Helicobacter ISSN 1523-5378 doi: 10.1111/hel.12228
EDITORIAL
Novel Advances in the Association Between Helicobacter pylori Infection, Metabolic Syndrome, and Related Morbidity Stergios A. Polyzos and Jannis Kountouras Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
Keywords Helicobacter pylori, homeostasis model of assessment, insulin resistance, metabolic syndrome. Reprint requests to: Stergios A. Polyzos, Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 13 Simou Lianidi, 551 34 Thessaloniki, Macedonia, Greece. E-mail: [email protected]
Metabolic syndrome (Mets) comprises a cluster of metabolic abnormalities closely related to insulin resistance (IR), the major underlying mechanism responsible for the MetS, and Helicobacter pylori (Hp) has been proposed to be a contributing factor. There is growing evidence for a potential association between Hp infection and IR syndrome or MetS and its related morbidity, including obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD), the end-point of MetS [1–4]. Both Hp infection [5,6] and MetS [7] are highly prevalent worldwide, and their prevalence is increasing with age, although local variations exist [5,7]; the prevalence of MetS follows the ongoing epidemics of obesity and T2DM [7]. MetS decreases lifespan, mainly due to T2DM, CVD, and related malignancies [7]. Although controversy still exists, Hp infection has been linked to diverse extragastric morbidity, including T2DM, CVD, and malignancies [8]. In our effort to systematically summarize the epidemiologic evidence concerning the association between Hp infection and IR quantitative only indices, a trend toward a positive association between Hp infection and homeostasis model of assessment IR (HOMA-IR) was observed, despite a significant heterogeneity between studies regarding the diagnostic methods of Hp infection and the study populations [1]. The association of Hp infection and MetS seems to be appealing, given that the prevalence of Hp is still high in most countries, its prevalence is frequently higher than 50% in south and east Europe, South
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 405–409
America, and Asia [6], the prevalence of MetS is increasing [7], and, if an association is proved, Hp eradication might have therapeutic beneficial effects on MetS-related morbidity.
What is New in “Helicobacter” “Helicobacter” has recently published three studies enhancing our knowledge on the association between Hp infection and MetS and related morbidity, thereby providing further evidence for a potential therapeutic implication. Chen et al. [9] performed a well-designed cross-sectional study to investigate the association between Hp infection and MetS (based on the National Cholesterol Education Program Adult Treatment Panel III Criteria). Apart from the relative large sample size of the study (n = 3578 participants, aged 18–64), strength of this study was the use of the safe and reliable Hp diagnostic 13C-urea breath test, for first time in such epidemiologic study attempting to investigate the association between Hp infection and MetS. This test is more accurate compared with serology [10], and to the best of our knowledge, Hp infection was diagnosed using Hp serology in most relevant studies. The diagnosis of Hp infection was also based on histologic detection of Hp in mucosal biopsy specimens, regarded as the diagnostic gold standard, in limited studies, which, on the other hand, are underpowered, because of the invasive nature of histologic diagnosis [1]. Chen et al. [9] showed that the prevalence of MetS was higher in Hp positive than negative individuals in both genders
405
Helicobacter pylori and MetS
(in men 12.4 vs 7.4%, respectively, and in women 7.4 vs 2.5%, respectively). When adjusted for cofounders, Hp infection remained independently associated with MetS in women, whereas the association marginally lost its statistical significance in men. Reversely, in both genders, there was a significant increase in the prevalence of Hp infection by increasing the number of metabolic factors contributing to MetS, that is, high waist circumference, blood pressure, glucose, triglycerides, and low high-density lipoprotein cholesterol (HDL-C) levels. As a conclusion, Chen et al. [9] provided important evidence for an association between active Hp infection and MetS. Although the cross-sectional design of the study does not allow drawing causative conclusions, this study strengthens the Hp infection and MetS interplay and warrants further research. In the second study, Nam et al. [11] performed a large prospective cohort study in individuals undergoing regular checkup (n = 4269). Participants were excluded if they had undergone previous gastric surgery, had received previous Hp eradication regimen or were on lipid-lowering drugs. The diagnosis of active Hp infection was based on rapid urease test by endoscopy. To treat Hp infection, a 1-week course consisting of omeprazole (20 mg two times a day), clarithromycin (500 mg two times a day), and amoxicillin (1 g two times a day) was given, according to clinical indications. At baseline, 55% of the participants were Hp positive and had higher low-density lipoprotein cholesterol (LDL-C) and lower HDL-C levels, although other parameters related to MetS were similar between groups (glucose and triglyceride levels) or marginally lost statistical significance (body mass index, blood pressure). Importantly, at baseline, Hp positivity was independently associated with CVD (adjusted OR 3.27; 95% CI 1.31–8.14) compared to Hp negativity [11]. Followup re-assessment, including endoscopy was performed 1–3 years after Hp eradication therapy. Successful Hp eradication (n = 529) decreased LDL-C and increased HDL-C levels, but not triglyceride levels or blood pressure compared to individuals with persistent Hp infection (n = 1806). Most importantly, Hp did not decrease the risk of CVD between individuals with successful Hp eradication and those with persistent infection, but the CVD risk decreased in the persistent Hp negative individuals (n = 1934) compared with those with persistent Hp infection (adjusted OR 0.57; 95% CI, 0.35–0.94) [11]. Given strengths of the study is that a large sample size was subjected to endoscopy for the needs of Hp diagnosis (being currently the larger sample subjected to endoscopy for this aim) and the endoscopic re-assessment at follow-up. Although the relative short time of follow-up and the relative young age of the participants
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(mean age of approximately 49 years) deter the generalization of the results in populations at higher risk for CVD, this study strengthens the Hp infection and lipid interplay and warrants further investigation. In the third study, Liu et al. [12] performed a metaanalysis to evaluate whether the risk of myocardial infarction (MI) is associated with Hp infection. MI is a potentially fatal CVD closely related to MetS, which is associated with a twofold increase in cardiovascular outcomes [13]. Liu et al. [12] included 26 case–control studies involving 5829 patients with MI and 16,131 controls. Overall, Hp infection was associated with an increased risk of myocardial infarction (OR 1.73; 95% CI 1.37–2.17). Following data stratification, the association between Hp infection and MI was shown to be significant regardless age (cut-off 40 years), race (Caucasians and Asians) and socioeconomic status (developed and developing countries) [12]. No publication bias was observed in this meta-analysis. Although the authors did not perform a meta-regression, they performed a sensitivity analysis including studies with well-matched case–controls, which provided similar results. This was the first meta-analysis for the association between Hp infection and MI, which provided important evidence and warrants further research on the effect of Hp eradication on the incidence of MI.
Potential Pathogenetic Associations Although a causative relationship between Hp infection and IR syndrome remains to be established, there are some possible mechanisms linking Hp to IR syndrome. Zhou et al. [14] have recently published one of the stronger pieces of evidence linking Hp infection with hepatic IR. They showed that Hp infection can cause hepatic IR in primary hepatocytes through c-Jun/suppressor of cytokine signaling (SOCS)3 pathway. More specifically, Hp infection can induce the transcription factor c-Jun, which upregulates the suppressor of cytokine signaling (SOCS)3, an established insulin and leptin signaling inhibitor. This effect may be mediated by the micro-RNA-203; micro-RNAs have recently been implicated in the pathogenesis of both IR and tumorigenesis [14]. Other potential links may be speculated, based on the observation that Hp infection and IR syndrome share common pathogenetic mediators in a milieu of chronic inflammation, oxidative stress and alterations in counter-regulatory hormones, as it was reviewed elsewhere [1]. More specifically, Hp infection: 1) releases proinflammatory and vasoactive mediators, including cytokines [interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, TNF-a, interferon-c], eicosanoids
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 405–409
Polyzos and Kountouras
(leukotrienes, prostaglandins), and acute phase proteins (fibrinogen, C-reactive protein), which are also involved in the pathogenesis of IR syndrome; 2) promotes platelet activation and platelet–leukocyte aggregation, which play a role in IR syndrome and associated atherosclerosis; 3) produces reactive oxygen species, also involved in the pathophysiology of IR syndrome; 4) induces chronic atrophic gastritis, which decreases vitamin B12 and folate levels, thereby increasing homocysteine, a risk factor for IR and related disorders; and 5) influences the apoptotic process, which also plays an important role in many IR-related disorders [1]. Although some authors reported weight gain after Hp eradication, possibly attributed to increased ghrelin secretion, others did not find any effect of Hp eradication on body weight, as it is elsewhere reviewed [15]. On the other hand, a meta-analysis of observational studies reported a slightly higher BMI in Hp-positive patients [16]. Furthermore, Hp infection may have an additive effect on the low-grade inflammation observed in obesity [17], and their combination may accelerate gastric carcinogenesis [18]. It has been also reported that available studies rarely have considered cofounders, and none have taken into account the marked changes in the food industry and its effects on eating habits during the last decades [19].
Clinical Implications and Future Perspectives Novel studies published in “Helicobacter” provide further evidence for an association between Hp infection and MetS, dyslipidemia, and CVD, which are closely related to MetS. An association between Hp infection and MetS, if further validated, may have epidemiologic, clinical and therapeutic implications, because Hp infection is still high in most countries [5,6], the prevalence of MetS is increasing together with the epidemics of obesity and T2DM [7] and Hp eradication might have therapeutic impact on NAFLD [1]. However, welldesigned prospective controlled trials are needed before Hp eradication is introduced in clinical practice to treat MetS and its components, including dyslipidemia and CVD. A main limitation of the studies investigating the association between Hp infection and MetS is the definition bias, which renders the review efforts hard: Different studies have adopted different criteria for MetS and different criteria for the diagnosis of Hp infection [20]. MetS has been defined by different semi-quantitative or nonquantitative criteria, including those of World Health Organization, European Group for the
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 405–409
Helicobacter pylori and MetS
study of IR, American Association of Clinical Endocrinologists, National Cholesterol Education Program Adult Treatment Panel III, and International Diabetes Foundation criteria. Furthermore, the diagnosis of Hp infection has been made by many diagnostic tests including noninvasive methods, such as serologic or urinary tests, 13C-urea breath test, and fecal antigen tests, and invasive techniques, including a combined use of endoscopic biopsy-based methods, such as rapid urease testing, histology, considered the practical diagnostic gold standard, culture, and molecular methods [10]. A way to partly over-ride the definition problem with MetS is the use of quantitative indices evaluating IR, including HOMA-IR, quantitative insulin sensitivity check index (QUICKI), and hyperinsulinemic-euglycemic clamp, which is regarded as the gold standard, but is also more invasive and meets practical difficulties and higher risk [1]. It is also of importance to differentiate studies in which Hp infection diagnosis is active or not, because only active infection induces humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of host, thereby possibly exerting extragastric effects, especially if it remains for long term, although this has not been well established yet [1]. It is important that both the novel original studies in “Helicobacter” [9,11] provide evidence based on the established methods for active Hp infection. Another important issue is that the association between Hp infection and IR may reflect uncontrolled confounding rather than a causative relationship. In this regard, it is highlighted that in our previous systematic review evaluating the association between Hp infection and HOMA-IR [1], adjustment for potential confounders was performed in only one of eight included cross-sectional studies [21]. Since then, other authors performed adjustment for potential confounders in a cross-sectional [2,22] or prospective fashion [23], with conflicting results on the effect of various confounders on the relationship between Hp infection and IR. Although it is hard to include all potential confounders, adjustment for confounders is highly suggested for the future studies. Well-designed future studies may elucidate whether the association between Hp infection and IR is or not causal. Moreover, it remains to clarify whether Hp infection is directly related to IR, or represents only a marker of microbiome change, which, in turn, affects IR. There is increasing evidence for the role of 1) Hp infection on changing microbiota composition along the gastrointestinal tract [24]; and 2) the role of gastrointestinal microbiota on IR and related disorders [25].
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Gastrointestinal dysbiosis appears to be a key player in triggering obesity, systemic inflammation, and IR. However, no study has to-date provided evidence for the sequence: Hp infection—microbiome changes—IR. Based on novel evidence, it is of importance that well-designed and randomized well-controlled prospective clinical trials be set. If eradication treatment provide favorable evidence for reducing the incidence of MetS or its related morbidity, including T2DM, dyslipidemia, NAFLD, and CVD, it would be of paramount importance in an epidemiologic, clinical, and possibly health-economic setting. Even more, the most important question remaining to be answered is whether MetS patients with concomitant Hp infection have higher mortality compared with MetS patients without Hp infection, and whether the successful eradication therapy decreases mortality. This also needs a large sample size followed up prospectively for long time, but a positive answer would radically impact the introduction of Hp eradication therapy in MetS individuals. It should be also highlighted that, even if Hp eradication treatment is established to decrease Mets morbidity and/or mortality, it could not be considered as a panacea for the management of MetS and its related morbidity. The pathogenesis of MetS, such as T2DM, NAFLD, and CVD [26], is multifactorial; genetic susceptibility, environmental factors cross talk between the adaptive and innate immune system, and personal habits interplay and affect its phenotypic expression and long-term outcomes. In this regard, Hp eradication treatment might potentially diminish the epidemics of MetS, but it cannot itself “eradicate” MetS. As closing remarks, new studies in “Helicobacter” expand our knowledge on the potential association between Hp infection and MetS and related morbidity, which may have clinical and therapeutic implication in the future, if further studies establish a causative link and an impact of Hp eradication on MetS morbidity and mortality.
Acknowledgements and Disclosures No grant or other source supported this study. Competing interest: The authors have no competing interests.
References 1 Polyzos SA, Kountouras J, Zavos C, Deretzi G. The association between Helicobacter pylori infection and insulin resistance: a systematic review. Helicobacter 2011;16:79–88.
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2 Polyzos SA, Kountouras J, Papatheodorou A, et al. Helicobacter pylori infection in patients with nonalcoholic fatty liver disease. Metabolism 2013;62:121–6. 3 Polyzos SA, Kountouras J, Zavos C, Deretzi G. Helicobacter pylori infection, insulin resistance and nonalcoholic fatty liver disease. Med Hypotheses 2014;82:795. 4 Romiopoulos I, Kountouras J, Polyzos SA, et al. Helicobacter pylori-related metabolic syndrome might justify earlier colorectal cancer screening. Gastrointest Endosc 2014;80:188–9. 5 Calvet X, Ramirez Lazaro MJ, Lehours P, Megraud F. Diagnosis and epidemiology of Helicobacter pylori infection. Helicobacter 2013;18(Suppl 1):5–11. 6 Eusebi LH, Zagari RM, Bazzoli F. Epidemiology of Helicobacter pylori infection. Helicobacter 2014;19(Suppl 1):1–5. 7 McCullough AJ. Epidemiology of the metabolic syndrome in the USA. J Dig Dis 2011;12:333–40. 8 Banic M, Franceschi F, Babic Z, Gasbarrini A. Extragastric manifestations of Helicobacter pylori infection. Helicobacter 2012;17 (Suppl 1):49–55. 9 Chen TP, Hung HF, Chen MK, et al. Helicobacter pylori infection is positively associated with metabolic syndrome in Taiwanese adults: a cross-sectional study. Helicobacter 2015; doi:10.1111/ hel.12190. 10 Megraud F, Bessede E, Lehours P. Diagnosis of Helicobacter pylori infection. Helicobacter 2014;19(Suppl 1):6–10. 11 Nam SY, Ryu KH, Park BJ, Park S. Effects of Helicobacter pylori infection and its eradication on lipid profiles and cardiovascular diseases. Helicobacter 2014; doi:10.1111/hel.12182. 12 Liu J, Wang F, Shi S. Helicobacter pylori infection increase the risk of myocardial infarction: a meta-analysis of 26 studies involving more than 20,000 participants. Helicobacter 2014; doi:10.1111/hel.12188. 13 Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010;56:1113–32. 14 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. J Gastroenterol 2015; doi:10.1007/s00535-015-1051-6. 15 Carabotti M, D’Ercole C, Iossa A, Corazziari E, Silecchia G, Severi C. Helicobacter pylori infection in obesity and its clinical outcome after bariatric surgery. World J Gastroenterol 2014;20:647–53. 16 Danesh J, Peto R. Risk factors for coronary heart disease and infection with Helicobacter pylori: meta-analysis of 18 studies. BMJ 1998;316:1130–2. 17 Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med 2009;72:299–314. 18 Ericksen RE, Rose S, Westphalen CB, et al. Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response. Gut 2014;63:385–94. 19 Graham DY. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits. Gastroenterology 2015;148:719– 31. 20 Polyzos SA, Kountouras J, Zavos C, Deretzi G. Helicobacter pylori and insulin resistance association: not just a myth, not yet a fact. Saudi J Gastroenterol 2011;17:425–6. 21 Gunji T, Matsuhashi N, Sato H, et al. Helicobacter pylori infection significantly increases insulin resistance in the asymptomatic Japanese population. Helicobacter 2009;14:144–50.
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22 Naja F, Nasreddine L, Hwalla N, et al. Association of H. pylori infection with insulin resistance and metabolic syndrome among lebanese adults. Helicobacter 2012;17: 444–51. 23 Jeon CY, Haan MN, Cheng C, et al. Helicobacter pylori infection is associated with an increased rate of diabetes. Diabetes Care 2012;35:520–5. 24 Lopetuso LR, Scaldaferri F, Franceschi F, Gasbarrini A. The gastrointestinal microbiome – functional interference between
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Helicobacter pylori and MetS
stomach and intestine. Best Pract Res Clin Gastroenterol 2014;28:995–1002. 25 Caricilli AM, Saad MJ. Gut microbiota composition and its effects on obesity and insulin resistance. Curr Opin Clin Nutr Metab Care 2014;17:312–8. 26 Polyzos SA, Kountouras J, Zavos C, Deretzi G. Nonalcoholic fatty liver disease: multimodal treatment options for a pathogenetically multiple-hit disease. J Clin Gastroenterol 2012;46:272–84.
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EDITORIAL
Novel Advances in the Association Between Helicobacter pylori Infection, Metabolic Syndrome, and Related Morbidity Stergios A. Polyzos and Jannis Kountouras Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
Keywords Helicobacter pylori, homeostasis model of assessment, insulin resistance, metabolic syndrome. Reprint requests to: Stergios A. Polyzos, Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 13 Simou Lianidi, 551 34 Thessaloniki, Macedonia, Greece. E-mail: [email protected]
Metabolic syndrome (Mets) comprises a cluster of metabolic abnormalities closely related to insulin resistance (IR), the major underlying mechanism responsible for the MetS, and Helicobacter pylori (Hp) has been proposed to be a contributing factor. There is growing evidence for a potential association between Hp infection and IR syndrome or MetS and its related morbidity, including obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD), the end-point of MetS [1–4]. Both Hp infection [5,6] and MetS [7] are highly prevalent worldwide, and their prevalence is increasing with age, although local variations exist [5,7]; the prevalence of MetS follows the ongoing epidemics of obesity and T2DM [7]. MetS decreases lifespan, mainly due to T2DM, CVD, and related malignancies [7]. Although controversy still exists, Hp infection has been linked to diverse extragastric morbidity, including T2DM, CVD, and malignancies [8]. In our effort to systematically summarize the epidemiologic evidence concerning the association between Hp infection and IR quantitative only indices, a trend toward a positive association between Hp infection and homeostasis model of assessment IR (HOMA-IR) was observed, despite a significant heterogeneity between studies regarding the diagnostic methods of Hp infection and the study populations [1]. The association of Hp infection and MetS seems to be appealing, given that the prevalence of Hp is still high in most countries, its prevalence is frequently higher than 50% in south and east Europe, South
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 405–409
America, and Asia [6], the prevalence of MetS is increasing [7], and, if an association is proved, Hp eradication might have therapeutic beneficial effects on MetS-related morbidity.
What is New in “Helicobacter” “Helicobacter” has recently published three studies enhancing our knowledge on the association between Hp infection and MetS and related morbidity, thereby providing further evidence for a potential therapeutic implication. Chen et al. [9] performed a well-designed cross-sectional study to investigate the association between Hp infection and MetS (based on the National Cholesterol Education Program Adult Treatment Panel III Criteria). Apart from the relative large sample size of the study (n = 3578 participants, aged 18–64), strength of this study was the use of the safe and reliable Hp diagnostic 13C-urea breath test, for first time in such epidemiologic study attempting to investigate the association between Hp infection and MetS. This test is more accurate compared with serology [10], and to the best of our knowledge, Hp infection was diagnosed using Hp serology in most relevant studies. The diagnosis of Hp infection was also based on histologic detection of Hp in mucosal biopsy specimens, regarded as the diagnostic gold standard, in limited studies, which, on the other hand, are underpowered, because of the invasive nature of histologic diagnosis [1]. Chen et al. [9] showed that the prevalence of MetS was higher in Hp positive than negative individuals in both genders
405
Helicobacter pylori and MetS
(in men 12.4 vs 7.4%, respectively, and in women 7.4 vs 2.5%, respectively). When adjusted for cofounders, Hp infection remained independently associated with MetS in women, whereas the association marginally lost its statistical significance in men. Reversely, in both genders, there was a significant increase in the prevalence of Hp infection by increasing the number of metabolic factors contributing to MetS, that is, high waist circumference, blood pressure, glucose, triglycerides, and low high-density lipoprotein cholesterol (HDL-C) levels. As a conclusion, Chen et al. [9] provided important evidence for an association between active Hp infection and MetS. Although the cross-sectional design of the study does not allow drawing causative conclusions, this study strengthens the Hp infection and MetS interplay and warrants further research. In the second study, Nam et al. [11] performed a large prospective cohort study in individuals undergoing regular checkup (n = 4269). Participants were excluded if they had undergone previous gastric surgery, had received previous Hp eradication regimen or were on lipid-lowering drugs. The diagnosis of active Hp infection was based on rapid urease test by endoscopy. To treat Hp infection, a 1-week course consisting of omeprazole (20 mg two times a day), clarithromycin (500 mg two times a day), and amoxicillin (1 g two times a day) was given, according to clinical indications. At baseline, 55% of the participants were Hp positive and had higher low-density lipoprotein cholesterol (LDL-C) and lower HDL-C levels, although other parameters related to MetS were similar between groups (glucose and triglyceride levels) or marginally lost statistical significance (body mass index, blood pressure). Importantly, at baseline, Hp positivity was independently associated with CVD (adjusted OR 3.27; 95% CI 1.31–8.14) compared to Hp negativity [11]. Followup re-assessment, including endoscopy was performed 1–3 years after Hp eradication therapy. Successful Hp eradication (n = 529) decreased LDL-C and increased HDL-C levels, but not triglyceride levels or blood pressure compared to individuals with persistent Hp infection (n = 1806). Most importantly, Hp did not decrease the risk of CVD between individuals with successful Hp eradication and those with persistent infection, but the CVD risk decreased in the persistent Hp negative individuals (n = 1934) compared with those with persistent Hp infection (adjusted OR 0.57; 95% CI, 0.35–0.94) [11]. Given strengths of the study is that a large sample size was subjected to endoscopy for the needs of Hp diagnosis (being currently the larger sample subjected to endoscopy for this aim) and the endoscopic re-assessment at follow-up. Although the relative short time of follow-up and the relative young age of the participants
406
Polyzos and Kountouras
(mean age of approximately 49 years) deter the generalization of the results in populations at higher risk for CVD, this study strengthens the Hp infection and lipid interplay and warrants further investigation. In the third study, Liu et al. [12] performed a metaanalysis to evaluate whether the risk of myocardial infarction (MI) is associated with Hp infection. MI is a potentially fatal CVD closely related to MetS, which is associated with a twofold increase in cardiovascular outcomes [13]. Liu et al. [12] included 26 case–control studies involving 5829 patients with MI and 16,131 controls. Overall, Hp infection was associated with an increased risk of myocardial infarction (OR 1.73; 95% CI 1.37–2.17). Following data stratification, the association between Hp infection and MI was shown to be significant regardless age (cut-off 40 years), race (Caucasians and Asians) and socioeconomic status (developed and developing countries) [12]. No publication bias was observed in this meta-analysis. Although the authors did not perform a meta-regression, they performed a sensitivity analysis including studies with well-matched case–controls, which provided similar results. This was the first meta-analysis for the association between Hp infection and MI, which provided important evidence and warrants further research on the effect of Hp eradication on the incidence of MI.
Potential Pathogenetic Associations Although a causative relationship between Hp infection and IR syndrome remains to be established, there are some possible mechanisms linking Hp to IR syndrome. Zhou et al. [14] have recently published one of the stronger pieces of evidence linking Hp infection with hepatic IR. They showed that Hp infection can cause hepatic IR in primary hepatocytes through c-Jun/suppressor of cytokine signaling (SOCS)3 pathway. More specifically, Hp infection can induce the transcription factor c-Jun, which upregulates the suppressor of cytokine signaling (SOCS)3, an established insulin and leptin signaling inhibitor. This effect may be mediated by the micro-RNA-203; micro-RNAs have recently been implicated in the pathogenesis of both IR and tumorigenesis [14]. Other potential links may be speculated, based on the observation that Hp infection and IR syndrome share common pathogenetic mediators in a milieu of chronic inflammation, oxidative stress and alterations in counter-regulatory hormones, as it was reviewed elsewhere [1]. More specifically, Hp infection: 1) releases proinflammatory and vasoactive mediators, including cytokines [interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, TNF-a, interferon-c], eicosanoids
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 405–409
Polyzos and Kountouras
(leukotrienes, prostaglandins), and acute phase proteins (fibrinogen, C-reactive protein), which are also involved in the pathogenesis of IR syndrome; 2) promotes platelet activation and platelet–leukocyte aggregation, which play a role in IR syndrome and associated atherosclerosis; 3) produces reactive oxygen species, also involved in the pathophysiology of IR syndrome; 4) induces chronic atrophic gastritis, which decreases vitamin B12 and folate levels, thereby increasing homocysteine, a risk factor for IR and related disorders; and 5) influences the apoptotic process, which also plays an important role in many IR-related disorders [1]. Although some authors reported weight gain after Hp eradication, possibly attributed to increased ghrelin secretion, others did not find any effect of Hp eradication on body weight, as it is elsewhere reviewed [15]. On the other hand, a meta-analysis of observational studies reported a slightly higher BMI in Hp-positive patients [16]. Furthermore, Hp infection may have an additive effect on the low-grade inflammation observed in obesity [17], and their combination may accelerate gastric carcinogenesis [18]. It has been also reported that available studies rarely have considered cofounders, and none have taken into account the marked changes in the food industry and its effects on eating habits during the last decades [19].
Clinical Implications and Future Perspectives Novel studies published in “Helicobacter” provide further evidence for an association between Hp infection and MetS, dyslipidemia, and CVD, which are closely related to MetS. An association between Hp infection and MetS, if further validated, may have epidemiologic, clinical and therapeutic implications, because Hp infection is still high in most countries [5,6], the prevalence of MetS is increasing together with the epidemics of obesity and T2DM [7] and Hp eradication might have therapeutic impact on NAFLD [1]. However, welldesigned prospective controlled trials are needed before Hp eradication is introduced in clinical practice to treat MetS and its components, including dyslipidemia and CVD. A main limitation of the studies investigating the association between Hp infection and MetS is the definition bias, which renders the review efforts hard: Different studies have adopted different criteria for MetS and different criteria for the diagnosis of Hp infection [20]. MetS has been defined by different semi-quantitative or nonquantitative criteria, including those of World Health Organization, European Group for the
© 2015 John Wiley & Sons Ltd, Helicobacter 20: 405–409
Helicobacter pylori and MetS
study of IR, American Association of Clinical Endocrinologists, National Cholesterol Education Program Adult Treatment Panel III, and International Diabetes Foundation criteria. Furthermore, the diagnosis of Hp infection has been made by many diagnostic tests including noninvasive methods, such as serologic or urinary tests, 13C-urea breath test, and fecal antigen tests, and invasive techniques, including a combined use of endoscopic biopsy-based methods, such as rapid urease testing, histology, considered the practical diagnostic gold standard, culture, and molecular methods [10]. A way to partly over-ride the definition problem with MetS is the use of quantitative indices evaluating IR, including HOMA-IR, quantitative insulin sensitivity check index (QUICKI), and hyperinsulinemic-euglycemic clamp, which is regarded as the gold standard, but is also more invasive and meets practical difficulties and higher risk [1]. It is also of importance to differentiate studies in which Hp infection diagnosis is active or not, because only active infection induces humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of host, thereby possibly exerting extragastric effects, especially if it remains for long term, although this has not been well established yet [1]. It is important that both the novel original studies in “Helicobacter” [9,11] provide evidence based on the established methods for active Hp infection. Another important issue is that the association between Hp infection and IR may reflect uncontrolled confounding rather than a causative relationship. In this regard, it is highlighted that in our previous systematic review evaluating the association between Hp infection and HOMA-IR [1], adjustment for potential confounders was performed in only one of eight included cross-sectional studies [21]. Since then, other authors performed adjustment for potential confounders in a cross-sectional [2,22] or prospective fashion [23], with conflicting results on the effect of various confounders on the relationship between Hp infection and IR. Although it is hard to include all potential confounders, adjustment for confounders is highly suggested for the future studies. Well-designed future studies may elucidate whether the association between Hp infection and IR is or not causal. Moreover, it remains to clarify whether Hp infection is directly related to IR, or represents only a marker of microbiome change, which, in turn, affects IR. There is increasing evidence for the role of 1) Hp infection on changing microbiota composition along the gastrointestinal tract [24]; and 2) the role of gastrointestinal microbiota on IR and related disorders [25].
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Gastrointestinal dysbiosis appears to be a key player in triggering obesity, systemic inflammation, and IR. However, no study has to-date provided evidence for the sequence: Hp infection—microbiome changes—IR. Based on novel evidence, it is of importance that well-designed and randomized well-controlled prospective clinical trials be set. If eradication treatment provide favorable evidence for reducing the incidence of MetS or its related morbidity, including T2DM, dyslipidemia, NAFLD, and CVD, it would be of paramount importance in an epidemiologic, clinical, and possibly health-economic setting. Even more, the most important question remaining to be answered is whether MetS patients with concomitant Hp infection have higher mortality compared with MetS patients without Hp infection, and whether the successful eradication therapy decreases mortality. This also needs a large sample size followed up prospectively for long time, but a positive answer would radically impact the introduction of Hp eradication therapy in MetS individuals. It should be also highlighted that, even if Hp eradication treatment is established to decrease Mets morbidity and/or mortality, it could not be considered as a panacea for the management of MetS and its related morbidity. The pathogenesis of MetS, such as T2DM, NAFLD, and CVD [26], is multifactorial; genetic susceptibility, environmental factors cross talk between the adaptive and innate immune system, and personal habits interplay and affect its phenotypic expression and long-term outcomes. In this regard, Hp eradication treatment might potentially diminish the epidemics of MetS, but it cannot itself “eradicate” MetS. As closing remarks, new studies in “Helicobacter” expand our knowledge on the potential association between Hp infection and MetS and related morbidity, which may have clinical and therapeutic implication in the future, if further studies establish a causative link and an impact of Hp eradication on MetS morbidity and mortality.
Acknowledgements and Disclosures No grant or other source supported this study. Competing interest: The authors have no competing interests.
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