PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jidLink to Publisher's site
 
J Infect Dis. 2012 April 15; 205(8): 1195–1202.
Published online 2012 March 13. doi:  10.1093/infdis/jis106
PMCID: PMC3308905
Editor's Choice

Association Between Gastric Helicobacter pylori Colonization and Glycated Hemoglobin Levels

Abstract

(See the editorial commentary by Cohen and Muhsen, on pages 1183–5.)

Background. Few studies have evaluated the potential influence of Helicobacter pylori on biomarkers for diabetes.

Methods. We conducted cross-sectional analyses using data from 7417 participants in the National Health and Nutrition Examination Survey (NHANES) III (aged ≥18 years) and 6072 participants in NHANES 1999–2000 (aged ≥3 years) to assess the association between H. pylori and levels of glycosylated hemoglobin (HbA1c).

Results. There was no association between H. pylori and history of self-reported diabetes. Helicobacter pylori seropositivity, especially H. pylori cagA positivity, was positively associated (P < .01, NHANES III; P = .02, NHANES 1999–2000) with HbA1c levels after excluding individuals with history of diabetes and controlling for potential confounders. There was also a synergistic interaction between H. pylori and higher body mass index (BMI), such that increased levels of HbA1c associated with having both H. pylori and higher BMI were greater than the sum of their individual effects (P for interaction < .01). This interaction was observed consistently in both NHANES III and NHANES 1999–2000 and for H. pylori cagA positivity in NHANES III.

Conclusions. The findings indicate a role of H. pylori in impaired glucose tolerance in adults that may be potentiated by higher BMI level.

Diabetes mellitus, a chronic disease marked by high levels of sugar in the blood, is common and increasing around the world [1]. Although major risk factors for type 2 diabetes, such as obesity, have been identified, research that assesses susceptibility to diabetes risk due to obesity is needed.

The mammalian stomach produces leptin and ghrelin, 2 hormones involved in energy homeostasis [2, 3] and whose interactions affect obesity, insulin sensitivity, and glucose homeostasis [4, 5]. Helicobacter pylori are gram-negative bacteria that colonize the human stomach; increasing evidence indicates that H. pylori is involved in the regulation of these 2 hormones [6]. Helicobacter pylori is an ancient organism that is highly prevalent in developing countries but is falling in incidence in developed countries [7, 8]. This change in the microecology of human populations due to the disappearance of H. pylori may have metabolic consequences both early and late in life and, in particular, could affect risk of obesity and diabetes by influencing the production of gastric leptin and ghrelin [6].

The literature on the relationship between H. pylori colonization and diabetes is inconsistent [915]. To better understand the pathophysiologic mechanisms by which H. pylori plays a role in diabetes etiology, studies of diabetes biomarkers are needed. Glycated hemoglobin (HbA1c) results from the nonenzymatic glycosylation of hemoglobin, reflecting integrated blood glucose levels during the preceding 3–4 months [1618]; as such, fasting is not necessary for its measurement. HbA1c levels are predictive of both prevalent and incident diabetes and are useful in diagnosing prediabetes and diabetes [1618]. Prior studies on the association between H. pylori and HbA1c have been limited [19].

In cross-sectional analyses using data from 7417 participants in the National Health and Nutrition Examination Survey (NHANES) III (aged ≥18 years) and 6072 participants in NHANES 1999–2000 (aged ≥3 years), we assessed the association between H. pylori and levels of HbA1c as well as self-reported diabetes status.

METHODS

Study Population

The study population included participants in NHANES III and NHANES 1999–2000 from whom data on H. pylori status were obtained. NHANES is a program of studies designed to assess the health and nutritional status of adults and children in the United States, using a stratified, multistage probability design to select a representative sample of the civilian, noninstitutionalized US population [20]. NHANES III, the seventh health examination survey performed in the United States since 1960 [20], was conducted October 1988–October 1994 in 2 phases, each comprising a national probability sample. In NHANES III, 39 695 persons were studied; of those, 10 120 were adults sampled during the first phase from 18 October 1988 to 24 October 1991. Beginning in 1999, NHANES became a continuous annual survey of 5000 people rather than a periodic survey [21]. NHANES 1999–2000 is the first phase of NHANES IV. The survey protocol was approved by the Institutional Review Board of the Centers for Disease Control and Prevention. All participants gave written informed consent. NHANES III and NHANES 1999–2000 are the only releases of this cross-sectional national survey that include laboratory data on H. pylori status. The present study included 7417 participants in NHANES III and 6072 participants in NHANES 1999–2000 with available data on H. pylori, HbA1c, and sociodemographic and lifestyle variables.

Helicobacter pylori Status

In NHANES III phase 1, examinees aged ≥18 years were tested for H. pylori immunoglobulin G (IgG) antibodies in 1996 using the H. pylori IgG enzyme-linked immunosorbent assay (ELISA) (Wampole Laboratories) and CagA IgG ELISA developed and standardized at Vanderbilt University, as described previously [22]. On the basis of H. pylori and cagA results, patients were classified into 3 groups: H. pylori–positive and cagA-positive; H. pylori–positive and cagA-negative; and H. pylori–negative and cagA-negative, as described previously [23, 24]. The H. pylori–negative cagA-positive group included all persons with a positive CagA assay regardless of the results of the H. pylori assay, based on the utility of the CagA antigen to detect true-positive responses in culture-positive persons in the face of negative or equivocal values in the H. pylori serologic assay [25]. By definition, all persons in the H. pylori–negative group had negative CagA assays.

Among all 8969 participants aged ≥3 years enrolled in NHANES 1999–2000 [21], H. pylori status was determined using the Wampole ELISA. For each specimen, an immune status ratio (ISR) was calculated by dividing the specimen optical density by the mean optical density of the cutoff controls. Specimens were considered negative if the ISR was 0–0.90 and positive if ISR was >0.90, as in prior studies [26, 27].

Diabetes Status and HbA1c Measurement

Diabetes was defined by either self-report of a physician diagnosis or insulin use. HbA1c measurements were performed by the Diabetes Diagnostic Laboratory at the University of Missouri–Columbia using the Diamat Analyzer System (Bio-Rad Laboratories) for NHANES III and CLC330/CLC 385 analyzer (Primus) for NHANES 1999–2000. Both assays were standardized to the reference method that was used for the Diabetes Control and Complications Trial [28].

Statistical Methods

Descriptive analyses were first conducted to compare the distributions of H. pylori status and means of HbA1c by sociodemographic and lifestyle variables. Multiple linear regression models were conducted to evaluate the relationship between H. pylori status and HbA1c levels. We computed adjusted least squares means of HbA1c by H. pylori status in the overall population. We also conducted analyses excluding cases of diabetes and insulin users to evaluate the associations in individuals whose HbA1c levels were not affected by treatments of diabetes, such as insulin use. Potential confounders including age, gender, race/ethnicity, body mass index (BMI), smoking status, and educational attainment were adjusted in the models. Analyses were conducted to evaluate HbA1c levels by H. pylori positive and negative status in both NHANES III and NHANES 1999–2000. Because cagA status was available only in NHANES III, analyses that assessed HbA1c levels by joint status of H. pylori and cagA (H. pylori–positive and cagA-positive; H. pylori–positive and cagA-negative; and H. pylori–negative) were performed only in NHANES III. In addition, we evaluated whether the association between H. pylori and HbA1c differed by BMI by including a cross-product term between H. pylori and BMI expressed as a continuous variable. The P value of the coefficient for the cross-product term was used to consider the significance of the interaction. We also conducted stratified analyses using the standard definition for overweight (BMI ≥25) vs normal (BMI <25).

To evaluate the association between H. pylori status and diabetes, we estimated odds ratios (ORs) for diabetes in relation to H. pylori using unconditional logistic regression, controlling for the same potential variables indicated above. Similar analyses for testing interaction by BMI and stratified BMI level also were conducted. To evaluate the association between H. pylori and diabetes using a more strict definition of diabetes, sensitivity analyses were conducted to evaluate the association between H. pylori status and current use of insulin due to diabetes.

All analyses were conducted using SAS 9.1.4 proc survey procedures (SAS Institute), accounting for the complex sampling design in NHANES. Sampling errors were estimated using the primary sampling units and strata provided in the data set. Sampling weights were used to adjust for nonresponse bias and the oversampling in NHANES.

RESULTS

In NHANES III, men had higher levels of HbA1c compared with women (Table 1). As expected, there was a positive association between age and HbA1c and between BMI and HbA1c in both NHANES study populations. Participants with higher educational attainment or who were past smokers had significantly lower HbA1c levels. There also were associations with race/ethnicity such that non-Hispanic blacks and Mexican Americans had a higher level of HbA1c compared with non-Hispanic whites (Table 1). Older participants, those who had lower educational attainment, non-Hispanic black and Mexican American participants, and those with a higher BMI were more likely to have been colonized by H. pylori compared with their counterparts. In total, these data confirm expected associations of demographic and lifestyle factors with HbA1c and H. pylori status and suggest a relationship between H. pylori and BMI.

Table 1.
Helicobacter pylori Prevalence and Glycated Hemoglobin by Demographic and Lifestyle Factors in the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999–2000

Association Between H. pylori and HbA1c

In NHANES 1999–2000, among the overall population, those who were H. pylori–positive had higher mean HbA1c levels (P = .02) (Table 2), a finding that persisted when subjects who had known diabetes or were insulin users were excluded (P = .02). The positive association was more apparent among those aged ≥18 years (P = .01). In contrast, among those aged ≤ 18 years, there was no association between H. pylori and HbA1c levels. There was a significant interaction between H. pylori and age, such that the increased levels of HbA1c associated with H. pylori positivity was greater in those who were aged >18 years (P for interaction <.01). When the population of adults was stratified on the basis of BMI (<25 and ≥25), there was a positive association between H. pylori positivity and HbA1c levels only among those with higher BMI. There was a significant interaction between H. pylori and BMI, such that the increased levels of HbA1c associated with H. pylori positivity were greater in those with higher BMI (P for interaction <.01)

Table 2.
Association Between Helicobacter pylori and Glycated Hemoglobin

In NHANES III, HbA1c levels were higher in participants who had been colonized with H. pylori only among those who did not have diabetes (P < .01) (Table 2). Consistent with NHANES 1999–2000, H. pylori positivity was significantly associated with higher mean levels of HbA1c among those with no history of diabetes who had a higher BMI (P < .01), but in addition, elevated HbA1c was observed in persons with BMI <25. The interaction between H. pylori and BMI also was significant, suggesting a synergistic effect between H. pylori positivity and higher BMI in relation to HbA1c. The magnitude of the positive associations between H. pylori and HbA1c levels in NHANES III and NHANES 1999–2000 appears to be comparable when cases of diabetes and current insulin use were excluded.

Association Between H. pylori cagA and HbA1c

Because H. pylori cagA status also was ascertained in NHANES III, we could determine whether persons who had cagA-positive or cagA-negative strains had differences in HbA1c (Table 3). These data showed a progressive increase in HbA1c comparing H. pylori–negative, H. pylori–positive/cagA-negative, and H. pylori–positive/cagA-positive subjects in the overall study population (P = .02), especially after those with diabetes or who were insulin users were excluded (P < .01) (Table 3). In stratified analyses by BMI, H. pylori cagA positivity was positively related to HbA1c levels in both participants with a lower BMI and participants with a higher BMI after excluding those with history of diabetes. The joint status of higher BMI and H. pylori cagA positivity (but not cagA negativity) was associated with increased HbA1c levels in relation to the sum of their individual effects (P for interaction < .01).

Table 3.
Association of Helicobacter pylori With Glycated Hemoglobin, in the National Health and Nutrition Examination Survey III

Association Between H. pylori and Diabetes

We also estimated ORs for diabetes in relation to H. pylori status in both NHANES III and NHANES 1999–2000 (Table 4). In NHANES 1999–2000, there was an overall positive association between H. pylori and prevalence of diabetes (OR, 1.30; 95% confidence interval [CI], .94–1.80), and the association was significant among participants with BMI >25 (OR, 1.43; 95% CI, 1.00–2.03). The data did not indicate that the association between H. pylori and diabetes differs by levels of BMI (P for interaction = .21).

Table 4.
Association of Helicobacter pylori With Self-reported Diabetes

In NHANES III, there was no association between H. pylori and diabetes overall nor was there an association in participants stratified by BMI (Table 4). We also further assessed whether there was an association between cagA positivity and diabetes. The data also indicate that there was no association between cagA positivity and diabetes overall and in stratified analyses by BMI.

In sensitivity analyses, we evaluated the association between H. pylori and current use of insulin due to diabetes. There was no significant association between H. pylori or H. pylori cagA positivity in the overall populations or within BMI strata, although the sample size was limited for this analysis (data not shown).

DISCUSSION

In this large, cross-sectional study, we found a positive association between H. pylori status and HbA1c levels among adult participants free of diabetes. The increased levels of HbA1c associated with H. pylori were greater among those with higher BMI. These associations were consistent in the independent populations from the 2 NHANES, completed about 10 years apart. In addition, H. pylori cagA positivity was related to high levels of HbA1c, and there was an interaction between H. pylori cagA positivity and higher levels of BMI in HbA1c. However, the data did not indicate that there was an association between H. pylori and self-report of diabetes.

Previous studies on the association between H. pylori and diabetes have had mixed results [914], likely due to inconsistencies in the methods used to define H. pylori positivity and diabetes status, the limited sample sizes, and adjustments for potential confounders [9]. In particular, the accuracy of self-reported data on medical history depends on the subjects’ knowledge and understanding of the relevant information, their ability to recall, and their willingness to report it [29], which also may change over time. In prior studies, the sensitivity of self-reported diabetes has ranged from 66.7% to 85.2% [2932], which may lead to nondifferential misclassification and a bias toward the null. In addition, the prevalence of H. pylori decreased substantially from NHANES III to NHANES 1999–2000, probably due to a cohort effect [27]. These issues may explain our inconsistent findings on the association between H. pylori and diabetes in the 2 NHANES populations. Alternatively, secular aspects of the distributional change of risk factors for diabetes that may interact with H. pylori may render the population more or less susceptible to H. pylori effects at different points in time. It has been estimated that the prevalence of obesity increased substantially from NHANES III to NHANES 1999–2000 [33, 34]. Future studies with accurate information on diagnosis of diabetes are needed to evaluate the association between H. pylori and diabetes.

We found a positive association between H. pylori status and HbA1c levels, a valid and reliable biomarker for long-term blood glucose level [1618]. The results from the 2 NHANES populations were consistent, suggesting validity of the findings. Although the present study is a cross-sectional study, reverse causation is not likely. Helicobacter pylori is acquired almost exclusively in childhood [8], and there is no clear mechanism for how glucose intolerance present only after the age of 18 would increase risk of H. pylori colonization. It also is unlikely that H. pylori positivity and high levels of HbA1c levels share a mutual antecedent cause because there is no diathesis to both acquire H. pylori and to cause glucose intolerance. The most plausible hypothesis is that H. pylori directly or indirectly increases levels of HbA1c in adulthood, particularly in obese individuals. We now know that H. pylori plays a role in the regulation of leptin and ghrelin [6, 3538], which are central to energy homeostasis and metabolism [4, 5]. Accumulating evidence also indicates that the metabolic syndrome is an inflammatory disorder. Helicobacter pylori induces gastric inflammation; the H. pylori–positive stomach and the H. pylori–negative stomach are markedly different in terms of T-cell and B-cell populations and proinflammatory cytokines [3941]—these have a local effect, but there is increasing evidence for global effects [42].

Helicobacter pylori strains possessing the cag genomic island express a type 4 secretion system that injects the CagA protein into human epithelial cells [43]. Antibody responses to the CagA protein permit detection of such cag-positive strains [22], which are more interactive with host cells than cag-negative strains [43, 44] and are associated with higher risk for gastric cancer and peptic ulcer disease and lower risk of esophageal reflux and sequelae and asthma [24, 27, 4549]. Our findings based on the NHANES III study population show a gradient in A1c levels from H. pylorinegative, to H. pylori–positive and cagA-negative to H. pylori–positive and cagA-positive. This consistency, predicted by the biological differences between the 3 states of gastric microecology [43, 44], provides evidence that the relationship is not due to artifacts.

Although the literature indicates that there is no clear relationship between H. pylori and obesity [23], our study provides further evidence that H. pylori affects host metabolic status. The increasing trend in diabetes and obesity can not be explained by the decreasing prevalence of H. pylori because diabetes and obesity are multifactorial disorders that involve environmental, lifestyle, genetic, and social factors. Given that the prevalence of H. pylori is decreasing, the proportion of diabetes that could be attributable to H. pylori is likely to also decrease. However, among older individuals and especially those with a higher BMI, glucose intolerance associated with H. pylori could remain significant. The findings add to the evidence of a model for age-related pleiotrophy of H. pylori or a life-course perspective in H. pylori [44]. The potential benefits of H. pylori occur predominantly earlier in life, including a reduced risk of asthma [24, 27], tuberculosis reactivation [50], childhood diarrhea [51], and gastroesophageal reflux disease [4549]. Among older individuals, the adverse health effects include peptic ulcer disease, gastric cancer, and perhaps increased glucose intolerance. The data from this study are consistent with findings that H. pylori eradication in older individuals may be beneficial.

Notes

Financial support.

This work was supported by grants from the National Institutes of Health (grants ES000260, CA016087, RO1GM63270, and R01DK090989) and the Diane Belfer Program in Human Microbial Ecology.

Potential conflicts of interest.

All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

1. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001;286:1195–200. [PubMed]
2. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest. 1996;98:1101–6. [PMC free article] [PubMed]
3. Shintani M, Ogawa Y, Ebihara K, et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes. 2001;50:227–32. [PubMed]
4. Sun Y, Asnicar M, Saha PK, Chan L, Smith RG. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 2006;3:379–86. [PubMed]
5. Williams J, Mobarhan S. A critical interaction: leptin and ghrelin. Nutr Rev. 2003;61:391–3. [PubMed]
6. Francois F, Roper J, Joseph N, et al. The effect of H. pylori eradication on meal-associated changes in plasma ghrelin and leptin. BMC Gastroenterol. 2011;11:37. [PMC free article] [PubMed]
7. Banatvala N, Mayo K, Megraud F, Jennings R, Deeks JJ, Feldman RA. The cohort effect and Helicobacter pylori. J Infect Dis. 1993;168:219–21. [PubMed]
8. Perez-Perez GI, Salomaa A, Kosunen TU, et al. Evidence that cagA(+) Helicobacter pylori strains are disappearing more rapidly than cagA(-) strains. Gut. 2002;50:295–8. [PMC free article] [PubMed]
9. Xia HH, Talley NJ, Kam EP, Young LJ, Hammer J, Horowitz M. Helicobacter pylori infection is not associated with diabetes mellitus, nor with upper gastrointestinal symptoms in diabetes mellitus. Am J Gastroenterol. 2001;96:1039–46. [PubMed]
10. Gasbarrini A, Ojetti V, Pitocco D, et al. Helicobacter pylori infection in patients affected by insulin-dependent diabetes mellitus. Eur J Gastroenterol Hepatol. 1998;10:469–72. [PubMed]
11. Gentile S, Turco S, Oliviero B, Torella R. The role of autonomic neuropathy as a risk factor of Helicobacter pylori infection in dyspeptic patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 1998;42:41–8. [PubMed]
12. Guvener N, Akcan Y, Paksoy I, et al. Helicobacter pylori associated gastric pathology in patients with type II diabetes mellitus and its relationship with gastric emptying: the Ankara study. Exp Clin Endocrinol Diabetes. 1999;107:172–6. [PubMed]
13. Oldenburg B, Diepersloot RJ, Hoekstra JB. High seroprevalence of Helicobacter pylori in diabetes mellitus patients. Dig Dis Sci. 1996;41:458–61. [PubMed]
14. Simon L, Tornoczky J, Toth M, Jambor M, Sudar Z. The significance of Campylobacter pylori infection in gastroenterologic and diabetic practice. Orv Hetil. 1989;130:1325–9. [PubMed]
15. Lutsey PL, Pankow JS, Bertoni AG, Szklo M, Folsom AR. Serological evidence of infections and type 2 diabetes: the MultiEthnic Study of Atherosclerosis. Diabet Med. 2009;26:149–52. [PMC free article] [PubMed]
16. Buell C, Kermah D, Davidson MB. Utility of A1C for diabetes screening in the 1999–2004 NHANES population. Diabetes Care. 2007;30:2233–5. [PubMed]
17. Herman WH, Engelgau MM, Zhang Y, Brown MB. Use of GHb (HbA(1c)) to screen for undiagnosed diabetes in the US population. Diabetes Care. 2000;23:1207–8. [PubMed]
18. Rohlfing CL, Little RR, Wiedmeyer HM, et al. Use of GHb (HbA1c) in screening for undiagnosed diabetes in the US population. Diabetes Care. 2000;23:187–91. [PubMed]
19. Eshraghian A. The continuous story of Helicobacter pylori infection and insulin resistance: this time in Japan. Helicobacter. 2010;15:160. author reply 161. [PubMed]
20. National Center for Health Statistics. Plan and operation of the Third National Health and Nutrition Examination Survey, 1988–94. Vital and health statistics, series 1, no. 32. Hyattsville, MD: National Center for Health Statistics; 2006.
21. National Center for Health Statistics. NHANES 1999–2000 data files—data, docs, codebooks, SAS code. Hyattsville, MD: National Center for Health Statistics; 2005.
22. Blaser MJ, Perez-Perez GI, Kleanthous H, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res. 1995;55:2111–5. [PubMed]
23. Cho I, Blaser MJ, Francois F, et al. Helicobacter pylori and overweight status in the United States: data from the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2005;162:579–84. [PubMed]
24. Chen Y, Blaser MJ. Inverse associations of Helicobacter pylori with asthma and allergy. Arch Intern Med. 2007;167:821–7. [PubMed]
25. Romero-Gallo J, Perez-Perez GI, Novick RP, Kamath P, Norbu T, Blaser MJ. Responses of endoscopy patients in Ladakh, India, to Helicobacter pylori whole-cell and Cag A antigens. Clin Diagn Lab Immunol. 2002;9:1313–7. [PMC free article] [PubMed]
26. Cardenas VM, Mulla ZD, Ortiz M, Graham DY. Iron deficiency and Helicobacter pylori infection in the United States. Am J Epidemiol. 2006;163:127–34. [PubMed]
27. Chen Y, Blaser MJ. Helicobacter pylori colonization is inversely associated with childhood asthma. J Infect Dis. 2008;198:553–60. [PMC free article] [PubMed]
28. Little RR, Wiedmeyer HM, England JD, et al. Interlaboratory standardization of measurements of glycohemoglobins. Clin Chem. 1992;38:2472–8. [PubMed]
29. Bowlin SJ, Morrill BD, Nafziger AN, Lewis C, Pearson TA. Reliability and changes in validity of self-reported cardiovascular disease risk factors using dual response: the behavioral risk factor survey. J Clin Epidemiol. 1996;49:511–7. [PubMed]
30. The Italian Longitudinal Study on Aging Working Group (CNR-Targeted Project on Aging, Florence, Italy). Prevalence of chronic diseases in older Italians: comparing self-reported and clinical diagnoses. Int J Epidemiol. 1997;26:995–1002. [PubMed]
31. Goldman N, Lin IF, Weinstein M, Lin YH. Evaluating the quality of self-reports of hypertension and diabetes. J Clin Epidemiol. 2003;56:148–54. [PubMed]
32. Molenaar EA, Van Ameijden EJ, Grobbee DE, Numans ME. Comparison of routine care self-reported and biometrical data on hypertension and diabetes: results of the Utrecht Health Project. Eur J Public Health. 2007;17:199–205. [PubMed]
33. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999–2008. JAMA. 2010;303:235–41. [PubMed]
34. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA. 1994;272:205–11. [PubMed]
35. Gunji T, Matsuhashi N, Sato H, et al. Helicobacter pylori infection is significantly associated with metabolic syndrome in the Japanese population. Am J Gastroenterol. 2008;103:3005–10. [PubMed]
36. Isomoto H, Ueno H, Nishi Y, Wen CY, Nakazato M, Kohno S. Impact of Helicobacter pylori infection on ghrelin and various neuroendocrine hormones in plasma. World J Gastroenterol. 2005;11:1644–8. [PMC free article] [PubMed]
37. Nwokolo CU, Freshwater DA, O'Hare P, Randeva HS. Plasma ghrelin following cure of Helicobacter pylori. Gut. 2003;52:637–40. [PMC free article] [PubMed]
38. Roper J, Francois F, Shue PL, et al. Leptin and ghrelin in relation to Helicobacter pylori status in adult males. J Clin Endocrinol Metab. 2008;93:2350–7. [PubMed]
39. Peek RM, Jr, Miller GG, Tham KT, et al. Heightened inflammatory response and cytokine expression in vivo to cagA+ Helicobacter pylori strains. Lab Invest. 1995;73:760–70. [PubMed]
40. Robinson K, Kenefeck R, Pidgeon EL, et al. Helicobacter pylori–induced peptic ulcer disease is associated with inadequate regulatory T cell responses. Gut. 2008;57:1375–85. [PubMed]
41. Harris PR, Wright SW, Serrano C, et al. Helicobacter pylori gastritis in children is associated with a regulatory T-cell response. Gastroenterology. 2008;134:491–9. [PubMed]
42. Arnold IC, Dehzad N, Reuter S, et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J Clin Invest. 2011;121:3088–93. [PMC free article] [PubMed]
43. Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori cagA protein. Nat Rev Cancer. 2004;4:688–94. [PubMed]
44. Atherton JC, Blaser MJ. Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J Clin Invest. 2009;119:2475–87. [PMC free article] [PubMed]
45. de Martel C, Llosa AE, Farr SM, et al. Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma. J Infect Dis. 2005;191:761–7. [PubMed]
46. Chow WH, Blaser MJ, Blot WJ, et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res. 1998;58:588–90. [PubMed]
47. Vaezi MF, Falk GW, Peek RM, et al. CagA-positive strains of Helicobacter pylori may protect against Barrett’s esophagus. Am J Gastroenterol. 2000;95:2206–11. [PubMed]
48. Vicari JJ, Peek RM, Falk GW, et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology. 1998;115:50–7. [PubMed]
49. Ye W, Held M, Lagergren J, et al. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst. 2004;96:388–96. [PubMed]
50. Perry S, de Jong BC, Solnick JV, et al. Infection with Helicobacter pylori is associated with protection against tuberculosis. PLoS One. 2010;5:e8804. [PMC free article] [PubMed]
51. Rothenbacher D, Blaser MJ, Bode G, Brenner H. Inverse relationship between gastric colonization of Helicobacter pylori and diarrheal illnesses in children: results of a population-based cross-sectional study. J Infect Dis. 2000;182:1446–9. [PubMed]

Articles from The Journal of Infectious Diseases are provided here courtesy of Oxford University Press