Introduction
Helicobacter pylori (Hp) is characterized as a gram-negative bacterium with microaerophilic metabolism, flagellated and helix-shaped that affects approximately 50% of the world population and, in some regions, this rate can exceed 80% [1,2]. Hp infection is well known to infect the epithelial tissue of the stomach, being involved with development of many stomach diseases, including gastric carcinoma[3,4]. However, less frequently, this bacterium might also be involved in the development of extragastric disorders, such as manifestations in the gastrointestinal tract, except stomach, autoimmune, dermatological, ophthalmic and cardiac diseases, in addition to neurological, respiratory and endocrine diseases [5,6]. The article titled “Helicobacter pylori infection: beyond gastric manifestations” shows these possibilities [7].
Extragastric Manifestations: Manifestations of the Gastrointestinal System, Except Stomach
Inflammatory Bowel Disease (IBD), as Crohn’s Disease (CD) and Ulcerative Colitis (UC), may offer a negative relationship with the infection, and some systematic reviews confirm the low prevalence of IBD in Hp positive patients, along with a positive CagA profile in these cases [8,9]. Thus, in this scenario, Hp gastric infection appears as a protective factor, since infected patients have less chance of progressing to CD or UC [10,11] and the severity of the disease can also be reduced by the infection [12]. Besides, it was also observed that gastritis by Hp infection is less often in children with IBD [13]. There are some mechanisms that explain this protection: The release of Interleukin (IL)-18 and IL-10 and decrease in the maturation of antigen-presenting cells can reduce intestinal inflammation [14]. Yet, the role of the bacterium in Gastroesophageal Reflux Disease (GERD) remains uncertain, given that depending on the affected site, gastritis can increase or reduce acid secretion. According to what is described in the article, hyperacidity worsens GERD, while hypoacidity offers protection, and Hp cytotoxin-associated gene A (CagA) seems to play a role in this outcome. A study reported that patients with both GERD and peptic ulcers (PUs) had a higher prevalence of the infection than patients without PUs [15]. Therefore, Hp infection is capable of influencing the course of some diseases, as well as protecting patients in certain situations.
On the other hand, Hp-positive patients may have a worse prognosis in some diseases, such as Non-Alcoholic Fatty Liver Disease (NAFLD) [16,17]. These patients have increased production of Tumoral Necrosis Factor and C-reactive Protein, which enhances insulin resistance and, consequently, favors the disease. Furthermore, the infection can also reduce the production of adiponectin, a molecule that inhibits fatty acid deposition [18] and influence the release of pro-inflammatory cytokines, as well as markers, which contributes to the onset of the inflammatory status and worse prognosis. Reduced adiponectin levels favor the development of diabetes mellitus, metabolic syndrome and cardiovascular diseases, such as atherosclerosis [19]. Thus, this bacterium may be associated with other diseases of a metabolic nature and accumulation of fat in the body. However, further studies are needed to better understand these mechanisms. In addition, the connection between Hp and inflammation, hepatic fibrosis and necrosis, which contributes to carcinogenic processes, such as hepatic carcinoma, is also possible [20]. Anyway, according to the commented manuscript, bacterial translocation in the biliary tractc an lead to direct tissue damage. Chronic inflammation of this tissue affects the acid secretion and leads to reduction of the dissolvability of calcium salts in bile, which predisposes to the formation of gallstones, and further cholelithiasis and cholecystitis [21], with Hp in bile being a risk factor for the second one.
B12 deficiency is also associated with this bacterium. According to the manuscript, regardless of gastric atrophy and dyspepsia, positive patients have reduced levels of cobalamin [7]. Several studies show that the malabsorption of food-cobalamin has been reported in cases of Hp gastritis [22,23]. As a result, the Maastricht V / Florence Consensus Report recommends screening for Hp patients with deficiency of this vitamin [24]. A study showed an association between lower levels of B12 vitamin and positive Hp patients, which has a 4.2 times greater risk of having low levels of cobalamin, when compared to healthy individuals [25]. Furthermore, the association of Hp infection and iron deficiency anemia, independently of tissue damage and bleeding, has been confirmed [26,27]. In this sense, it is recommended that infected patients undergo eradication therapy in cases of iron deficiency anemia, given that a bacterium is capable of using the host’s iron, which decreases its bioavailability. As an additional factor, these individuals usually have higher levels of pro-inflammatory cytokines, favoring anemia. Moreover, it has been suggested that there is a relationship between iron deficiency and growth disorders in children and adolescents, which reveals the need to screen for Hp in children with unexplained anemia and growth disorder [24,28].
Extragastric Manifestations: Dermatological, Ophthalmic, Allergic and Respiratory Diseases
Dermatological and ophthalmic diseases
Hp infection can also cause autoimmune skin diseases. Rosacea, psoriasis, alopecia areata, urticaria and idiopathic thrombocytopenic purpura have been identified in Hp infection [6]. A possible explanation for the emergence of these autoimmune diseases is a dysregulation of the immune system in response to Hp infection, which can lead to loss of tolerance to autoantigens [29]. Furthermore, Hp cytokines can cause early stress-induced senescence of skin cells, leading to inflammatory skin diseases [28].
Regarding autoimmune diseases, the studies addressed in the article bring positive associations for Hp, which produces antigens that mimic platelet membrane proteins. This process leads to the autoimmune effect and clinical picture of idiopathic thrombocytopenic purpura. In addition, some factors, as an improvement in platelet counts of patients who eradicated the bacteria with antibiotic therapy, are still being studied and evaluated [30].
The manuscript also showed a possible association of psoriasis and its severity with the intensity of the bacterial infection. The disease is dermatological in nature and clinically presents with erythematous, papular, and scaly lesions. The pathogenesis remains uncertain, but there are some possibilities. One of them is the chronic degree of inflammation generated by the microaerophilic microorganism, which produces substances that induce the immune system more intensely. Furthermore, the intermediation of IL-6 release by Hp may be associated, as well as the production of IL-8 by Hp CagA, which is a chemotactic factor for immune cells and is also involved in the pathogenicity process of psoriasis [6,31,32].
Even though alopecia areata is a condition associated with various organic diseases or psychiatric factors, its relationship with the bacteria is much debated. Some studies have reported a prevalence of Hp infection in patients with this type of alopecia, along with an improvement in the condition after antibiotic treatment for the infection. However, these studies still show some limitations in the management of the variables involved and, therefore, further investigations are needed [6,32].
Urticaria is another idiopathic dermatological disorder that causes skin rash, itching and papules. It is also the target of studies to determine possible correlations with the bacterium, but there is great controversy among researchers. In the article, there are references that positively and negatively supplant the interaction with Hp. In other situations, such as in bullous immune diseases, there is consistent evidence of an increased presence of antibodies to Hp, as well as infections, then in the control group, which confirms the relationship between diseases and the presence of the bacterium [6,32].
Despite this, some studies highlight the lack of evidence to prove a strong association between Hp, dermatological, autoimmune manifestations and their mechanism [33,34].
Based on the manuscript, some ophthalmologic diseases have also been associated with Hp infection, such as glaucoma, central serous chorioretinopathy, blepharitis, and dry eye. However, studies and evidence are still controversial [35,36,37].
Its expression occurs due to a systemic inflammatory reaction induced by cytokines that are able to release vasoactive and proinflammatory substances [20]. This process can provoke oxidative stress, mitochondrial dysfunction, damage to DNA, and, finally, apoptosis [37-39]. Blepharitis presents as an eyelid inflammation, with oily particles and bacteria covering the eyelid margin [40]. Rosacea blepharitis clinical signs include flushing, persistent erythema, papules and pustule, and sprays of vessels, while seborrheic blepharitis includes greasylooking scales, crusts, increased redness, and cutaneous color variability [40,41]. Central serous chorioretinopathy expresses acute and serous detachment of the sensory retina in the macular region [42,43]. Dry eye disease occurs when tears provide insufficient lubrication to eyes, characterized by discomfort, visual disturbance, and tear film instability [44,39]. Glaucoma is a progressive optic neuropathy, with degeneration of the optic nerve and visual field damage [45]. Regarding its physiopathology, apoptosis occurs mainly in retinal ganglion cells and axonal loss within the optic nerve, which results in elevated intraocular pressure (IOP) [46,47]. Another study analyzed the relationship between Hp infection, dry eye, and Sjogren’s syndrome, which was significantly higher in the Hp positive group [48].
Allergic and respiratory diseases
According to the manuscript, Hp infection can act as a protective factor, mostly related to CagA positivity [49,50]. Thus, the efficiency of Hp infections in reducing allergic processes and asthma occur due to its interference in Th1 and Th2 lymphocytes proportion [50-52]; there is also a PD-L1 and IFN-γ suppression mechanism, eosinophil-mediated [48], that happens as a result of the bacterium’s influence in dendritic cells (DC) through NLRP3 activation, which leads to a TLR2 / NLRP3 / IL-18 stimulation and the raising of regulatory Foxp3 + T lymphocytes, increasing allergic asthma immunotolerance [52]. Otherwise, some studies indicate that the depletion of DCs might increase the inflammation of the airways by suppressing ILC2-mediated airway hyperreactivity [52,53]. Hp is also capable of decreasing asthma inflammation through the reduction of heat shock protein 70 expression, an important stimulatory factor for antigen presentation [54], as a result of the stomach hormone alterations that affect the autonomic nervous system [55]. Research shows that Hp without type 4 secretion systems are not able to influence Th1 via eosinophils, failing to present the protective effect [51]. Concerning age influence in patients with asthma and allergic cough, a clinical observational study related that patient with <40 years old infected with Hp presented lower levels of atopy and immunoglobulin E in comparison to those who do not have the bacterium [56]. Also, younger patients who presented with Hp infection, showed a lower risk of developing respiratory disease [55]. The development of chronic obstructive pulmonary disease and chronic bronchitis, linked to positive Hp CagA infections, demonstrated twice as much pathogenicity, when compared to healthy patients and those without the factor. The increased risk of diseases may be correlated to the action of IL-1, IL-8 and tumor necrosis factor that are released during the infection and acts on the respiratory tissue [57].
Extragastric Manifestations: Neurological, Cardiac and Vascular and Endocrine Diseases Neurological Disease
The manuscript showed a positive relation between the infection by Hp and the commitment of the nervous system. The immune response to Hp provides release of cytokines, chemokines, free radicals and pro-inflammatory factors that are capable of stimulating a systemic inflammation that can lead to neurotoxicity through axon and neuron damage, besides destruction of the blood-brain barrier.
Studies have demonstrated an increased risk of Parkinson’s disease in Hp-positive patients, while the eradication of the bacterium doesn’t seem to contribute to the reduction of the risk [58]. The overproduction of interleukin 17 (IL-17) and interferon-gamma (INF-Y) release can be related to reduced hippocampal neurogenesis and destruction of the myelin sheath, respectively. This neuroinflammation has been associated with the emergence of neurological symptoms, being a possible risk factor for dementias, such as Parkinson’s disease [59]. Furthermore, Hp was also related to Parkinson’s treatment impairment and maintenance of the motor symptoms in infected people, by reducing intestinal motility and delaying gastric emptying, which decreases the L-3,4-dihydroxyphenylalanine intestinal absorption, one of the main drugs used in the treatment. The bacterium is able to modify the gastric pH and alter the bioavailability of this drug through the liberation of the pro-inflammatory cytokine- 1b [60].
Chronic atrophic gastritis caused by Hp can reduce the absorption of nutrients that are necessary for the proper functioning of the brain, such as folic acid and vitamin B12, which can lead to excessive protein digestion and neuronal degeneration, leading to Alzheimer’s. Furthermore, possible cross-reactions between bacterial antigens and neuronal structures can provoke dementia conditions [61]. Reduced levels of vitamin B12 in the body are related to the development of Alzheimer’s disease and higher risk of stroke, due to the increase in homocysteine levels, which contribute to an excess of free radicals, that damage blood vessels and cell membranes. Besides, hypovitaminosis can lead to the development of optic neuropathies, sensorimotor polyneuropathy and cognitive impairment, since it causes changes in the white and gray matter of the brain [5].
The Hp was responsible for causing the misfolding of a protein called tau, which is one of the proteins related to the emergence of Alzheimer’s disease. In this sense, the bacterium can change the protective function of some genes in the nervous system through the action of the peptide Hp (2-20), which can change the anti-inflammatory capacity of ANXA1 gene and protective capacity of MTRNR2L2, APOE genes, stimulating neurological damages [62]. Another finding present in patients with Alzheimer’s disease infected by Hp was the alteration of the blood-brain barrier. The chronic infection can stimulate a Th2 response, which is able to produce autoantibodies that are related to detection and reaction against the barrier components, causing its disruption and proportioning both the accumulation and reduction of the depuration of amyloid-β, peptide related to Alzheimer’s pathophysiology, in the brain [63].
Moreover, this mimicry between antigens of the bacterium and the components of the nervous system can contribute to autoimmune damages to host structures, and the emergence of Guillain Barre Syndrome (GBS). Studies have demonstrated a higher prevalence of IgG antibodies against Hp in the cerebrospinal fluid of people with GBS than in individuals without the syndrome, indicating that the infection and the GBS are possibly correlated [64]. The antibodies IgG against the vacuolating cytotoxin A have been related to the crossreaction with components of the Nervous System, causing the demyelination of motor neurons and involving proximal regions of peripheral nerves [65]. On the other hand, bacterial eradication was related to the improvement of cognitive functions [61].
Lastly, researches have also reported a possible link between strokes and Hp infection, especially with strains that carry CagA, since during the immune response, there might occur a liberation of inflammatory molecules that are able to stimulate a coagulation cascade and platelet production and, consequently, increase the risk of ischemic stroke [66]. Corroborating, studies have demonstrated that after the Hp eradication, the levels of some risk factors to the stroke such as fibrinogen and low-density lipoprotein-cholesterol, were lower than in control patients [65].
Therefore, the assessment of sequelae of Hp infection, as well as its early treatment is extremely important to prevent the emergence of neurological impairments, which may contribute to health promotion worldwide and reduce the burden on health services, taking into account that this bacterium is extremely prevalent throughout the world.
Cardiac and vascular diseases
The manuscript demonstrated that the presence of inflammatory factors related to the response to Hp could be related to the emergence of cardiovascular symptoms. Atherosclerosis is a multifactorial disorder in which inflammatory diseases, including chronic bacterial infections, could play a major role. [61] Infectious agents can induce atherosclerosis by increasing the levels of some circulating cytokines, such as interleukin-1 (IL-1), the IL-1β receptor and its haplotypes, interleukin-6 (IL-6) and the like, leading to stimulation of the immune system system-mediated responses, i.e., inflammation [68].
Yet, another finding evidenced a strict correlation between increased serum levels of some pro-inflammatory cytokines (IL1β, IL-8, TNFα) and cardiovascular risk factors [69].
A recent study showed that CagA potentially stimulates foam production within macrophages, contributing to increased atherosclerotic plaque and arterial dysfunction [70].
The other study evaluated the prevalence of Hp positive CagA-strains in patients with CAD. Their studies have demonstrated a higher prevalence of Hp CagA positive strains in patients with CAD, compared with the control group (52% vs 43% or 43% vs 17%) [71].
Coronary artery diseases (CAD) are a major cause of disability and death worldwide [72]. The pathogenetic basis of the possible association between CAD and Hp infection may also reside in the existence of antigenic mimicry phenomena between bacterial peptides and some substances contained in the cardiac muscle and coronary wall [73].
In a meta-analysis on the association between Hp and coronary heart disease (CHD) risk, involving studies published from 1992 to 2014, it demonstrated that Hp infection increased the risk of CHD by 11% (RR 1.11; CI 1.01-1.22), especially in patients with a follow-up period of 5 years [74]. Concerning possible pathogenic mechanisms, another study showed not only a higher prevalence of Hp infection in patients with CHD but also a higher production of anti-Hp HspB IgG crossreacting with human Hsp-60, a well-known risk factor for cardiovascular diseases (CVD) [75].
Thus, Hp infection may be another aggravating factor to cardiac and vascular diseases worldwide, in addition to various factors, such as the social determinants in health, contributing to the increased prevalence of non-communicable chronic diseases.
Endocrine disease
The infection by Hp has been related to endocrine diseases. A study conducted in a population of Cameroon reported a higher prevalence rate of infection in diabetic patients [76]. Besides, it has been related that infected people can present higher rates of metabolic syndrome than those uninfected [77]. Studies have also showed that Hp infection has been indirectly related to control of energy capture and impact on body weight and metabolism, since it is related to the alteration of the gut microbiome, which contributes to the stimulation of gastric acid secretion, through increased production of gastrin, and further impact on the production of ghrelin and leptin, hormones related to appetite regulation [78].
Furthermore, studies with Asian patients demonstrated that CagA-positive Hp strains could provoke impairments in the glycemic control of people with type 2 Diabetes Mellitus [79]. In addition, some works have found higher seropositivity to Hp in diabetic patients, when compared to a non-diabetic population, which demonstrates that, in the first public, Hp was related to an increase of insulin resistance, possibly associated with chronic inflammation caused by the infection and alteration in the normal secretion of the gastric hormones [80]. On the other hand, the bacterium is also capable of favoring insulin resistance through the positive regulation of the suppressor of cytokine signaling 3 (SOCS3) and the c-Jun expression, both related to the suppression of miR-203 [81]. Such facts reinforce what was previously exposed in the manuscript, which demonstrates that Hp would be related to alterations in glycemic control and increase of glycated hemoglobin A. However, there are limitations that make it difficult to properly assess the relation between Hp and Diabetes Mellitus, since, often, variables such as the patient’s economic status and age are not detailed in many studies [79].
Conclusion
With what is exposed in this manuscript and in “Infection by Helicobacter pylori: beyond the gastric manifestations”, it is possible to realize the wide spectrum of diseases that are, somehow, correlated to Helicobacter pylori, and see the several oc currences and relationships it can exert on the host, both as a protective or pathogenic factor. According to the manuscript, an Hp infection can influence the functioning of the gastrointestinal, cardiovascular and nervous system, which can lead to hematological, autoimmune, dermatological, allergic, respiratory, endocrine and cardiovascular disorders and neurological conditions.
However, the material present in the literature needs to be improved, especially with regard to dermatological and ophthalmological diseases. Therefore, there is a need for larger and more complex studies, making the results more specific, relevant and reliable, enabling better explanations and understandings about the pathogenesis of diseases and its correlation to Hp infection.
References
2. Suerbaum S, Michetti P. Helicobacter pylori infection. New England Journal of Medicine. 2002 Oct 10;347(15):1175-86.
3. Alipour M. Molecular mechanism of Helicobacter pylori-induced gastric cancer. Journal of Gastrointestinal Cancer. 2021 Mar;52(1):23-30.
4. Tsukamoto T, Nakagawa M, Kiriyama Y, Toyoda T, Cao X. Prevention of gastric cancer: eradication of Helicobacter pylori and beyond. International Journal of Molecular Sciences. 2017 Aug;18(8):1699.
5. Baj J, Forma A, Flieger W, Morawska I, Michalski A, Buszewicz G, et al. Helicobacter pylori Infection and Extragastric Diseases—A Focus on the Central Nervous System. Cells. 2021 Sep;10(9):2191.
6. Gravina AG, Zagari RM, De Musis C, Romano L, Loguercio C, Romano M. Helicobacter pylori and extragastric diseases: a review. World Journal of Gastroenterology. 2018 Aug 7;24(29):3204-3221.
7. Santos ML, de Brito BB, da Silva FA, Sampaio MM, Marques HS, e Silva NO, et al. Helicobacter pylori infection: Beyond gastric manifestations. World Journal of Gastroenterology. 2020 Jul 28;26(28):4076-93.
8. O. Väre, B. Heikius, JA Silvennoinen, R. Karttunen, SE Niemelä, JK Lehtola, et al. Seroprevalence of Helicobacter pylori infection in inflammatory bowel disease: is Helicobacter pylori infection a protective factor?. Scandinavian Journal of Gastroenterology. 2001 Jan 1;36(12):1295-300.
9. Tepler A, Narula N, Peek Jr RM, Patel A, Edelson C, Colombel JF, et al. Systematic review with meta-analysis: association between Helicobacter pylori CagA seropositivity and odds of inflammatory bowel disease. Alimentary Pharmacology & Therapeutics. 2019 Jul;50(2):121-31.
10. Castaño-Rodríguez N, Kaakoush NO, Lee WS, Mitchell HM. Dual role of Helicobacter and Campylobacter species in IBD: a systematic review and meta-analysis. Gut. 2017 Feb 1;66(2):235-49.
11. Wu XW, Ji HZ, Yang MF, Wu L, Wang FY. Helicobacter pylori infection and inflammatory bowel disease in Asians: a meta-analysis. World Journal of Gastroenterology: WJG. 2015 Apr 21;21(15):4750- 4756.
12. Fialho A, Fialho A, Nassri A, Muenyi V, Malespin M, Shen B, et al. Helicobacter pylori is associated with less fistulizing, stricturing, and active colitis in Crohn’s disease patients. Cureus. 2019 Nov;11(11):e6226.
13. Roka K, Roubani A, Stefanaki K, Panayotou I, Roma E, Chouliaras G. The prevalence of Helicobacter pylori gastritis in newly diagnosed children with inflammatory bowel disease. Helicobacter. 2014 Oct;19(5):400-5.
14. Müller A, Arnold I, Hitzler I. The immunomodulatory properties of Helicobacter pylori confer protection against allergic and chronic inflammatory disorders. Frontiers in Cellular and Infection Microbiology. 2012 Feb 16;2:10.
15. Jie W, Qinghong X, Zhitao C. Association of Helicobacter pylori infection with gastroesophageal reflux disease. Journal of International Medical Research. 2019 Feb;47(2):748-53.
16. Sumida Y, Kanemasa K, Imai S, Mori K, Tanaka S, Shimokobe H, et al. Helicobacter pylori infection might have a potential role in hepatocyte ballooning in nonalcoholic fatty liver disease. Journal of Gastroenterology. 2015 Sep;50(9):996-1004.
17. Wijarnpreecha K, Thongprayoon C, Panjawatanan P, Manatsathit W, Jaruvongvanich V, Ungprasert P. Helicobacter pylori and risk of nonalcoholic fatty liver disease. Journal of Clinical Gastroenterology. 2018 May 1;52(5):386-91.
18. Adolph TE, Grander C, Grabherr F, Tilg H. Adipokines and nonalcoholic fatty liver disease: multiple interactions. International Journal of Molecular Sciences. 2017 Aug;18(8):1649.
19. Yanai H, Yoshida H. Beneficial effects of adiponectin on glucose and lipid metabolism and atherosclerotic progression: Mechanisms and perspectives. International Journal of Molecular Sciences. 2019 Jan;20(5):1190.
20. Nilsson HO, Mulchandani R, Tranberg KG, Stenram U, Wadström T. Helicobacter species identified in liver from patients with cholangiocarcinoma and hepatocellular carcinoma. Gastroenterology. 2001 Jan 1;120(1):323-4.
21. Cen L, Pan J, Zhou B, Yu C, Li Y, Chen W, et al. Helicobacter pylori infection of the gallbladder and the risk of chronic cholecystitis and cholelithiasis: A systematic review and meta-analysis. Helicobacter. 2018 Feb;23(1):e12457.
22. Carmel R, Aurangzeb I, Qian D. Associations of food-cobalamin malabsorption with ethnic origin, age, Helicobacter pylori infection, and serum markers of gastritis. The American journal of Gastroenterology. 2001 Jan 1;96(1):63-70.
23. Serin E, Gümürdülü Y, Özer B, Kayaselçuk F, Yilmaz U, Koçak R. Impact of Helicobacter pylori on the development of vitamin B12 deficiency in the absence of gastric atrophy. Helicobacter. 2002 Dec;7(6):337-41.
24. Malfertheiner P, Megraud F, O’morain CA, Gisbert JP, Kuipers EJ, Axon AT, et al. Management of Helicobacter pylori infection—the Maastricht V/Florence consensus report. Gut. 2017 Jan 1;66(1):6-30.
25. Mwafy SN, Afana WM. Hematological parameters, serum iron and vitamin B12 levels in hospitalized Palestinian adult patients infected with Helicobacter pylori: a case–control study. Hematology, Transfusion and Cell Therapy. 2018 Apr;40:160-5.
26. Tsay FW, Hsu PI. H. pylori infection and extra-gastroduodenal diseases. Journal of Biomedical Science. 2018 Dec;25(1):1-8.
27. Ferrara M, Capozzi L, Russo R. Influence of Helicobacter pylori infection associated with iron deficiency anaemia on growth in preadolescent children. Hematology. 2009 Jun 1;14(3):173-6.
28. Ražuka-Ebela D, Giupponi B, Franceschi F. Helicobacter pylori and extragastric diseases. Helicobacter. 2018 Sep;23:e12520.
29. Ram M, Barzilai O, Shapira Y, Anaya JM, Tincani A, Stojanovich L, et al. Helicobacter pylori serology in autoimmune diseases–fact or fiction?. Clinical Chemistry and Laboratory Medicine. 2013 May 1;51(5):1075-82.
30. Vanegas YA, Vishnu P. Management of Helicobacter pylori in patients with immune thrombocytopenia. Hämostaseologie. 2019 Aug;39(03):279-83.
31. Yu M, Zhang R, Ni P, Chen S, Duan G. Helicobacter pylori infection and psoriasis: a systematic review and meta-analysis. Medicina. 2019 Oct;55(10):645.
32. Guarneri C, Ceccarelli M, Rinaldi L, Cacopardo B, Nunnari G, Guarneri F. Helicobacter pylori and skin disorders: a comprehensive review of the available literature. European Review for Medical and Pharmacological Sciences. 2020 Dec 1;24(23):12267-87.
33. Jørgensen AH, Egeberg A, Gideonsson R, Weinstock LB, Thyssen EP, Thyssen JP. Rosacea is associated with Helicobacter pylori: a systematic review and meta-analysis. Journal of the European Academy of Dermatology and Venereology. 2017 Dec;31(12):2010- 5.
34. Lazaridou E, Korfitis C, Kemanetzi C, Sotiriou E, Apalla Z, Vakirlis E, et al. Rosacea and Helicobacter pylori: links and risks. Clinical, Cosmetic and Investigational Dermatology. 2017;10:305-10.
35. Saccà SC, Vagge A, Pulliero A, Izzotti A. Helicobacter pylori infection and eye diseases: a systematic review. Medicine. 2014 Dec;93(28):e216
36. Ala S, Maleki I, Sanjari Araghi A, Sahebnasagh A, Shahraki A. Helicobacter pylori eradication in the management of glaucoma. Caspian Journal of Internal Medicine. 2020;11(2):143-149
37. Baim AD, Movahedan A, Farooq AV, Skondra D. The microbiome and ophthalmic disease. Experimental Biology and Medicine. 2019 Apr;244(6):419-29.
38. Kim JM, Park KH, Choi MJ, Ha MM, Sohn YH, Kim HK, et al. The effects of Helicobacter pylori infection on intraocular pressure in anterior uveitis. Eye. 2012 Dec;26(12):1503-10.
39. Dogru M, Kojima T, Simsek C, Tsubota K. Potential role of oxidative stress in ocular surface inflammation and dry eye disease. Investigative Ophthalmology & Visual Science. 2018 Nov 1;59(14):DES163-8.
40. Böni R. Rosacea, acne and other diseases of the seborrheic spectrum. Praxis. 2000 Mar 1;89(14):566-70.
41. Gupta AK, Bluhm R, Cooper EA, Summerbell RC, Batra R. Seborrheic dermatitis. Dermatologic clinics. 2003 Jul 1;21(3):401-12.
42. Wang M, Munch IC, Hasler PW, Prünte C, Larsen M. Central serous chorioretinopathy. Acta Ophthalmologica. 2008 Mar;86(2):126-45.
43. Moshirfar M, Hsu M, Schulman J, Armenia J, Sikder S, Hartnett ME. The incidence of central serous chorioretinopathy after photorefractive keratectomy and laser in situ keratomileusis. Journal of Ophthalmology. 2012 Jan 1;2012:904215.
44. Seen S, Tong L. Dry eye disease and oxidative stress. Acta Ophthalmologica. 2018 Jun;96(4):e412-20.
45. Saccà SC, Izzotti A. Focus on molecular events in the anterior chamber leading to glaucoma. Cellular and Molecular Life Sciences. 2014 Jun;71(12):2197-218.
46. Izzotti A, Saccà SC, Bagnis A, Recupero SM. Glaucoma and Helicobacter pylori infection: correlations and controversies. British Journal of Ophthalmology. 2009 Nov 1;93(11):1420-7.
47. Qian D. Helicobacter pylori Infection and Glaucoma. InIntegrative Ophthalmology. Advances in Visual Science and Eye Diseases. 2020 (pp. 145-148). Springer, Singapore.
48. Lee S, Nam S, Lew H. Clinical Aspects of Patients with Dry Eye Disease according to Helicobacter pylori Infection. Journal of Ophthalmology and Research. 2021;4(2):104-13.
49. Chen C, Xun P, Tsinovoi C, He K. Accumulated evidence on Helicobacter pylori infection and the risk of asthma: a meta-analysis. Annals of Allergy, Asthma & Immunology. 2017 Aug 1;119(2):137- 45.
50. Zuo ZT, Ma Y, Sun Y, Bai CQ, Ling CH, Yuan FL. The Protective Effects of Helicobacter pylori Infection on Allergic Asthma. International Archives of Allergy and Immunology. International Archives of Allergy and Immunology. 2021;182(1):53-64.
51. Ondari E, Calvino-Sanles E, First NJ, Gestal MC. Eosinophils and Bacteria, the Beginning of a Story. International Journal of Molecular Sciences. 2021 Jan;22(15):8004.
52. Lerardi E, Losurdo G, Giorgio F, Di Leo A. Might Helicobacter pylori play a role in allergic or cross-reaction related disorders?. Expert Review of Gastroenterology & Hepatology; 14(8): 643-646.
53. Maazi H, Banie H, Muench GR, Patel N, Wang B, Sankaranarayanan I, et al. Activated plasmacytoid dendritic cells regulate type 2 innate lymphoid cell–mediated airway hyperreactivity. Journal of Allergy and Clinical Immunology. 2018 Mar 1;141(3):893-905.
54. Donno D. Heat shock protein 70 upregulation is related to HLADR expression in bronchial asthma. Effects of inhaled glucocorticoids. Clinical & Experimental Allergy. 1998 May;28(5):551-60.
55. Zuo ZT, Ma Y, Sun Y, Bai CQ, Ling CH, Yuan FL. The Protective Effects of Helicobacter pylori Infection on Allergic Asthma. International Archives of Allergy and Immunology. 2021;182(1):53-64.
56. He M, Zheng Y, Ma A, Zhang C, Yu Y, Wang H, et al. Helicobacter pylori is associated with weakened pulmonary function and reduced incidence of allergic conditions in patients with chronic cough. Experimental and Therapeutic Medicine. 2020 Nov 1; 20(5): 47.
57. Wang F, Liu J, Zhang Y, Lei P. Association of Helicobacter pylori infection with chronic obstructive pulmonary disease and chronic bronchitis: a meta-analysis of 16 studies. Infectious Diseases. 2015 Sep 2;47(9):597-603.
58. Smeyne RJ, Noyce AJ, Byrne M, Savica R, Marras C. Infection and Risk of Parkinson’s Disease. Journal of Parkinson’s Disease. 2021 Feb 2;11(1):31-43.
59. Gorlé N, Bauwens E, Haesebrouck F, Smet A, Vandenbroucke RE. Helicobacter and the Potential Role in Neurological Disorders: There Is More Than Helicobacter pylori. Frontiers in Immunology. 2021 Jan 28;11:3541.
60. Mridula KR, Borgohain R, Reddy VC, Bandaru VC, Suryaprabha T. Association of Helicobacter pylori with Parkinson’s Disease. Journal of Clinical Neurology. 2017 Apr 1;13(2):181-6.
61. Han M-L, Chen J-H, Tsai M-K, Liou J-M, Chiou J-M, Chiu M-J, et al. Association between Helicobacter pylori infection and cognitive impairment in the elderly. Journal of the Formosan Medical Association. 2018 Nov;117(11):994–1002.
62. Zendehdel A, Roham M. Role of Helicobacter pylori infection in the manifestation of old age-related diseases. Molecular Genetics & Genomic Medicine. 2020 Apr;8(4):e1157.
63. Tsunoda I. Lymphatic system and gut microbiota affect immunopathology of neuroinflammatory diseases, including multiple sclerosis, neuromyelitis optica and Alzheimer’s disease. Clinical and Experimental Neuroimmunology. 2017;8(3):177-179.
64. Dardiotis E, Sokratous M, Tsouris Z, Siokas V, Mentis AF, Aloizou AM, et al. Association between Helicobacter pylori infection and Guillain-Barré Syndrome: A meta-analysis. European Journal of Clinical Investigation. 2020 May;50(5):e13218.
65. Álvarez-Arellano L, Maldonado-Bernal C. Helicobacter pylori and neurological diseases: Married by the laws of inflammation. World Journal of Gastrointestinal Pathophysiology. 2014 Nov 15;5(4):400-404.
66. Gravina AG, Priadko K, Ciamarra P, Granata L, Facchiano A, Miranda A, et al. Extra-gastric manifestations of Helicobacter pylori infection. Journal of Clinical Medicine. 2020 Dec;9(12):3887.
67. Epstein SE, Zhou YF, Zhu J. Infection and atherosclerosis: emerging mechanistic paradigms. Circulation. 1999 Jul 27;100(4):e20-8.
68. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000 Apr 18;101(15):1767-72.
69. Mendall MA, Goggin PM, Molineaux N, Levy J, Toosy T, Strachan D, et al. Relation of Helicobacter pylori infection and coronary heart disease. Heart. 1994 May 1;71(5):437-9.
70. Yang S, Xia YP, Luo XY, Chen SL, Li BW, Ye ZM, et al. Exosomal CagA derived from Helicobacter pylori-infected gastric epithelial cells induces macrophage foam cell formation and promotes atherosclerosis. Journal of Molecular and Cellular Cardiology. 2019 Oct 1;135:40-51.
71. Pasceri V, Cammarota G, Patti G, Cuoco L, Gasbarrini A, Grillo RL, et al. Association of virulent Helicobacter pylori strains with ischemic heart disease. Circulation. 1998 May 5;97(17):1675-9.
72. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. New England Journal of Medicine. 1998 Jul 30;339(5):321-8.
73. Franceschi F, Sepulveda AR, Gasbarrini A, Pola P, Silveri NG, Gasbarrini G, et al. Cross-reactivity of anti-CagA antibodies with vascular wall antigens: possible pathogenic link between Helicobacter pylori infection and atherosclerosis. Circulation. 2002 Jul 23;106(4):430-4.
74. Sun J, Rangan P, Bhat SS, Liu L. A Meta-Analysis of the Association between Helicobacter pylori Infection and Risk of Coronary Heart Disease from Published Prospective Studies. Helicobacter. 2016 Feb;21(1):11-23.
75. Matusiak A, Chalubinski M, Broncel M, Rechcinski T, Rudnicka K, Miszczyk E, et al. Putative consequences of exposure to Helicobacter pylori infection in patients with coronary heart disease in terms of humoral immune response and inflammation. Archives of Medical Science: AMS. 2016 Feb 1;12(1):45–54.
76. Mabeku LB, Ngamga ML, Leundji H. Helicobacter pylori infection, a risk factor for Type 2 diabetes mellitus: a hospital-based crosssectional study among dyspeptic patients in Douala-Cameroon. Scientific Reports. 2020 Jul 22;10(1):1-1.
77. Chen TP, Hung HF, Chen MK, Lai HH, Hsu WF, Huang KC, et al. Helicobacter pylori infection is positively associated with metabolic syndrome in Taiwanese adults: a cross-sectional study. Helicobacter. 2015 Jun;20(3):184-91.
78. Mohammadi SO, Yadegar A, Kargar M, Mirjalali H, Kafilzadeh F. The impact of Helicobacter pylori infection on gut microbiotaendocrine system axis; modulation of metabolic hormone levels and energy homeostasis. Journal of Diabetes & Metabolic Disorders. 2020;19(2):1855-1861.
79. Li JZ, Li JY, Wu TF, Xu JH, Huang CZ, Cheng D, et al. Helicobacter pylori infection is associated with type 2 diabetes, not type 1 diabetes: an updated meta-analysis. Gastroenterology Research and Practice. 2017 Aug 13;2017.
80. Vafaeimanesh J, Parham M, Seyyedmajidi M, Bagherzadeh M. Helicobacter pylori infection and insulin resistance in diabetic and nondiabetic population. The Scientific World Journal. 2014 Oct 23;2014:391250.
81. Zhou X, Liu W, Gu M, Zhou H, Zhang G. Helicobacter pylori infection causes hepatic insulin resistance by the c-Jun/miR-203/ SOCS3 signaling pathway. Journal of Gastroenterology. 2015 Oct;50(10):1027-40.