Abstract
Helicobacter pylori is one of the most prevalent infection worldwide. It affects individuals of different age groups. Elderly people tend to resist eradication treatment and worsening of infection can lead to several gastric and non‐gastric pathologies. Aging‐associated cellular and molecular alteration can increase the risk of other pathologies such as osteoporosis, Alzheimer's disease, Parkinson's disease, respiratory and renal dysfunction, and cancer in geriatric patients, more than other age groups. This review article highlights some of the most common old age diseases and the role of H. pylori infection as a risk factor to worsen the conditions, presented by the molecular evidences of these associations. These studies can help clinicians to understand the underlying pathogenesis of the disease and identify high‐risk patients, aiding clearer diagnosis and treatment.
Keywords: aging-associated disease, elderly population, Helicobacter pylori
Helicobacter pylori is one of the most prevalent infection worldwide. It affects individuals of different age groups. Aging‐associated risk factors should be considered. Future studies, related to aging and H. pylori infection with extragastric disease can help to provide vivid evidences.
1. INTRODUCTION
Aging is one of the inevitably dominant risk associated with many diseases.
Several biological factors contribute to this etiology which include loss of telomeres, stem cells activity and metabolism, escalation of environmental and biological stress, dysfunctioning of various micro‐ and macromolecules, and cell cycle and weakening of immune system (Franceschi et al., 2018). In case of cellular and molecular damage before elderly age, injury is healed to maintain the hemostasis. Nonetheless, with aging, repair mechanism is slowed or completely halted, leading to number of pathologies (Cortopassi, Gurung, & Pinto‐Plata, 2017).
Nearly half of the world's population is infected by Helicobacter pylori; however, its prevalence varies geographically (Melese, Genet, Zeleke, & Andualem, 2019).
Cytotoxin‐associated gene A (CagA) and vacuolating cytotoxin (VacA) antigens are chiefly responsible for the pathogenesis of H. pylori infection. Lipopolysaccharides, flagellin, and other toxins have strong ability to manipulate host immune response by the activation of chemokine and cytokine production pathways, recruitment of immune cells, production of autoantibodies, and having a long‐term chronic systemic inflammatory response (Chmiela & Gonciarz, 2017).
With age, H. pylori infection is seen to bring about gastric changes such as increase in pepsinogen II and gastrin‐17, and subsequent decline in pepsinogen I:II ratio, which might manifest other pathologies (Morandini et al., 2018; Shan, Bai, Han, Yuan, & Sun, 2017). H. pylori‐infected patients remain asymptomatic in a greater portion of their lives, whereas greatest zone of gastric problems is consequently associated with H. pylori infection such as peptic ulcers, mucosa‐associated lymphoid tissue lymphoma, functional dyspepsia, and gastric cancer. Additionally, it is also associated with the risk of extragastric diseases (Zendehdel & Roham, 2019). In geriatric patients, 70% of the infection is seen in the form of gastric diseases, with higher severity and hospitalization rate.
Treatment of H. pylori infection is based on triple therapy that includes: clarithromycin, metronidazole, and a proton pump inhibitor (PPI). Failure to respond to this treatment is likely due to the development of resistance against antibiotics, particularly in geriatric population (Moradniani et al., 2018). Elderly patients, who are already on drugs, also fail to respond to this treatment, caused by alteration in the interaction of the drugs such as omeprazole (PPI) with cardiovascular medicines (Cizginer, Ordulu, & Kadayifci, 2014). Recent studies have shown that elderly patients are 2–3 times more prone to antibiotic resistance against 100s of strains of H. pylori (Boyanova et al., 2017; Shavakhi et al., 2007). In a recent study, Kobayashi et al. (2019) demonstrated that super‐elderly patients (aged > 75 years) are more prone to acquire H. pylori‐associated gastric and duodenal ulcers; nonetheless, the eradication efficacy did not vary in comparison to the other age groups.
The main aim of this review is to highlight extragastric risk factor associated with H. pylori infection in geriatric patients (summarized in Figure 1) and the corresponding mechanisms that associated H. pylori infection with the diseases.
Figure 1.
summarizes the links between aging, Helicobacter pylori infection, and extragastric diseases
2. MUSCULOSKELETAL DISORDERS
Numerous orthopedic diseases are concerned with aging such as osteoarthritis, osteopenia, and sarcopenia. Degeneration of tissues, ligaments and cartilage, loss of strength, frailty, obesity, infection, and several deficiencies can be the cause of these pathologies.
2.1. Osteoporosis
Reduction in bone mineral density (BMD) and bone quality are two main etiologies of osteoporosis. Most of these cases are mediated by aging due to loss of equilibrium between bone formation and bone loss, mediated by osteoblasts and osteoclasts, respectively. The imbalance of osteoprotegerin and receptor activator of nuclear factor‐κ kappa B ligand (OPG/RANKL) pathway plays a significant role in pathogenesis of the disease (Song, Xie, Peng, Yu, & Peng, 2015).
Studies have shown that H. pylori infection can lead to osteoporosis due to age‐related decline in BMD and systemic inflammation caused by the infection (Heidari, 2015; Pan, Huang, Chuah, Chiang, & Loke, 2018). Nonetheless, contradictory reports are also seen in this regard (Abdolahi, Aghaei, & Naghdi, 2017; Upala, Sanguankeo, Wijarnpreecha, & Jaruvongvanich, 2016). Kim et al. (2014) reported that atrophic gastritis can increase the risk of osteoporosis by 1.89‐fold in elderly population.
H. pylori infection, leading to metabolic abnormalities, is also associated with the onset of osteoporosis in aged people (Lu, Hao, Liu, Li, & Wang, 2018). Furthermore, treatment with PPI, such as pantoprazole, can also exacerbate loss of bone density and growth, marked with decrease in levels of calcium and osteocalcin concentrations (Matuszewska et al., 2016). However, early eradication therapy for H. pylori infection is likely to reduce the odds of developing osteoporosis (Shih et al., 2016). H. pylori can also cause severe decline in serum vitamin D levels, hence compromising bone health (Mut Surmeli et al., 2018) and leading to metabolic syndrome (discussed later) (Chen et al., 2016a; Zendehdel & Arefi, 2019).
2.2. Osteoarthritis (OA)
It is a chronic condition associated with the progressive loss of functionality of bones and associated joints. In geriatric population, loss of cell function, increased oxidative stress, chronic inflammation, and genetic changes can lead to the onset of OA (Loeser & Lotz, 2016).
Different mechanisms have been proposed to understand the pathology of the disease. Studies have shown that decrease in the expression of tissue growth factor‐β (TGF‐β), upregulation of matrix metalloproteinase (MMP), age‐related alteration in the methylation of DNA, and elevated chronic inflammation and related cytokines such as TNF‐α, IL‐1β, IL‐6, IL‐8 are some of the causes of OA (Chen, Shen, et al., 2017).
Studies have shown that H. pylori‐related upper gastrointestinal bleeding is common in aged patients with OA (Kim et al., 2016). To it, the usage of drugs like nonsteroidal anti‐inflammatory drugs (NSAIDs) and PPI in patients with OA might worsen this effect (Chan et al., 2010; Rogoveanu, Streba, Vere, Petrescu, & Traistaru, 2015).
2.3. Sarcopenia
Sarcopenia is characterized by the age‐related reduced skeletal muscle mass and associated activity, as seen in elderly patients. It leads to physical and systemic disabilities. Exercise and hormone‐based treatment, such as testosterone, insulin‐like growth factor‐1 (Dhillon & Hasni, 2017), and ghrelin, have been used to increase the muscle mass. Ghrelin is found to play a significant role in muscle mass and boosting of physical activity (Tamaki et al., 2017). Baeg et al. (2015) demonstrated that elderly women who are H. pylori positive, as compared to the ones who took H. pylori eradication treatment, had lower muscle mass. These results were parallel with the prevalence of sarcopenia‐associated risk factors obesity, diabetes, increased WBC count and metabolic syndrome. The study by Mantero et al. (2018) also predicted that eradication of H. pylori normalizes the levels of ghrelin, thereby suggesting that it might play a significant role in restoring muscle mass.
Furthermore, the vast amount of studies has proven that H. pylori infection leads to impairment of systemic immunity. It also leads to chronic inflammation by activation of various pathways and expression of microRNAs for the production of inflammatory cytokines (IL‐1β, INF‐γ, IL‐6, and TNF‐α). Macrophages (M1) and neutrophil‐mediated inflammation is also elevated due to the infection (Cadamuro, Rossi, Maniezzo, & Silva, 2014). Once these macrophages and neutrophil migrate to the skeletal muscle, they can lead to inflammation in the muscles and injury. Progression of the age if seen in the form of chronic systemic inflammation, can cause loss of muscle mass by the breakdown of muscle protein (Franceschi et al., 2018).
3. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
Chronic obstructive pulmonary disease is defined by the obstruction in the airflow to the lungs to due chronic inflammation due to presence of harmful particles (e.g., cigarette smoke). It is widely associated with several other morbidities and is highly prevalent in geriatric population (Azargoon, Gholami, Farhadi, Chegni, & Zendedel, 2016). Changes in the recoiling capacity of the lungs, lead to difficult expiration with the aging. Underlying causes such as loss of physical activity, history of smoking, and exposure of harmful gases adds to pathophysiology of the disease (Cortopassi et al., 2017).
H. pylori infection is strongly characterized as one of the risk factors for the development of COPD in elderly patients; CagA and IgG seropositivity are seen in these patients (Samareh Fekri, Hashemi Bajgani, Rasti, Yazdani, & Mollaie, 2014; Wang, Liu, Zhang, & Lei, 2015). Peng et al. (2017) and Wang, Guan, et al. (2015) reported that odds ratio of H. pylori infection in COPD patients is 2.11. H. pylori pathogens and DNA have been seen in the lungs and oral cavity of the infected individuals, thereby it is likely to initiate inflammatory response in the lungs. Expression of receptors like Toll‐like receptors 2 and 4 (TLR‐2 and TLR‐4) and advanced glycation end‐products (RAGE) in the pulmonary epithelium is responsible for the recognition of H. pylori. Long‐term exposure to these pathogens, leads to chronic inflammatory response and oxidative stress‐like conditions (Zendedel et al., 2015). The presence of other harmful particles in the lungs can significantly enhance the immune response, initiated by the bacterial invasion (GonzÁlez, Araya, & Rojas, 2018).
4. RENAL ABNORMALITIES
Similar to other tissues, upon aging, functions of renal tissue are largely compromised too. The decrease in glomeruli filtration rate, alterations in the permeability, reabsorption and urine concentration, lessening of podocytes, nephrons and kidney volume, nephrosclerosis, hypertrophy, and cyst formation are some of the normal renal changes associated with healthy aging (Denic, Glassock, & Rule, 2016).
Chronic kidney disease (CKD) and end‐stage renal disease (ESRD) are the most significant age‐related renal diseases, reported in elderly patients (Portilla Franco, Tornero Molina, & Gil Gregorio, 2016; Poveda et al., 2017). Eradication of H. pylori is likely to have a protective effect against CKD (hazard ratio: 0.69) (Wang et al., 2016a).
Studies have shown that in geriatric patients, co‐existence of peptic ulcer and CKD is higher than other age groups (Liang et al., 2014) To it, its severity can advance to renal transplant stage (Hussein et al., 2016). Similarly, infected patients above 75 + years are also more prone to develop ESRD, compared to other ages. These patients are mostly hypertensive and diabetic, thereby increasing the risk of ESRD. Cardiovascular disorders are also common in H. pylori‐infected individuals; hence this could connect the two pathologies. Furthermore, systemic inflammation, as a result of H. pylori infection marked by elevated levels of C‐reactive protein (CRP), TNF‐α, and IL‐6, are also associated with the loss‐of‐kidney function. H. pylori can lead to several alterations in the renal function that can be seen as, proteinuria, microalbuminuria and other metabolic products. It also increases levels of homocysteine and asymmetric dimethylarginine, markers of CKD, in serum (Lin et al., 2015). H pylori‐mediated decrease in pepsinogen I/II ratio is characterized by the diabetes‐associated nephropathy (Senmaru et al., 2013). Eradication therapy of H. pylori infection can decrease the risk of CKD (Wang et al., 2016a).
5. METABOLIC SYNDROME
Metabolic syndrome is a cluster of several disorders comprising abnormality in the lipid profile, insulin resistance, visceral obesity, hypertension, increased levels of white blood cells (Li et al., 2016), and hyperglycemia. These factors can lead to several cardiovascular disorders and diabetes mellitus. It is a common condition affecting geriatric population (Kapil et al., 2018; Kapil et al., 2018), also leading to frailty (Lopez‐Garcia et al., 2017), sarcopenia (Chang et al., 2015), increasing the risk of fracture (Chen, Chen, Hsieh, Kuo, & Chien, 2017), osteoporosis (Cui et al., 2016), and affecting cognitive and functional abilities in this group of population (Viscogliosi, Donfrancesco, Palmieri, & Giampaoli, 2017). Yang and Xuan (2016) demonstrated that H. pylori infection is associated with the increased risk of metabolic syndrome in Chinese population with the odds ratio of 5.427.
Helicobacter pylori infection in geriatrics can increase the risk for the development of insulin resistance (Chen et al., 2015), hyperglycemia, and increased body mass index (BMI) (Yang, Xuan, & practice, 2016; Zhang et al., 2015). Together H. pylori infection and vitamin D deficiency can increase the risk of developing metabolic syndrome up to twofold (Chen et al., 2016a). Additionally, eradication of H. pylori can restore the levels of adiponectin, a marker of obesity in metabolic syndrome (Ando et al., 2013).
6. CARDIOVASCULAR DISEASES (CVD)
Aging in cardiac tissue is seen in the formation of decline in contractility of the myocardium, ejection fraction, and elevation in the arterial stiffness. These phenomena are validated in different studies. Vendrov et al. (2015) demonstrated that NAPDH‐mediated oxidative stress corresponds to aging‐related incidence of CVD. Increased concentration of mitochondrial reactive oxygen species leads to aortic stiffness and atherosclerosis. In a recent article, cellular senescence with the progression of the age is seen to be related with CVD. This is due to elevated systemic inflammatory response and oxidative stress. Senescence of endothelium is seen to result in heart failure with persevered ejection fraction that is also commonly seen in geriatric population (Shakeri, Lemmens, Gevaert, Meyer, & Segers, 2018). It is seen that H. pylori‐seropositive patients have high levels of low‐density lipoproteins and eradication of H. pylori infection can lower these levels (Nam, Ryu, Park, & Park, 2015. To it, H. pylori‐positive geriatric patients have increased risk of developing atherosclerosis and acute coronary syndrome (Carvalho et al., 2018; Lai, Yang, Lin, & Kao, 2015). They are also at the risk of acquiring myocardial infraction, stroke, and peripheral artery disease (Rahmani et al., 2017; Vijayvergiya & Vadivelu, 2015).
Aging and H. pylori infection is associated with changes in gastric chemicals and progression of cardiovascular diseases (Mladenova, 2019; Shan et al., 2017). H. pylori infection is seen to result in hypertension, increased arterial stiffness, and lipid profile. Atherosclerosis is one of the outcomes of chronic inflammation via different pathways. Patients with H. pylori infection are found with increased endothelial dysfunction due to high levels of CRPs, and vascular and intracellular adhesion molecules that mediate inflammation. To it, other inflammatory markers like TNF‐α, IL‐1β, IL‐6, IL‐8, INF‐γ (interferon gamma), and several coagulation factors are also elevated in such conditions that lead to vasoconstriction, impaired endothelial function, that is also mediated by the levels of homocysteine, overproliferation of skeletal muscle cells, and production of matrix metalloproteinase, leading to atherosclerosis and acute coronary syndrome, respectively. These inflammatory chemicals are upregulated by H. pylori infection via cyclooxygenase enzyme‐2, toll‐like receptors, and activation of mitogen activated protein kinase (MAPK), c‐Jun N‐terminal kinase (JNK), and other such pathways (Vijayvergiya & Vadivelu, 2015). Furthermore, cross‐reacting antibodies of H. pylori, such as anti‐urease and anti‐heat shock protein (anti‐Hsp) antibodies, can bind to antigens of endothelium, skeletal muscle cells, and cardiomyocytes, thereby maintaining plaques formation and directing immune‐destruction of the tissue (Chmiela & Gonciarz, 2017).
In recent studies, it is found that H. pylori and associated morbidities are likely to increase the risk of atherosclerosis (Hu et al., 2017; Yu et al., 2019).
6.1. Diabetes mellitus (DM)
Ample studies have reported evidence‐based report regarding the positive association between diabetes mellitus and H. pylori infection (Hosseininasab Nodoushan & Nabavi, 2019), particularly in aged individuals (Dat, Yip, & Hanegbi, 2016). Besides, diabetes‐related complications such as diabetic nephropathy (Bajaj et al., 2014) and neuropathy (Wang, Fu, & Lv, 2014), diabetic gastroparesis (Huang, 2017), and retinopathy (Agrawal et al., 2010) also validate the association between diabetes mellitus and H. pylori infection. Li et al. (2017) in a meta‐analysis reported that H. pylori infection is chiefly greater in diabetes mellitus patients than in non‐ diabetes mellitus individuals (odds ratio: 1.69).
H. pylori‐positive individuals have higher HOMA‐IR (homeostatic model assessment‐insulin resistance) levels and corresponding oxidative stress (Vijayvergiya & Vadivelu, 2015). Subsequently, HbA1 (glycated hemoglobin) and 8‐hydroxydeoxy guanosine (8‐OHdG), damage to guanine in DNA due to oxidative and nitrosactive stress (Flint, Stintzi, & Saraiva, 2016) as a result of infiltration of neutrophil, are also elevated parameters in infected diabetic patients (Nasif, Mukhtar, Nour Eldein, & Ashgar, 2016).
Likewise, the control of diabetes by the usage of glucophage can also lead to lower risk of developing H. pylori infection (Tseng, 2018). Treatment of H. pylori might be affected by the imbalance in glucose levels (Nam et al., 2019). In elderly patients, hyperglycemic conditions with H. pylori infection can also lead to colorectal cancer and arterial plaques (Hu et al., 2017).
7. NEUROLOGICAL DISORDER
Dementia (vascular dementia [VD] and Parkinson's disease [PD]) and Alzheimer's disease (AD) are the most common types of neurological disorders associated with the progression of age (Callixte et al., 2015). These are characterized by the loss of memory (dementia), difficulty to perform cognitive and physical function, and follow orientation. Both, AD and PD, are characterized by the deposits of misfolded protein like β‐amyloid and α‐synuclein, respectively. These neurobiological markers and scans are performed to detect the disease.
Pathogenesis of AD as seen from different aspects include aging of brain, oxidative stress, impairment of mitochondrial function, neuroflammation (involving brain cells and other immune cells), and corresponding increased levels of serum TNF‐α, IL‐1β, IL‐6, INFγ, and tissue growth factor‐β (TGF‐β). IL‐6 is permeable to blood–brain barrier (BBB), and IL‐1β and TNF‐α mediate changes in β‐amyloid protein (ligand for formyl peptide receptor [FPR]) and alter synapses. Similarly, oxidative stress leads to increased levels of oxidized protein and lipid products and cause cell senescence, which are also identified in AD. Variations in the input from the gut can also impose their effects via gut–brain axis. These can include degenerative signals from the bacterial toxins and thereby studies have also found association of AD with different infectious agents (Caputi & Giron, 2018; Franceschi et al., 2018). H. pylori is found to alter the gut–brain axis such that it can lead to neurological disorders like depression, anxiety, dementia, schizophrenia, and neurodegenerative pathologies (Budzyński & Kłopocka, 2014). Animal‐based study has shown that H. pylori infection upregulates the expression of various classes of FPRs and other genes, significant for the AD, by Hp (2–20) peptide of the bacteria. These genes have neuroprotective (MTRNR2L2, APOE) and anti‐inflammatory (ANXA1) roles (Contaldi et al., 2017). Other evidences suggest that H. pylori can enter brain via oral–nasal passage and H. pylori‐infected monocytes, able to bypass the process of autophagy, can cross BBB, and lead to inflammation (Doulberis et al., 2018). Moreover, H. pylori can also cause misfolding of tau protein, one of the misfolded proteins responsible for AD (Wang, Zeng, et al., 2015).
A systemic review of 260 studies concluded that H. pylori is likely to induce risk of dementia. Most of these studies were conducted on patients with the age of 60‐years and above (Shindler‐Itskovitch, Ravona‐Springer, Leibovitz, & Muhsen, 2016). This is likely because of the chronic inflammation in both the diseases, cross‐linking each other (Xu, Wang, Liu, Cui, & Zhao, 2016). Consequently, elevated levels of serum YKL‐40 (also known as chitinase‐3‐like protein 1 [CHI3L1]) are a significant marker for many inflammatory diseases, including neurodegenerative ones, such as Alzheimer's (Muszyński, Groblewska, Kulczyńska‐Przybik, Kułakowska, & Mroczko, 2017). Xu, Wang, Liu, Cui, Lu, et al. (2016) demonstrated that CHI3L1 is upregulated in H. pylori‐positive individuals, presenting vascular dementia and hyperlipidemia in aged individuals.
Bu et al. (2015) in their study showed that onset of Alzheimer's disease in elderly patients, as seen by the increased levels of β‐amyloid, is associated with exposure to infectious microbes, including H. pylori.
H. pylori infection is also associated with the increased risk of PD in geriatric individuals (Dardiotis et al., 2018). Augustin et al. (2019) reported that PD patients presenting H. pylori infection have 12 times increased rate of mortality. There are several different hypotheses to justify these studies. The levels of neurotoxins like cholesterol glucosides and methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) are increased as a result of chronic infection that can deteriorate brain functionality. Accumulation of α‐synuclein in the nerve endings of the gut due to infection correspondingly contributes to the pathology of PD (Ito et al., 2013). It can also lead to the destruction of neuron by crossing the BBB via nasal passage. Additionally, disruption of the motor function as a result of bacterial invasion can affect the absorption of levodopa drug (for the treatment of PD), where the eradication therapy can alleviate these effects. These motor functions are greatly impaired in elderly patients especially (Çamcı & Oğuz, 2016). Autoantibodies, primarily generated against bacterial antigens can also cross the BBB and trigger the degenerative response. Alterations in BBB, as a result of changes in gut microbiota, has also been suggested as one of the causes of H. pylori infection‐mediated PD (McGee, Lu, & Disbrow, 2018).
8. CANCER
Despite cancerous and aging cells being functionally opposite (hyperproliferation vs. cell senescence), there are several other factors that can lead to carcinogenesis in aging cells. These include age‐associated genetic and epigenetic alterations, abnormal proliferation of damaged stem cells, loss of protein homeostasis such as that of heat shock proteins, lysosome, decline in autophagy, and nutritional imbalance (Aunan, Cho, & Søreide, 2017). Levi, Sochacki, Khoury, Patel, and Majumdar (2014) showed that H. pylori infection cancer stem cells aid progression of neoplasm. This is mediated by the upregulation of the Wnt/β‐catenin pathway, increasing the levels of Nanog, Oct4, and c‐myc that is also overregulated in carcinogenic conditions (Yong et al., 2016; Zhan, Rindtorff, & Boutros, 2017).
Chronic systemic inflammation, due to long‐term colonization of H. pylori infection, increases the risk of lung cancer in geriatric population (Samareh‐Fekri et al., 2016). Traces of H. pylori has been seen in prostate tumors in elderly (Al‐Marhoon et al., 2015), which is facilitated by imbalance between apoptosis and growth of the cells (Verit et al., 2015). One of the possible links between the two diseases could be the chronic inflammation and activation of cell proliferating pathways (already discussed) (Dang & Liou, 2018).
The odds ratios of correlation between colorectal cancer/adenoma and H. pylori infection have been reported from 1.15 to 10.6 (Butt & Epplein, 2019). Co‐existence of insulin resistance, hyperglycemia, and H. pylori is associated with the increased risk of colorectal adenoma in aged people (Hu et al., 2017; Hu et al., 2017). VacA virulency is associates H. pylori with colorectal cancer (Mut Surmeli et al., 2018), verified in a recent meta‐analysis (Zhao, Wang, & Wang, 2016), it increases the risk of colorectal neoplasm and adenocarcinoma (Kim et al., 2017). In such patients, immune tolerance of the bacteria is elevation of tryptophan:kynurenine ratio and its metabolite, neoprotein, that mark the inflammatory response (Christensen et al., 2018; Engin, Karahalil, Karakaya, & Engin, 2015).
H. pylori‐seropositive patients are also more prone to acquire laryngeal and hypopharyngeal carcinoma (Guilemany, Langdon, Ballesteros, & Blanch, 2014; Zhou, Zhang, Yang, Zhou, & Tao, 2016).
9. CONCLUSION
Helicobacter pylori infection can be chronic and bypass various eradication therapies. In elderly patients, antibiotic resistance, chronic inflammation, compromised immunity, and retardation of cell activities are the suggested causes in this regard. Due to long‐term colonization of H. pylori infection, its effects are seen systematically, leading to several other extragastric disorders. Despite contradictory studies reporting no association between H. pylori infection and some extragastric pathologies (Fotouk‐Kiai et al., 2015; Yu et al., 2014), aging‐associated risk factors should be considered. Future studies relating aging and H. pylori infection with extragastric disease can help to provide vivid evidences.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
Zendehdel A, Roham M. Role of Helicobacter pylori infection in the manifestation of old age‐related diseases. Mol Genet Genomic Med. 2020;8:e1157 10.1002/mgg3.1157
REFERENCES
- Abdolahi, N. , Aghaei, M. , & Naghdi, M. (2017). AB0850 Helicobacter pylori infection and osteoporosis in post menopausal women. J Annals of the Rheumatic Diseases, 76(Suppl 2), 1354‐1354. 10.1136/annrheumdis-2017-eular.6445% [DOI] [Google Scholar]
- Agrawal, R. P. , Sharma, R. , Garg, D. , Pokharna, R. , Kochar, D. K. , & Kothari, R. P. (2010). Role of Helicobacter pylori in causation of diabetic gastropathies and non‐gastrointestinal complications in type 2 diabetes. Journal of the Indian Medical Association, 108(3), 140–143. [PubMed] [Google Scholar]
- Al‐Marhoon, M. S. , Ouhtit, A. , Al‐Abri, A. O. , Venkiteswaran, K. P. , Al‐Busaidi, Q. , Mathew, J. , … Ganguly, S. S. (2015). Molecular evidence of Helicobacter pylori infection in prostate tumors. Current Urology, 8(3), 138–143. 10.1159/000365705 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ando, T. , Ishikawa, T. , Takagi, T. , Imamoto, E. , Kishimoto, E. , Okajima, A. , … Yoshikawa, T. (2013). Impact of Helicobacter pylori eradication on circulating adiponectin in humans. Helicobacter, 18(2), 158–164. 10.1111/hel.12028 [DOI] [PubMed] [Google Scholar]
- Augustin, A. D. , Savio, A. , Nevel, A. , Ellis, R. J. , Weller, C. , Taylor, D. , … Charlett, A. (2019). Helicobacter suis is associated with mortality in Parkinson's disease. Frontiers in Medicine, 6, 188–188. 10.3389/fmed.2019.00188 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aunan, J. R. , Cho, W. C. , & Søreide, K. (2017). The biology of aging and cancer: A brief overview of shared and divergent molecular hallmarks. Aging and Disease, 8(5), 628–642. 10.14336/AD.2017.0103 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Azargoon, A. , Gholami, M. , Farhadi, A. , Chegni, M. H. , & Zendedel, A. (2016). Evaluation of the Persian Transcript of the COPD Assessment Test in the Measurement of COPD Health Status in Iranian COPD Patients. Global Journal of Health Science, 8(5), 225 10.5539/gjhs.v8n5p225 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baeg, M. K. , Choi, M.‐G. , Ko, S.‐H. , Lim, C.‐H. , Kim, J. S. , Cho, Y. K. , … Lee, I.‐S. (2015). Elderly women who received Helicobacter pylori‐eradicating therapy have reduced risk of low skeletal muscle mass. Clinical Interventions in Aging, 10, 1771–1777. 10.2147/CIA.S95007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bajaj, S. , Rekwal, L. , Misra, S. P. , Misra, V. , Yadav, R. K. , & Srivastava, A. (2014). Association of Helicobacter pylori infection with type 2 diabetes. Indian Journal of Endocrinology and Metabolism, 18(5), 694–699. 10.4103/2230-8210.139235 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boyanova, L. , Gergova, G. , Markovska, R. , Kandilarov, N. , Davidkov, L. , Spassova, Z. , & Mitov, I. (2017). Primary Helicobacter pylori resistance in elderly patients over 20 years: A Bulgarian study. Diagnostic Microbiology and Infectious Disease, 88(3), 264–267. 10.1016/j.diagmicrobio.2017.05.001 [DOI] [PubMed] [Google Scholar]
- Bu, X.‐L. , Yao, X.‐Q. , Jiao, S.‐S. , Zeng, F. , Liu, Y.‐H. , Xiang, Y. , … Wang, Y.‐J. (2015). A study on the association between infectious burden and Alzheimer's disease. European Journal of Neurology, 22(12), 1519–1525. 10.1111/ene.12477 [DOI] [PubMed] [Google Scholar]
- Budzyński, J. , & Kłopocka, M. (2014). Brain‐gut axis in the pathogenesis of Helicobacter pylori infection. World Journal of Gastroenterology, 20(18), 5212–5225. 10.3748/wjg.v20.i18.5212 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Butt, J. , & Epplein, M. (2019). Helicobacter pylori and colorectal cancer‐A bacterium going abroad? PLoS Path, 15(8), e1007861–e1007861. 10.1371/journal.ppat.1007861 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cadamuro, A. C. T. , Rossi, A. F. T. , Maniezzo, N. M. , & Silva, A. E. (2014). Helicobacter pylori infection: Host immune response, implications on gene expression and microRNAs. World Journal of Gastroenterology, 20(6), 1424–1437. 10.3748/wjg.v20.i6.1424 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Callixte, K.‐T. , Clet, T. B. , Jacques, D. , Faustin, Y. , François, D. J. , & Maturin, T.‐T. (2015). The pattern of neurological diseases in elderly people in outpatient consultations in Sub‐Saharan Africa. BMC Research Notes, 8, 159–159. 10.1186/s13104-015-1116-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- Çamcı, G. , & Oğuz, S. (2016). Association between Parkinson's disease and Helicobacter pylori . Journal of Clinical Neurology (Seoul, Korea), 12(2), 147–150. 10.3988/jcn.2016.12.2.147 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caputi, V. , & Giron, M. C. (2018). Microbiome‐gut‐brain axis and toll‐like receptors in Parkinson's disease. International Journal of Molecular Sciences, 19(6), 1689 10.3390/ijms19061689 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carvalho, N. , Cóias, A. , Coelho, H. , Marcelino, G. , Albergaria, D. , Ferreira, M. J. , Costa, P. M. J. A. (2018). Helicobacter pylori and the atherogenic process in cardiovascular disease. Angiologia E Cirurgia Vascular,14(3), 182–185. [Google Scholar]
- Chan, F. K. , Lanas, A. , Scheiman, J. , Berger, M. F. , Nguyen, H. , & Goldstein, J. L. (2010). Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): A randomised trial. Lancet, 376(9736), 173–179. 10.1016/s0140-6736(10)60673-3 [DOI] [PubMed] [Google Scholar]
- Chang, K.‐V. , Hung, C.‐Y. , Li, C.‐M. , Lin, Y.‐H. , Wang, T.‐G. , Tsai, K.‐S. , & Han, D.‐S. (2015). Reduced flexibility associated with metabolic syndrome in community‐dwelling elders. PLoS ONE, 10(1), e0117167 10.1371/journal.pone.0117167 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen, D. , Shen, J. , Zhao, W. , Wang, T. , Han, L. , Hamilton, J. L. , & Im, H.‐J. (2017). Osteoarthritis: Toward a comprehensive understanding of pathological mechanism. Bone Research, 5, 16044–16044. 10.1038/boneres.2016.44 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen, L. W. , Chen, F. P. , Hsieh, C. W. , Kuo, S. F. , & Chien, R. N. (2017). Analysis of the associations among Helicobacter pylori infection, adiponectin, leptin, and 10‐year fracture risk using the fracture risk assessment tool: A cross‐sectional community‐based study. PLoS ONE, 12(4), e0175365 10.1371/journal.pone.0175365 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen, L.‐W. , Chien, C.‐Y. , Hsieh, C.‐W. , Chang, L.‐C. , Huang, M.‐H. , Huang, W.‐Y. , … Chien, R.‐N. (2016a). The associations between Helicobacter pylori infection, serum Vitamin D, and metabolic syndrome: A community‐based study. Medicine, 95(18), e3616 10.1097/md.0000000000003616 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen, L.‐W. , Chien, C.‐Y. , Yang, K.‐J. , Kuo, S.‐F. , Chen, C.‐H. , & Chien, R.‐N. (2015). Helicobacter pylori infection increases insulin resistance and metabolic syndrome in residents younger than 50 years old: A community‐based study. PLoS ONE, 10(5), e0128671 10.1371/journal.pone.0128671 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chmiela, M. , & Gonciarz, W. (2017). Molecular mimicry in Helicobacter pylori infections. World Journal of Gastroenterology, 23(22), 3964–3977. 10.3748/wjg.v23.i22.3964 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Christensen, M. H. E. , Fadnes, D. J. , Røst, T. H. , Pedersen, E. R. , Andersen, J. R. , Våge, V. , … Mellgren, G. (2018). Inflammatory markers, the tryptophan‐kynurenine pathway, and vitamin B status after bariatric surgery. PLoS ONE, 13(2), e0192169–e0192169. 10.1371/journal.pone.0192169 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cizginer, S. , Ordulu, Z. , & Kadayifci, A. (2014). Approach to Helicobacter pylori infection in geriatric population. World Journal of Gastrointestinal Pharmacology and Therapeutics, 5(3), 139–147. 10.4292/wjgpt.v5.i3.139 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Contaldi, F. , Capuano, F. , Fulgione, A. , Aiese Cigliano, R. , Sanseverino, W. , Iannelli, D. , … Capparelli, R. (2017). The hypothesis that Helicobacter pylori predisposes to Alzheimer's disease is biologically plausible. Scientific Reports, 7(1), 7817 10.1038/s41598-017-07532-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cortopassi, F. , Gurung, P. , & Pinto‐Plata, V. (2017). Chronic obstructive pulmonary disease in elderly patients. Clinics in Geriatric Medicine, 33(4), 539–552. 10.1016/j.cger.2017.06.006 [DOI] [PubMed] [Google Scholar]
- Cui, R. , Zhou, L. , Li, Z. , Li, Q. , Qi, Z. , & Zhang, J. (2016). Assessment risk of osteoporosis in Chinese people: Relationship among body mass index, serum lipid profiles, blood glucose, and bone mineral density. Clinical Interventions in Aging, 11, 887–895. 10.2147/cia.S103845 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dang, T. , & Liou, G.‐Y. (2018). Macrophage cytokines enhance cell proliferation of normal prostate epithelial cells through activation of ERK and Akt. Scientific Reports, 8(1), 7718–7718. 10.1038/s41598-018-26143-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dardiotis, E. , Tsouris, Z. , Mentis, A.‐F. , Siokas, V. , Michalopoulou, A. , Sokratous, M. , … Kountouras, J. (2018). H. pylori and Parkinson's disease: Meta‐analyses including clinical severity. Clinical Neurology and Neurosurgery, 175, 16–24. 10.1016/j.clineuro.2018.09.039 [DOI] [PubMed] [Google Scholar]
- Dat, A. , Yip, C. L. , & Hanegbi, U. (2016). Beware of the ‘Ascites’ patient: Delayed presentation of traumatic intraperitoneal bladder rupture. Urology Case Reports, 4, 11–13. 10.1016/j.eucr.2015.10.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Denic, A. , Glassock, R. J. , & Rule, A. D. (2016). Structural and functional changes with the aging kidney. Advances in Chronic Kidney Disease, 23(1), 19–28. 10.1053/j.ackd.2015.08.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dhillon, R. J. S. , & Hasni, S. (2017). Pathogenesis and management of sarcopenia. Clinics in Geriatric Medicine, 33(1), 17–26. 10.1016/j.cger.2016.08.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doulberis, M. , Kotronis, G. , Thomann, R. , Polyzos, S. A. , Boziki, M. , Gialamprinou, D. , … Kountouras, J. (2018). Review: Impact of Helicobacter pylori on Alzheimer's disease: What do we know so far? Helicobacter, 23(1), 10.1111/hel.12454 [DOI] [PubMed] [Google Scholar]
- Engin, A. B. , Karahalil, B. , Karakaya, A. E. , & Engin, A. (2015). Helicobacter pylori and serum kynurenine‐tryptophan ratio in patients with colorectal cancer. World Journal of Gastroenterology, 21(12), 3636–3643. 10.3748/wjg.v21.i12.3636 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Flint, A. , Stintzi, A. , & Saraiva, L. M. (2016). Oxidative and nitrosative stress defences of Helicobacter and Campylobacter species that counteract mammalian immunity. FEMS Microbiology Reviews, 40(6), 938–960. 10.1093/femsre/fuw025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fotouk‐Kiai, M. , Hoseini, S. R. , Meftah, N. , Ghadimi, R. , Bijani, A. , Noreddini, H. , … Shokri‐Shirvani, J. (2015). Relationship between Helicobacter pylori infection (HP) and bone mineral density (BMD) in elderly people. Caspian Journal of Internal Medicine, 6(2), 62–66. [PMC free article] [PubMed] [Google Scholar]
- Franceschi, C. , Garagnani, P. , Morsiani, C. , Conte, M. , Santoro, A. , Grignolio, A. , … Salvioli, S. (2018). The continuum of aging and age‐related diseases: Common mechanisms but different rates. Frontiers in Medicine, 5, 61–61. 10.3389/fmed.2018.00061 [DOI] [PMC free article] [PubMed] [Google Scholar]
- GonzÁlez, I. , Araya, P. , & Rojas, A. (2018). Helicobacter pylori infection and lung cancer: New insights and future challenges. Chinese Journal of Lung Cancer, 21(9), 658–662. 10.3779/j.issn.1009-3419.2018.09.03. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guilemany, J. M. , Langdon, C. , Ballesteros, F. , & Blanch, J. L. (2014). Prognostic significance and association of Helicobacter pylori infection in pharyngolaryngeal cancer. European Archives of Oto‐Rhino‐Laryngology, 271(9), 2539–2543. 10.1007/s00405-013-2794-4 [DOI] [PubMed] [Google Scholar]
- Heidari, B. (2015). Helicobacter Pylori Infection and Osteoporosis in Elderly Patients. Caspian Journal of Internal Medicine, 6(2), 48. [PMC free article] [PubMed] [Google Scholar]
- Hosseininasab Nodoushan, S. A. , & Nabavi, A. (2019). The interaction of Helicobacter pylori Infection and Type 2 diabetes mellitus. Advanced Biomedical Research, 8, 15–15. 10.4103/abr.abr_37_18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hu, K.‐C. , Wu, M.‐S. , Chu, C.‐H. , Wang, H.‐Y. , Lin, S.‐C. , Liu, S.‐C. , … Shih, S.‐C. (2017). Synergistic effect of hyperglycemia and Helicobacter pylori infection status on colorectal adenoma risk. Journal of Clinical Endocrinology and Metabolism, 102(8), 2744–2750. 10.1210/jc.2017-00257 [DOI] [PubMed] [Google Scholar]
- Hu, K.‐C. , Wu, M.‐S. , Chu, C.‐H. , Wang, H.‐Y. , Lin, S.‐C. , Po, H. L. , … Shih, S.‐C. (2017). Hyperglycemia combined Helicobacter pylori infection increases risk of synchronous colorectal adenoma and carotid artery plaque. Oncotarget, 8(65), 108655–108664. 10.18632/oncotarget.22094 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huang, J. (2017). Analysis of the relationship between helicobacter pylori infection and diabetic gastroparesis. Chinese Medical Journal, 130(22), 2680–2685. 10.4103/0366-6999.218012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hussein, N. R. , Saleem, Z. , Balatay, A. A. , Abd, K. H. , Daniel, S. , Taha, A. A. , … Assafi, M. S. (2016). Seroprevalence of Helicobacter pylori infection in renal transplant recipient attending Duhok kidney disease center. Transplantation Proceedings, 48(1), 92–95. 10.1016/j.transproceed.2016.01.006 [DOI] [PubMed] [Google Scholar]
- Ito, Y. , Vela, J. L. , Matsumura, F. , Hoshino, H. , Tyznik, A. , Lee, H. , … Fukuda, M. (2013). Helicobacter pylori cholesteryl α‐glucosides contribute to its pathogenicity and immune response by natural killer T cells. PLoS ONE, 8(12), e78191–e78191. 10.1371/journal.pone.0078191 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kapil, U. , Khandelwal, R. , Ramakrishnan, L. , Khenduja, P. , Gupta, A. , Pandey, R. M. , … Belwal, R. S. (2018). Prevalence of hypertension, diabetes, and associated risk factors among geriatric population living in a high‐altitude region of rural Uttarakhand, India. Journal of Family Medicine and Primary Care, 7(6), 1527–1536. 10.4103/jfmpc.jfmpc_108_18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kapil, U. , Khandelwal, R. , Ramakrishnan, L. , Khenduja, P. , Gupta, A. , Sareen, N. , … Belwal, R. S. (2018). Prevalence of metabolic syndrome and associated risk factors among geriatric population living in a high altitude region of rural Uttarakhand, India. Journal of Family Medicine and Primary Care, 7(4), 709–716. 10.4103/jfmpc.jfmpc_261_17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim, H. W. , Kim, Y.‐H. , Han, K. , Nam, G. E. , Kim, G. S. , Han, B.‐D. , … Ko, B. J. (2014). Atrophic gastritis: A related factor for osteoporosis in elderly women. PLoS ONE, 9(7), e101852–e101852. 10.1371/journal.pone.0101852 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim, S. H. , Yun, J. M. , Chang, C. B. , Piao, H. , Yu, S. J. , & Shin, D. W. (2016). Prevalence of upper gastrointestinal bleeding risk factors among the general population and osteoarthritis patients. World Journal of Gastroenterology, 22(48), 10643–10652. 10.3748/wjg.v22.i48.10643 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim, T. J. , Kim, E. R. , Chang, D. K. , Kim, Y. H. , Baek, S. Y. , Kim, K. , & Hong, S. N. (2017). Helicobacter pylori infection is an independent risk factor of early and advanced colorectal neoplasm. Helicobacter, 22(3), 10.1111/hel.12377 [DOI] [PubMed] [Google Scholar]
- Kobayashi, S. , Joshita, S. , Yamamoto, C. , Yanagisawa, T. , Miyazawa, T. , Miyazawa, M. , … Tanaka, E. (2019). Efficacy and safety of eradication therapy for elderly patients with Helicobacter pylori infection. Medicine (Baltimore), 98(30), e16619–e16619. 10.1097/MD.0000000000016619 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lai, C. Y. , Yang, T. Y. , Lin, C. L. , & Kao, C. H. (2015). Helicobacter pylori infection and the risk of acute coronary syndrome: A nationwide retrospective cohort study. European Journal of Clinical Microbiology & Infectious Diseases, 34(1), 69–74. 10.1007/s10096-014-2207-7 [DOI] [PubMed] [Google Scholar]
- Levi, E. , Sochacki, P. , Khoury, N. , Patel, B. B. , & Majumdar, A. P. (2014). Cancer stem cells in Helicobacter pylori infection and aging: Implications for gastric carcinogenesis. World Journal of Gastrointestinal Pathophysiology, 5(3), 366–372. 10.4291/wjgp.v5.i3.366 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li, J.‐Z. , Li, J.‐Y. , Wu, T.‐F. , Xu, J.‐H. , Huang, C.‐Z. , Cheng, D. , … Yu, T. (2017). Helicobacter pylori infection is associated with type 2 diabetes, not type 1 diabetes: An updated meta‐analysis. Gastroenterology Research and Practice, 2017, 5715403–5715403. 10.1155/2017/5715403 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li, P.‐F. , Chen, J.‐S. , Chang, J.‐B. , Chang, H.‐W. , Wu, C.‐Z. , Chuang, T.‐J. , … Chen, Y.‐L. (2016). Association of complete blood cell counts with metabolic syndrome in an elderly population. BMC Geriatrics, 16(1), 10 10.1186/s12877-016-0182-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liang, C.‐C. , Muo, C.‐H. , Wang, I.‐K. , Chang, C.‐T. , Chou, C.‐Y. , Liu, J.‐H. , … Chung, C.‐J. (2014). Peptic ulcer disease risk in chronic kidney disease: Ten‐year incidence, ulcer location, and ulcerogenic effect of medications. PLoS ONE, 9(2), e87952 10.1371/journal.pone.0087952 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin, S.‐Y. , Lin, C.‐L. , Liu, J.‐H. , Yang, Y.‐F. , Huang, C.‐C. , & Kao, C.‐H. (2015). Association between Helicobacter pylori infection and the subsequent risk of end‐stage renal disease: A nationwide population‐based cohort study. International Journal of Clinical Practice, 69(5), 604–610. 10.1111/ijcp.12602 [DOI] [PubMed] [Google Scholar]
- Loeser, R. F. , & Lotz, M. (2016). Osteoarthritis in the Elderly In Sierra F., & Kohanski R. (Eds.), Advances in Geroscience (pp. 309–353). Cham: Springer International Publishing. [Google Scholar]
- Lopez‐Garcia, E. , Rodríguez‐Artalejo, F. , Gutierrez‐Fisac, J. L. , León‐Muñoz, L. M. , Laclaustra, M. , Guallar‐Castillón, P. , Pérez‐Tasigchana, R. F. (2017). Metabolic syndrome and insulin resistance are associated with frailty in older adults: a prospective cohort study. Age and Ageing, 46(5), 807–812. 10.1093/ageing/afx023 [DOI] [PubMed] [Google Scholar]
- Lu, L.‐J. , Hao, N.‐B. , Liu, J.‐J. , Li, X. , & Wang, R.‐L. (2018). Correlation between Helicobacter pylori infection and metabolic abnormality in general population: A cross‐sectional study. J Gastroenterology Research and Practice, 2018, 6 10.1155/2018/7410801 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mantero, P. , Matus, G. S. , Corti, R. E. , Cabanne, A. M. , Zerbetto de Palma, G. G. , Marchesi Olid, L. , … Goldman, C. G. (2018). Helicobacter pylori and corpus gastric pathology are associated with lower serum ghrelin. World Journal of Gastroenterology, 24(3), 397–407. 10.3748/wjg.v24.i3.397 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matuszewska, A. , Nowak, B. , Rzeszutko, M. , Zduniak, K. , Szandruk, M. , Jędrzejuk, D. , … Szeląg, A. (2016). Effects of long‐term administration of pantoprazole on bone mineral density in young male rats. Pharmacological Reports, 68(5), 1060–1064. 10.1016/j.pharep.2016.06.012 [DOI] [PubMed] [Google Scholar]
- McGee, D. J. , Lu, X.‐H. , & Disbrow, E. A. (2018). Stomaching the possibility of a pathogenic role for Helicobacter pylori in Parkinson's Disease. Journal of Parkinson's Disease, 8(3), 367–374. 10.3233/JPD-181327 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Melese, A. , Genet, C. , Zeleke, B. , & Andualem, T. (2019). Helicobacter pylori infections in Ethiopia; prevalence and associated factors: A systematic review and meta‐analysis. BMC Gastroenterology, 19(1), 8–8. 10.1186/s12876-018-0927-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mladenova, I. (2019). Helicobacter pylori and cardiovascular disease: Update 2019. Minerva Cardioangiologica, 67(5), 425–432. 10.23736/s0026-4725.19.04986-7 [DOI] [PubMed] [Google Scholar]
- Moradniani, M. , Firouzi, M. , Baharvand, S. P. , Maleki, H. , Ghaderi, S. , & Sherkatolabbasieh, H. (2018). A randomized clinical trial; co levofloxacin based sequential based sequential versus triple Helicobacter pylori eradication. [PMC free article] [PubMed]
- Morandini, M. , Firouzi, M. , Shafizadeh, S. , Jaferian, S. , Beiranvand, S. F. , Roostae, F. , … Bahmani, M. (2018). Investigating prevalence of Helicobacter pylori and histological changes in patients with dyspepsia in Khorramabad City during 2013–2015. Medical Science, 22(90), 111–117. [Google Scholar]
- Muszyński, P. , Groblewska, M. , Kulczyńska‐Przybik, A. , Kułakowska, A. , & Mroczko, B. (2017). YKL‐40 as a potential biomarker and a possible target in therapeutic strategies of Alzheimer's disease. Current Neuropharmacology, 15(6), 906–917. 10.2174/1570159X15666170208124324 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mut Surmeli, D. , Surmeli, Z. G. , Bahsi, R. , Turgut, T. , Selvi Oztorun, H. , Atmis, V. , … Aras, S. (2018). Vitamin D deficiency and risk of Helicobacter pylori infection in older adults: a cross‐sectional study. Aging Clinical and Experimental Research. 10.1007/s40520-018-1039-1 [DOI] [PubMed] [Google Scholar]
- Nam, S. J. , Park, S. C. , Lee, S. H. , Choi, D. W. , Lee, S. J. , Bang, C. S. , … Park, J. K. (2019). Helicobacter pylori eradication in patients with type 2 diabetes mellitus: Multicenter prospective observational study. SAGE Open Medicine, 7, 2050312119832093 10.1177/2050312119832093 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nam, S. Y. , Ryu, K. H. , Park, B. J. , & Park, S. (2015). Effects of Helicobacter pylori infection and its eradication on lipid profiles and cardiovascular diseases. Helicobacter, 20(2), 125–132. 10.1111/hel.12182 [DOI] [PubMed] [Google Scholar]
- Nasif, W. A. , Mukhtar, M. H. , Nour Eldein, M. M. , & Ashgar, S. S. (2016). Oxidative DNA damage and oxidized low density lipoprotein in Type II diabetes mellitus among patients with Helicobacter pylori infection. Diabetology & Metabolic Syndrome, 8, 34–34. 10.1186/s13098-016-0149-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pan, B.‐L. , Huang, C.‐F. , Chuah, S.‐K. , Chiang, J.‐C. , & Loke, S.‐S. (2018). Relationship between Helicobacter pylori infection and bone mineral density: A retrospective cross‐sectional study. BMC Gastroenterology, 18(1), 54–54. 10.1186/s12876-018-0780-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peng, Y. H. , Chen, C. K. , Su, C. H. , Liao, W. C. , Muo, C. H. , Hsia, T. C. , … Kao, C. H. (2017). Increased risk of chronic obstructive pulmonary disease among patients with Helicobacter pylori infection: A population‐based cohort study. The Clinical Respiratory Journal, 11(5), 558–565. 10.1111/crj.12382 [DOI] [PubMed] [Google Scholar]
- Portilla Franco, M. E. , Tornero Molina, F. , & Gil Gregorio, P. (2016). Frailty in elderly people with chronic kidney disease. Nefrologia, 36(6), 609–615. 10.1016/j.nefro.2016.03.020 [DOI] [PubMed] [Google Scholar]
- Poveda, V. , Filgueiras, M. , Miranda, V. , Santos‐Silva, A. , Paul, C. , & Costa, E. (2017). Frailty in end‐stage renal disease patients under dialysis and its association with clinical and biochemical markers. The Journal of Frailty Aging, 6(2), 103–106. 10.14283/jfa.2017.14 [DOI] [PubMed] [Google Scholar]
- Rahmani, Y. , Mohammadi, S. , Babanejad, M. , Rai, A. , Zalei, B. , & Shahmohammadi, A. (2017). Association of Helicobacter pylori with presence of myocardial infarction in Iran: A systematic review and meta‐analysis. Ethiopian Journal of Health Sciences, 27(4), 433–440. 10.4314/ejhs.v27i4.15 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rogoveanu, O. C. , Streba, C. T. , Vere, C. C. , Petrescu, L. , & Traistaru, R. (2015). Superior digestive tract side effects after prolonged treatment with NSAIDs in patients with osteoarthritis. Journal of Medicine and Life, 8(4), 458–461. [PMC free article] [PubMed] [Google Scholar]
- Samareh Fekri, M. , Hashemi Bajgani, S. M. , Rasti, A. , Yazdani, R. , & Mollaie, H. R. (2014). Detection of Helicobacter pylori in bronchoalveolar lavage of patients with chronic obstructive pulmonary disease by real time polymerase chain reaction. Jundishapur Journal of Microbiology, 8(1), e14551–e14551. 10.5812/jjm.14551 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Samareh‐Fekri, M. , Hashemi Bajgani, S. M. , Shafahi, A. , Asadi‐Zarandi, M. , Mollaie, H. , & Jamali Paghalhe, A. (2016). Detection of Helicobacter pylori in the bronchoalveolar lavage of patients with lung cancer using real‐time PCR. Jundishapur Journal of Microbiology, 9(11), e32144 10.5812/jjm.32144 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Senmaru, T. , Fukui, M. , Kuroda, M. , Tanaka, M. , Ushigome, E. , Sakabe, K. , … Nakamura, N. (2013). Serum pepsinogen I/II ratio is correlated with albuminuria in patients with type 2 diabetes. Endocrine Journal, 60(2), 161–166. 10.1507/endocrj.EJ12-0244 [DOI] [PubMed] [Google Scholar]
- Shakeri, H. , Lemmens, K. , Gevaert, A. B. , Meyer, G. R. Y. D. , & Segers, V. F. M. (2018). Cellular Senescence Links Aging and Diabetes in Cardiovascular Disease. American Journal of Physiology‐Heart and Circulatory Physiology, 315(3), H448–H462. 10.1152/ajpheart.00287.2018 [DOI] [PubMed] [Google Scholar]
- Shan, J. H. , Bai, X. J. , Han, L. L. , Yuan, Y. , & Sun, X. F. (2017). Changes with aging in gastric biomarkers levels and in biochemical factors associated with Helicobacter pylori infection in asymptomatic Chinese population. World Journal of Gastroenterology, 23(32), 5945–5953. 10.3748/wjg.v23.i32.5945 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shavakhi, A. , Zafarghandi, M. , Gachkar, L. , Firouzi, M. , Ehsani, A. M. , Soumi, M. , … Zali, M. R. (2007). Seroprevalence of anti‐Helicobacter pylori antibodies in hepatitis B and C patients with cirrhosis: a case‐control study.
- Shih, H.‐M. , Hsu, T.‐Y. , Chen, C.‐Y. , Lin, C.‐L. , Kao, C.‐H. , Chen, C.‐H. , … Chen, W.‐K. (2016). Analysis of Patients with Helicobacter pylori infection and the subsequent risk of developing osteoporosis after eradication therapy: A nationwide population‐based cohort study. PLoS ONE, 11(9), e0162645 10.1371/journal.pone.0162645 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shindler‐Itskovitch, T. , Ravona‐Springer, R. , Leibovitz, A. , Muhsen, K. (2016). A systematic review and meta‐analysis of the association between Helicobacter pylori infection and dementia. Journal of Alzheimer's Disease, 52(4), 1431–1442. 10.3233/JAD-160132 [DOI] [PubMed] [Google Scholar]
- Song, L. , Xie, X.‐B. , Peng, L.‐K. , Yu, S.‐J. , & Peng, Y.‐T. (2015). Mechanism and treatment strategy of osteoporosis after transplantation. International Journal of Endocrinology, 2015, 280164–280164. 10.1155/2015/280164 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tamaki, M. , Miyashita, K. , Hagiwara, A. , Wakino, S. , Inoue, H. , Fujii, K. , … Itoh, H. (2017). Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation. Endocrine Journal, 64(Suppl.), S47–s51. 10.1507/endocrj.64.S47 [DOI] [PubMed] [Google Scholar]
- Tseng, C.‐H. (2018). Metformin and Helicobacter pylori infection in patients with type 2 diabetes, Vol. 41 (pp. e42–e43). %J Diabetes Care. 10.2337/dc17-2551 [DOI] [PubMed]
- Upala, S. , Sanguankeo, A. , Wijarnpreecha, K. , & Jaruvongvanich, V. (2016). Association between Helicobacter pylori infection and osteoporosis: A systematic review and meta‐analysis. Journal of Bone and Mineral Metabolism, 34(4), 482–483. 10.1007/s00774-015-0703-1 [DOI] [PubMed] [Google Scholar]
- Vendrov, A. E. , Vendrov, K. C. , Smith, A. , Yuan, J. , Sumida, A. , Robidoux, J. , … Madamanchi, N. R. (2015). NOX4 NADPH oxidase‐dependent mitochondrial oxidative stress in aging‐associated cardiovascular. Disease., 23(18), 1389–1409. 10.1089/ars.2014.6221 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Verit, A. , Yuksel, O. H. , Kivrak, M. , Yazicilar, H. A. , Ozbay, N. , & Uruc, F. (2015). Are Helicobacter pylori and benign prostatic hyperplasia related, and if so, How? Urol J, 12(4), 2271–2275. [PubMed] [Google Scholar]
- Vijayvergiya, R. , & Vadivelu, R. (2015). Role of Helicobacter pylori infection in pathogenesis of atherosclerosis. World Journal of Cardiology, 7(3), 134–143. 10.4330/wjc.v7.i3.134 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Viscogliosi, G. , Donfrancesco, C. , Palmieri, L. , & Giampaoli, S. (2017). The metabolic syndrome and 10‐year cognitive and functional decline in very old men. A population‐based study. Archives of Gerontology and Geriatrics, 70, 62–66. 10.1016/j.archger.2016.12.008 [DOI] [PubMed] [Google Scholar]
- Wang, F. , Fu, Y. , & Lv, Z. (2014). Association of Helicobacter pylori infection with diabetic complications: A meta‐analysis. Endocrine Research, 39(1), 7–12. 10.3109/07435800.2013.794426 [DOI] [PubMed] [Google Scholar]
- Wang, F. , Liu, J. , Zhang, Y. , & Lei, P. (2015). Association of Helicobacter pylori infection with chronic obstructive pulmonary disease and chronic bronchitis: A meta‐analysis of 16 studies. Infectious Disease (London), 47(9), 597–603. 10.3109/00365548.2014.989539 [DOI] [PubMed] [Google Scholar]
- Wang, J.‐W. , Hsu, C.‐N. , Tai, W.‐C. , Ku, M.‐K. , Hung, T.‐H. , Tseng, K.‐L. , … Chuah, S.‐K. (2016a). The Association of Helicobacter pylori eradication with the occurrences of chronic kidney diseases in patients with peptic ulcer diseases. PLoS ONE, 11(10), e0164824–e0164824. 10.1371/journal.pone.0164824 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang, L. , Guan, Y. , Li, Y. , Liu, X. , Zhang, Y. , Wang, F. , … Guo, Q. (2015). Association between chronic respiratory diseases and Helicobacter pylori: A meta‐analysis. Archivos De Bronconeumologia, 51(6), 273–278. 10.1016/j.arbres.2014.03.019 [DOI] [PubMed] [Google Scholar]
- Wang, X. L. , Zeng, J. , Yang, Y. , Xiong, Y. , Zhang, Z. H. , Qiu, M. , … Wang, J. Z. (2015). Helicobacter pylori filtrate induces Alzheimer‐like tau hyperphosphorylation by activating glycogen synthase kinase‐3beta. Journal of Alzheimer's Disease, 43(1), 153–165. 10.3233/jad-140198 [DOI] [PubMed] [Google Scholar]
- Xu, Y. , Wang, Q. , Liu, Y. , Cui, R. , Lu, K. , & Zhao, Y. (2016). Association between Helicobacter pylori infection and carotid atherosclerosis in patients with vascular dementia. Journal of the Neurological Sciences, 362, 73–77. 10.1016/j.jns.2016.01.025 [DOI] [PubMed] [Google Scholar]
- Xu, Y. , Wang, Q. , Liu, Y. , Cui, R. , & Zhao, Y. (2016). Is Helicobacter pylori infection a critical risk factor for vascular dementia? International Journal of Neuroscience, 126(10), 899–903. 10.3109/00207454.2015.1081387 [DOI] [PubMed] [Google Scholar]
- Yang, W. , & Xuan, C. (2016). Influence of Helicobacter pylori Infection on metabolic syndrome in old Chinese people. Gastroenterology Research and Practice, 2016, 6951264–6951264. 10.1155/2016/6951264 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yong, X. , Tang, B. , Xiao, Y. F. , Xie, R. , Qin, Y. , Luo, G. , … Yang, S. M. (2016). Helicobacter pylori upregulates Nanog and Oct4 via Wnt/beta‐catenin signaling pathway to promote cancer stem cell‐like properties in human gastric cancer. Cancer Letters, 374(2), 292–303. 10.1016/j.canlet.2016.02.032 [DOI] [PubMed] [Google Scholar]
- Yu, L.‐Y. , Hu, K.‐C. , Liu, C.‐J. , Hung, C.‐L. , Bair, M.‐J. , Chen, M.‐J. , … Liu, C.‐C. (2019). Helicobacter pylori infection combined with non‐alcoholic fatty liver disease increase the risk of atherosclerosis: Focus in carotid artery plaque. Medicine (Baltimore), 98(9), e14672 10.1097/md.0000000000014672 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yu, M. , Zhang, Y. , Yang, Z. , Ding, J. , Xie, C. , & Lu, N. (2014). Association between Helicobacter pylori infection and stroke: A meta‐analysis of prospective observational studies. Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association, 23(9), 2233–2239. 10.1016/j.jstrokecerebrovasdis.2014.04.020 [DOI] [PubMed] [Google Scholar]
- Zendedel, A. , Gholami, M. , Anbari, K. , Ghanadi, K. , Bachari, E. C. , & Azargon, A. (2015). Effects of vitamin D intake on FEV1 and COPD exacerbation: A randomized clinical trial study. Global Journal of Health Science, 7(4), 243 10.5539/gjhs.v7n4p243 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zendehdel, A. , & Arefi, M. (2019). Molecular evidence of role of vitamin D deficiency in various extraskeletal diseases. Journal of Cellular Biochemistry, 120(6), 8829–8840. 10.1002/jcb.28185 [DOI] [PubMed] [Google Scholar]
- Zendehdel, A. , & Roham, M. (2019). Biological evidence of the relationship between Helicobacter pylori and associated extragastric diseases. Journal of Cellular Biochemistry. [DOI] [PubMed] [Google Scholar]
- Zhan, T. , Rindtorff, N. , & Boutros, M. (2017). Wnt signaling in cancer. Oncogene, 36(11), 1461–1473. 10.1038/onc.2016.304 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang, Y. , Du, T. , Chen, X. , Yu, X. , Tu, L. , Zhang, C. (2015). Association between Helicobacter pylori Infection and overweight or obesity in a Chinese population, The Journal of Infection in Developing Countries, 9(09), 945–953. 10.3855/jidc.6035 [DOI] [PubMed] [Google Scholar]
- Zhao, Y. , Wang, X. , & Wang, Y. (2016). Helicobacter pylori infection and colorectal carcinoma risk: A meta‐analysis. Journal of Cancer Research & Therapy, 12(Supplement), 15–18. 10.4103/0973-1482.191621 [DOI] [PubMed] [Google Scholar]
- Zhou, J. , Zhang, D. , Yang, Y. , Zhou, L. , & Tao, L. (2016). Association between Helicobacter pylori infection and carcinoma of the larynx or pharynx. Head and Neck, 38(Suppl 1), E2291–2296. 10.1002/hed.24214 [DOI] [PubMed] [Google Scholar]