induction of CagA, a dramatic change in cell morphology was observed that was concomitantly associated with the loss of the endothelial cells to form tube-like structures. Induction of CagA also activated the pro-inflammatory transcription factor STAT3. Thus, exosome-delivered CagA deregulates signals that activates STAT3 in endothelial cells, which accelerates inflammation that promotes arteriosclerosis/atherosclerosis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611526/
32) Aramouni, Karl, et al. “Infection with Helicobacter pylori may predispose to atherosclerosis: role of inflammation and thickening of intima-media of carotid arteries.” Frontiers in Pharmacology 14 (2023): 1285754.
Indeed, H. pylori infection appears to stimulate foam cell formation as well as chronic immune responses that could upregulate key inflammatory mediators including cytokines, C-reactive protein, and lipoproteins. These factors are involved in the thickening of intima-media of carotid arteries (CIMT), a hallmark of atherosclerosis. Interestingly, H. pylori infection was found to increase (CIMT), which along with other evidence, could implicate H. pylori in the pathogenesis of atherosclerosis. Nevertheless, the involvement of H. pylori in CVD and atherosclerosis remains controversial as several studies report no connection between H. pylori and atherosclerosis. This review examines and critically discusses the evidence that argues for a potential role of this bacterium in atherogenesis. However, additional basic and clinical research studies are warranted to convincingly establish the association between H. pylori and atherosclerosis.

https://www.ajol.info/index.php/ajcem/article/view/193407
33) El-Ageery, S. M., et al. “Serological evidence of association between Helicobacter pylori infection and coronary artery disease.” African Journal of Clinical and Experimental Microbiology 21.2 (2020): 88-96.

This study included 70 patients with stable angina and 70 age and gender-matched controls. …H. pylori IgG, CagA IgG and HSP60 IgG were measured by enzyme-linked immunosorbent assay (ELISA) for both groups.

Conclusion: There is serological evidence that H. pylori infection may pose a significant risk factor for CAD. Since H. pylori can be eliminated by specific treatment, this may be a good preventive approach for CAD.

34) Guo, Yinjie, et al. “Helicobacter pylori infection acts as an independent risk factor for intracranial atherosclerosis in women less than 60 Years old.” Frontiers in Cardiovascular Medicine 8 (2022): 819315.

35) Aramouni, Karl, et al. “Infection with Helicobacter pylori may predispose to atherosclerosis: role of inflammation and thickening of intima-media of carotid arteries.” Frontiers in Pharmacology 14 (2023): 1285754.

36) Qiang, Liming, et al. “Extracellular vesicles from helicobacter pylori‐infected cells and helicobacter pylori outer membrane vesicles in atherosclerosis.” Helicobacter 27.2 (2022): e12877.

https://pubmed.ncbi.nlm.nih.gov/34841620/
37) Shi, Hongshuo, et al. “Helicobacter pylori infection and the progression of atherosclerosis: A systematic review and meta-analysis.” Helicobacter 27.1 (2022): e12865.
Conclusion: Helicobacter pylori infection can promote the process of AS (atherosclerosis), especially in people under the age of 60 and people without cardiovascular risk factors, and we hope that our meta-analysis can provide ideas for the early prevention of AS.

CagA and Antibiotic Resistance

38) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9233856/
Karbalaei, Mohsen, Amin Talebi Bezmin Abadi, and Masoud Keikha. “Clinical relevance of the cagA and vacA s1m1 status and antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis.” BMC Infectious Diseases 22 (2022).

According to our findings, it was clearly demonstrated that cagA-positive strains are resistance to metronidazole, especially in Western countries. In Western countries, vacA s1m1 increases resistance to amoxicillin and levofloxacin. Based on the present findings, the vacA s1m1 genotype significantly increases resistance to metronidazole, while the vacA s1m2 decreases resistance to clarithromycin and metronidazole. Resistance to antibiotics in less virulent (vacA s2m2) strains is statistically significant lower than others.

Chronic Colitis/ Exosomal CagA

39) Guo, Yinjie, et al. “Exosomal CagA from Helicobacter pylori aggravates intestinal epithelium barrier dysfunction in chronic colitis by facilitating Claudin-2 expression.” Gut Pathogens 14.1 (2022): 13.

Chronic colitis models of CagA+ H. pylori-colonized mice treated with 2% Dextran sulphate sodium (DSS) were established to assess the disease activity and pertinent expression of tight junction proteins closely related to mucosal integrity. The aggravating effect of CagA+ H. pylori infection on DSS-induced chronic colitis was confirmed in mouse models.

Conclusions These data suggest that exosomes containing CagA facilitate CDX2-dependent Claudin-2 maintenance. The exosome-dependent mechanisms of CagA+ H. pylori infection are indispensable for damaging the mucosal barrier integrity in chronic colitis, which may provide a new idea for inflammatory bowel disease (IBD) treatment.

Racial Disparity/CagA

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584346/
40) Varga, Matthew G., et al. “Racial differences in Helicobacter pylori CagA sero-prevalence in a consortium of adult cohorts in the United States.” Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 29.10 (2020): 2084.

African Americans were 3-times more likely to be H. pylori-CagA sero-positive than whites.

Refractry to Treatment due to H Pylori

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567260/
41) Gupta, P., et al. “A case of H. pylori infection presenting as refractory hypothyroidism.” Journal of Family Medicine and Primary Care 9.7 (2020): 3770-3772.
We present the case of a 45-year-old lady with long standing hypothyroidism who was euthyroid on replacement for many years, but stopped responding even to supraphysiological doses of LT4 since the last five years. She complained of abdominal discomfort, bloating, and nausea. She did not have diarrhea or weight loss. Levothyroxine absorption test was done which was suggestive of malabsorption and she was started on triple therapy for H. pylori eradication after confirmation of diagnosis. After 10 days of treatment initiation, she developed symptoms of thyrotoxicosis with her supraphysiological dose of LT4, which was then tapered to a lower dose. Euthyroid state was ultimately achieved with lower doses of LT4 replacement.

42) Bugdaci, Mehmet Sait, et al. “The role of Helicobacter pylori in patients with hypothyroidism in whom could not be achieved normal thyrotropin levels despite treatment with high doses of thyroxine.” Helicobacter 16.2 (2011): 124-130.

43) Jamil Sr, Muhammad Zahid Z., et al. “Determining the Association Between Helicobacter pylori Infection and Treatment-Refractory Hypothyroidism.” Cureus 14.1 (2022).

44) Fallahi, Poupak, et al. “Liquid L-T4 therapy in hypothyroid patients with gastric diseases, an observational study.” Frontiers in Endocrinology 15 (2024): 1386629.
These data suggest that the liquid L-T4 formulation therapy can
result in a more stable control of TSH levels in hypothyroid patients with gastric disorders in the long-term follow-up

45) Altuntaş, S. Ç., et al. “Two cases of pseudomalabsorption treated successfully with parenteral levothyroxine.” Clin Med Rev Case Rep 4.3 (2017): 1-4.

46) Kwek, Kevin, Xuyan Teoh, and Winston Kon. “Hypothyroidism treated with weekly intramuscular thyroxine injections.” Endocrine Abstracts. Vol. 56. Bioscientifica, 2018.

47) Gamboa, María de los Ángeles Garayalde, Melina Saban, and Marina Ines Curriá. “Treatment with intramuscular levothyroxine in refractory hypothyroidism.” European Thyroid Journal 8.6 (2019): 319-323.’

48) Buoso, Caterina, et al. “Myxedema coma secondary to levothyroxine malabsorption in a patient previously submitted to bariatric surgery.” Archives of Endocrinology and Metabolism 68 (2024): e230095.

49) Stupperich, Sophie, et al. “Primary hypothyroidism resolves after switching from L‐thyroxine solid tablets to liquid oral substitution. A rare case without evidence of an underlying gastrointestinal malabsorption syndrome.” Clinical Case Reports 10.8 (2022): e6223.

50) Topf, Albert, et al. “Subcutaneous administration of levothyroxine: a novel approach to refractory hypothyroidism–A review and a case report.” Archives of endocrinology and metabolism 65 (2021): 664-668.

60) Vita, Roberto, and Salvatore Benvenga. “Tablet levothyroxine (L-T4) malabsorption induced by proton pump inhibitor; a problem that was solved by switching to L-T4 in soft gel capsule.” Endocrine practice 20.3 (2014): e38-e41.

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61) Bertalot, Giovanni, et al. “Decrease in thyroid autoantibodies after eradication of Helicobacter pylori infection.” Clinical endocrinology 61.5 (2004): 650-652.

A study showed that the TPOAb titers and TgAb titers of 5 AITD patients who were H. pylori positive decreased to varying degrees after H. pylori elimination, while the TPOAb titers and TgAb titers of AITD patients without H. pylori eradication as the control group remained unchanged. It was found that infection of H. pylori is likely to be an essential trigger for AITDs (50).

All Auto Immune Diseases

62) Wang, Li, et al. “Helicobacter pylori and autoimmune diseases: involving multiple systems.” Frontiers in Immunology 13 (2022): 833424.

The researches have revealed that H. pylori is a potential trigger of gastric autoimmunity, and it may be associated with other autoimmune diseases, both innate and acquired. This paper reviews the current support or opposition about H. pylori as the role of potential triggers of autoimmune diseases, including inflammatory bowel disease, autoimmune thyroiditis, type 1 diabetes mellitus, autoimmune liver diseases, rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, as well as Sjogren’s syndrome, chronic urticaria and psoriasis, and tried to explain the possible mechanisms.

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63) Youssefi, Masoud, et al. “Helicobacter pylori infection and autoimmune diseases; Is there an association with systemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis and autoimmune pancreatitis? A systematic review and meta-analysis study.” Journal of Microbiology, Immunology and Infection 54.3 (2021): 359-369.
The frequency and relationship between H. pylori infection and systemic lupus erythematosus, rheumatoid arthritis, autoimmune atrophy gastritis, and autoimmune pancreatitis were evaluated using the data from 43 studies involving 5052 patients. According to statistical analysis it is probable that infection with more virulent strains of H. pylori (such as H. pylori cagA positive) can increase the risk of autoimmune diseases.

Bacterial Infections and Autoimmune Disease

64) Sherbet, Gajanan Sherbet Gajanan. “Bacterial infections and the pathogenesis of autoimmune conditions bacterial infections and the pathogenesis of autoimmune conditions.” British Journal of Medical Practitioners 2.1 (2009): 6-13.

65) Ebringer A, Rashid T. Rheumatoid arthritis is an autoimmune disease triggered by Proteus urinary tract infection. Clinical & developmental immunology. 2006;13(1):41-48.

66) Puccetti A, Dolcino M, Tinazzi E, et al. Antibodies Directed against a Peptide Epitope of a Klebsiella pneumoniae-Derived Protein Are Present in Ankylosing Spondylitis. PLoS ONE. 2017;12(1):e0171073.

67) Rashid T, Wilson C, Ebringer A. The link between ankylosing spondylitis, Crohn’s disease, Klebsiella, and starch consumption. Clinical & developmental immunology. 2013;2013:872632.

68) Halenius A, Hengel H. Human cytomegalovirus and autoimmune disease. BioMed research international. 2014;2014:472978.

69) Draborg AH, Duus K, Houen G. Epstein-Barr virus in systemic autoimmune diseases. Clinical & developmental immunology. 2013;2013:535738.

70) Dittfeld A, Gwizdek K, Michalski M, Wojnicz R. A possible link between the Epstein-Barr virus infection and autoimmune thyroid disorders. Cent Eur J Immunol. 2016;41(3):297-301.

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microbe              disorder
Klebsiella Ankylosing spondylitis
Citrobacter Proteus R.A.
Yersinia Graves, Hashimotos
Camplbacter Guillan Barre
Chlamydia M.S.
E.Coli, Proteus autoimmunity

———————————–

Microorganisms Autoimmune association

Citrobacter spp. and Citrobacter freundii                  Rheumatoid arthritis
Klebsiella spp. and Klebsiella pneumoniae Crohn’s disease, ulcerative colitis, ankylosing spondylitis, and other spondyloarthropathies (which include ankylosing spondylitis, arthritis associated with Crohn’s or ulcerative colitis, psoriatic arthritis, and reactive arthritis)
Mycobacterium avium subsp. paratuberculosis (MAP)       Rheumatoid arthritis, Crohn’s disease
Prevotella copri                                   Rheumatoid arthritis
Proteus spp.                                        Rheumatoid arthritis
Proteus mirabilis                             Rheumatoid arthritis and spondyloarthropathies (listed above)
Yersinia enterocolitica                    Grave’s disease, Hashimoto’s thyroiditis, reactive arthritis
Cytomegalovirus (CMV)             Systemic lupus erythematosus, systemic sclerosis, type 1 diabetes, rheumatoid arthritis
Epstein-Barr Virus (EBV) Rheumatoid arthritis, lupus, Sjogren’s, multiple sclerosis, autoimmune thyroid disorders

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Last updated on September 1st, 2024 by Jeffrey Dach MD