Helicobacter pylori and Overweight Status in the United States: Data from the Third National Health and Nutrition Examination Survey

Ilseung Cho1, Martin J. Blaser1,2, Fritz François1,2, Jomol P. Mathew3, Xiang Y. Ye3, Judith D. Goldberg3 and Edmund J. Bini1,2

1 Department of Medicine, New York University School of Medicine, New York, NY
2 VA New York Harbor Healthcare System, New York, NY
3 Division of Biostatistics, Department of Environmental Medicine, New York University School of Medicine, New York, NY

Correspondence to Dr. Edmund J. Bini, Division of Gastroenterology, VA New York Harbor Healthcare System, 423 East 23rd Street, New York, NY 10010 (e-mail: Edmund.Bini{at}med.va.gov).

Received for publication October 18, 2004. Accepted for publication April 19, 2005.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Obesity is an important public health problem in the United States. Because of its potential effects on gastric leptin homeostasis, Helicobacter pylori may play a role in regulating body weight. The authors' aim in this study was to examine the association between H. pylori colonization and overweight status. Nonpregnant participants in the Third National Health and Nutrition Examination Survey (1988–1994) aged ≥20 years who had had H. pylori testing performed and body mass index (weight (kg)/height (m)2) measured were studied. Overweight was defined as a body mass index greater than or equal to 25. On the basis of serologic results, the participants were categorized into three H. pylori status groups: H. pylori-positive and cytotoxin-associated gene A (cagA)-positive (H. pylori+cagA+), H. pylori-positive and cagA-negative (H. pylori+cagA), and H. pylori-negative (H. pylori). Of the 7,003 subjects with complete body mass index and H. pylori data, 2,634 (weighted percentage, 22.9%) were H. pylori+cagA+, 1,385 (15.1%) were H. pylori+cagA, and 2,984 (62.0%) were H. pylori. The adjusted odds of being overweight were 1.17 (95% confidence interval: 0.98, 1.39; p = 0.075) for the H. pylori+cagA+ group and 0.99 (95% confidence interval: 0.80, 1.22; p = 0.92) for the H. pylori+cagA group in comparison with H. pylori subjects. Serum leptin levels did not differ significantly between the three H. pylori groups. In this US population-based study, there was no significant association between H. pylori colonization, cagA+ strains of H. pylori, and being overweight.

body mass index; body weight; cagA protein, Helicobacter pylori; Helicobacter pylori; obesity


Abbreviations: cagA, cytotoxin-associated gene A; NHANES III, Third National Health and Nutrition Examination Survey


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Obesity is a significant and growing public health problem in the United States (1Go). More than 60 percent of the US adult population is considered either overweight or obese (2Go), and nearly 300,000 deaths annually are attributable to obesity (3Go), making it the second leading cause of preventable death in the United States (4Go).

Leptin is a protein secreted by fat cells that plays a role in the regulation of body weight through effects on food intake (5Go). Serum leptin levels show a positive linear relation with body mass index (6Go). Leptin is also produced by chief cells in the human stomach, and levels are affected by Helicobacter pylori-associated gastritis (7Go, 8Go). H. pylori are gram-negative bacteria that colonize the human stomach and increase the risk of peptic ulcer disease and gastric cancer (9Go, 10Go). Gastric inflammation is highest with cytotoxin-associated gene A (cagA) strains of H. pylori (11Go, 12Go). Much evidence indicates that H. pylori is an ancient colonizer of humans (13Go, 14Go) that is highly prevalent in developing countries but is disappearing in developed countries, including the United States (15Go). This change in the microecology of human populations may have metabolic consequences and, in particular, could affect risk of obesity by influencing gastric leptin production (16Go). We hypothesized that colonization with H. pylori, particularly cagA strains, is associated with a decreased body mass index. Our aim in this study was to evaluate the association between H. pylori and body mass index using data from the Third National Health and Nutrition Examination Survey (NHANES III), in which information on H. pylori status, body mass index, and other relevant variables was ascertained in a population-based study of more than 7,000 persons.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Study population
NHANES III was conducted by the National Center for Health Statistics in two phases (phase 1: 1988–1991; phase 2: 1991–1994) (17Go). This cross-sectional study used a complex, highly stratified, multistage probability sample of the civilian, noninstitutionalized US population. The weighted distribution of participants was similar to that of the US population as a whole. The survey protocol was reviewed and approved by an institutional review board at the Centers for Disease Control and Prevention, and all participants provided written informed consent.

H. pylori status was ascertained only in phase 1 of NHANES III. There were 8,442 participants in this phase of the study who were aged ≥20 years and were interviewed and examined. Pregnant women (n = 138), persons belonging to the race/ethnicity category "other" (n = 261), and persons with equivocal H. pylori serologic results and negative cagA assays (n = 78) were excluded. Of the remaining 7,965 participants, 7,003 had data on both body mass index measurements and H. pylori testing.

Study design
The NHANES III staff conducted surveys in households, administered questionnaires, and conducted standardized medical examinations at mobile examination centers at a single visit. Criteria for overweight status were established according to published National Heart, Lung, and Blood Institute guidelines (4Go). Body mass index was calculated as weight (kg) divided by height squared (m2). H. pylori testing was performed using a commercial immunoglobulin G enzyme-linked immunosorbent assay (Wampole Laboratories, Cranbury, New Jersey). Each 96-well plate contained the manufacturer's three cutoff controls (negative, high positive, and low positive) and three positive and two negative controls provided by the testing laboratory. For each specimen, an immune status ratio was calculated by dividing the specimen absorbance by the mean absorbance of the three cutoff controls. Specimens were considered negative if the immune status ratio was 0–0.90, equivocal if the immune status ratio was 0.91–1.09, and positive if the immune status ratio was greater than or equal to 1.10. Results were validated using coded replicate samples with the laboratory workers blinded as to status (17Go). Serologic testing for cagA was done using a noncommercial assay developed and standardized at Vanderbilt University, as previously described (12Go).

Fasting serum leptin levels were examined using a radioimmunoassay with a polyclonal antibody raised in rabbits against highly purified recombinant human leptin (Linco Research, Inc., St. Louis, Missouri) (18Go). The minimum detectable leptin concentration of the assay was 0.5 µg/liter, and intra- and interassay coefficients of variation were less than 5 percent (18Go).

Variable definitions
The primary outcome variable, overweight, was defined as a body mass index greater than or equal to 25, and normal weight was defined as a body mass index less than 25. H. pylori serologic test results were categorized as positive, negative, or equivocal, and cagA serologic results were categorized as positive or negative. On the basis of H. pylori and cagA results, patients were classified into three groups: H. pylori-positive and cagA-positive (H. pylori+cagA+), H. pylori-positive and cagA-negative (H. pylori+cagA), and H. pylori-negative (H. pylori). The H. pylori+cagA+ 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 in detecting true-positive responses in culture-positive persons in the face of negative or equivocal values in the H. pylori serologic assay (19Go). All persons in the H. pylori group had negative cagA assays. Demographic variables (age, sex, race/ethnicity, country of birth, geographic location) and lifestyle variables (years of education, economic status (poverty:income ratio ≤1.30, 1.31–3.49, or ≥3.50), cigarette smoking history, alcohol drinking history, and activity level) were considered in these analyses.

Statistical methods
Characteristics of overweight and normal-weight participants were compared using the F test (20Go) for categorical variables and the two-sample t test for continuous variables, with adjustments for the stratified sampling design of NHANES III. Odds ratios and 95 percent confidence intervals for the association between H. pylori and being overweight were estimated using multivariable logistic regression models with and without adjustment for other covariates. The covariates included in the models were those significantly associated with overweight in the univariate analyses (p ≤ 0.05). The final model was developed using a stepwise procedure with forward selection and backward elimination, with both inclusion and exclusion criteria set at the significance level of p ≤ 0.05.

In an additional exploratory analysis, we evaluated the association between H. pylori and leptin levels in 2,648 participants in whom serum leptin levels had been measured. Median leptin levels were compared between the three H. pylori groups. In addition, Spearman correlation coefficients for correlations between body mass index and leptin levels were calculated within each of the three H. pylori groups.

All analyses incorporated sampling weights that adjusted for the complex survey design of NHANES III. A two-sided p value less than or equal to 0.05 was considered statistically significant. The software packages Stata SE 8.2 (Stata Corporation, College Station, Texas), and SAS 9.0 (SAS Institute, Inc., Cary, North Carolina) were used for data analysis.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Baseline characteristics
Of the 7,003 participants (mean age = 45.2 years; standard deviation, 0.45) with data on both body mass index and H. pylori status, 3,576 were male and 3,427 were female. Non-Hispanic Whites accounted for 3,285 members of the total study group; 1,785 were non-Hispanic Blacks, and 1,933 were Mexican Americans. Of the 7,003 subjects with H. pylori data, 2,634 (weighted percentage, 22.9 percent) were classified as H. pylori+cagA+, 1,385 (15.1 percent) as H. pylori+cagA, and 2,984 (62.0 percent) as H. pylori.

Overweight and normal-weight participants differed according to all characteristics but geographic region, economic status, and country of birth (table 1). This suggests that many of these characteristics might have confounded any apparent association between H. pylori status and body mass index.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Characteristics of 7,003 subjects by overweight* status, Third National Health and Nutrition Examination Survey, 1988–1994

 
Odds ratios for the association between H. pylori and being overweight
To evaluate the association between H. pylori and being overweight, we estimated odds ratios for overweight status according to H. pylori status using logistic regression models with and without adjustment for participant characteristics that were significantly associated with being overweight (table 2). Although the unadjusted odds of being overweight were significantly higher in the H. pylori+cagA+ and H. pylori+cagA groups than in the H. pylori group, the association was not statistically significant after adjustment for potentially confounding variables. In addition, we analyzed the association between H. pylori status and body mass index using body mass index as a continuous variable; this did not change the main findings (data not shown).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Odds ratios for the association of overweight* with Helicobacter pylori and cytotoxin-associated gene A status, Third National Health and Nutrition Examination Survey, 1988–1994{dagger}

 
We examined pairwise correlation coefficients among all of the covariates. While many covariates were significantly correlated because of the large sample size, the magnitudes of the correlation coefficients in the final model were between –0.30 and 0.30.

Serum leptin analyses
Data on fasting serum leptin level were available for 2,648 of the 7,003 participants with complete body mass index and H. pylori data. In unadjusted analysis, median serum leptin levels were slightly higher in the 969 H. pylori+cagA+ participants (8.1 µg/liter (range, 0.5–145.0)) and the 501 H. pylori+cagA participants (8.1 µg/liter (range, 0.8–94.6)) than in the 1,178 H. pylori participants (7.3 µg/liter (range, 0.7–67.9)). However, the coefficients for correlations between body mass index and serum leptin level were similar in all three H. pylori groups (r = 0.595, r = 0.539, and r = 0.511, respectively).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The purpose of this cross-sectional study was to examine the association between H. pylori colonization and overweight status, as demonstrated by increased body mass index. While unadjusted and adjusted odds ratios for overweight status in the H. pylori+cagA+ group compared with the H. pylori group were greater than 1.0, this association was not statistically significant after adjustment for potentially confounding variables. A similar relation was found for the H. pylori+cagA group. To examine the possible effects of H. pylori on serum leptin levels, we compared serum leptin levels among the groups that differed with regard to H. pylori status. In the unadjusted analysis, serum leptin levels were slightly higher in the H. pylori+cagA+ and H. pylori+cagA groups than in the H. pylori group, but these differences were not clinically meaningful.

Serum leptin, which is primarily synthesized by adipose tissue, regulates food intake and body weight homeostasis (21Go). Leptin is now known to be synthesized in the stomach as well (22Go), and this source may also be involved in the regulation of food intake and satiety (23Go). Gastric inflammation, such as that induced by H. pylori (10Go), alters leptin secretion in the stomach. The change in gastric leptin level resulting from H. pylori-induced inflammation may influence food intake and body mass index. Azuma et al. (8Go) reported that eradication of H. pylori is associated with decreased gastric leptin levels and subsequent weight gain, although serum leptin levels did not change. Furuta et al. (24Go) found that H. pylori eradication was associated with increases in body mass index and cholesterol and triglyceride levels. Our results are consistent with those of prior studies showing that H. pylori colonization does not alter serum leptin levels (8Go, 25Go). In addition, our findings agree with those of several smaller studies that have found no association between H. pylori colonization and risk of obesity (26Go, 27Go).

One of the strengths of this study was our use of the database from NHANES III, a large, national, cross-sectional survey specifically developed to accurately represent the adult population in the United States. In addition, we controlled for multiple covariates that could have confounded interpretation of the results. However, there were several limitations of our study. Since the study was cross-sectional and both H. pylori colonization and overweight are chronic conditions, a specific causative relation between the two may not necessarily be inferred. In addition, the serum samples that were tested for the leptin assays were excess samples that remained after the required laboratory tests for NHANES III had been completed; thus, selection of the samples did not follow any statistical sampling strategy. However, statistical analyses directed towards the assessment of biases that might have been introduced into the subset of participants with leptin measurements were negative. Although serum leptin level does not appear to be affected by H. pylori colonization, other gut peptide hormones that affect metabolism may play a role in the regulation of body weight. Ghrelin has also been implicated in the control of food intake and energy homeostasis, with effects opposite those of leptin (28Go). After H. pylori eradication, plasma ghrelin levels have been observed to increase by 75 percent over pretreatment levels, suggesting that eradication may contribute to increased appetite and weight gain (29Go). Because ghrelin levels were not measured in NHANES III, they could not be investigated in this study.

In summary, in this large, US population-based study, we found that there was no significant relation between H. pylori status, cagA status, and being overweight, after adjusting for confounding covariates. Our findings suggest that future studies of relations involving H. pylori and alterations of metabolism homeostasis might focus on interactions with other gut peptide hormones in colonized persons.


    ACKNOWLEDGMENTS
 
Dr. Martin J. Blaser is a codiscoverer of cytotoxin-associated gene A and could potentially receive royalties from licensed tests, though none exist at present.


    References
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Stein CJ, Colditz GA. The epidemic of obesity. J Clin Endocrinol Metab 2004;89:2522–5.[Abstract/Free Full Text]
  2. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002;288:1723–7.[Abstract/Free Full Text]
  3. Allison DB, Fontaine KR, Manson JE, et al. Annual deaths attributable to obesity in the United States. JAMA 1999;282:1530–8.[Abstract/Free Full Text]
  4. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—the evidence report. National Institutes of Health. Obes Res 1998;6(suppl 2):51S–209S.[ISI][Medline]
  5. Schwartz MW, Erickson JC, Baskin DG, et al. Effect of fasting and leptin deficiency on hypothalamic neuropeptide Y gene transcription in vivo revealed by expression of a lacZ reporter gene. Endocrinology 1998;139:2629–35.[Abstract/Free Full Text]
  6. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292–5.[Abstract/Free Full Text]
  7. Sobhani I, Bado A, Vissuzaine C, et al. Leptin secretion and leptin receptor in the human stomach. Gut 2000;47:178–83.[Abstract/Free Full Text]
  8. Azuma T, Suto H, Ito Y, et al. Gastric leptin and Helicobacter pylori infection. Gut 2001;49:324–9.[Abstract/Free Full Text]
  9. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med 2002;347:1175–86.[Free Full Text]
  10. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:1311–15.[CrossRef][ISI][Medline]
  11. Censini S, Lange C, Xiang Z, et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci U S A 1996;93:14648–53.[Abstract/Free Full Text]
  12. 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;55:2111–15.[Abstract]
  13. Ghose C, Perez-Perez GI, Dominguez-Bello MG, et al. East Asian genotypes of Helicobacter pylori strains in Amerindians provide evidence for its ancient human carriage. Proc Natl Acad Sci U S A 2002;99:15107–11.[Abstract/Free Full Text]
  14. Falush D, Wirth T, Linz B, et al. Traces of human migrations in Helicobacter pylori populations. Science 2003;299:1582–5.[Abstract/Free Full Text]
  15. Brown LM. Helicobacter pylori: epidemiology and routes of transmission. Epidemiol Rev 2000;22:283–97.[ISI][Medline]
  16. Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and disease. J Clin Invest 2004;113:321–33.[Abstract/Free Full Text]
  17. 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, 1994. (DHHS publication no. (PHS) 94-1308).
  18. Ma Z, Gingerich RL, Santiago JV, et al. Radioimmunoassay of leptin in human plasma. Clin Chem 1996;42:942–6.[Abstract/Free Full Text]
  19. Romero-Gallo J, Perez-Perez GI, Novick RP, et al. Responses of endoscopy patients in Ladakh, India, to Helicobacter pylori whole-cell and CagA antigens. Clin Diagn Lab Immunol 2002;9:1313–17.[Abstract/Free Full Text]
  20. Rao JN, Scott AJ. On chi-squared tests for multiway contingency tables with cell proportions estimated from survey data. Ann Stat 1984;12:46–60.[ISI]
  21. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543–6.[ISI][Medline]
  22. Dockray GJ. Luminal sensing in the gut: an overview. J Physiol Pharmacol 2003;54(suppl 4):9–17.
  23. Bado A, Levasseur S, Attoub S, et al. The stomach is a source of leptin. Nature 1998;394:790–3.[CrossRef][ISI][Medline]
  24. Furuta T, Shirai N, Xiao F, et al. Effect of Helicobacter pylori infection and its eradication on nutrition. Aliment Pharmacol Ther 2002;16:799–806.[CrossRef][ISI][Medline]
  25. Kawano S, Kawahara A, Nakai R, et al. Helicobacter pylori infection does not affect serum leptin concentration and body mass index (BMI) in asymptomatic subjects. J Gastroenterol 2001;36:579–80.[CrossRef][ISI][Medline]
  26. Kyriazanos ID, Sfiniadakis I, Gizaris V, et al. The incidence of Helicobacter pylori infection is not increased among obese young individuals in Greece. J Clin Gastroenterol 2002;34:541–6.[CrossRef][ISI][Medline]
  27. Archimandritis AJ, Chronaki M, Kalogeras D, et al. The incidence of Helicobacter pylori is not increased in obese people, but the risk of duodenal ulcer is higher in H. pylori-positive people of high obesity. J Clin Gastroenterol 2003;36:184–5.[CrossRef][ISI][Medline]
  28. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001;86:5992.[Abstract/Free Full Text]
  29. Nwokolo CU, Freshwater DA, O'Hare P, et al. Plasma ghrelin following cure of Helicobacter pylori. Gut 2003;52:637–40.[Abstract/Free Full Text]




This Article
Abstract
Full Text (PDF)
All Versions of this Article:
162/6/579    most recent
kwi237v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Cho, I.
Articles by Bini, E. J.
PubMed
PubMed Citation
Articles by Cho, I.
Articles by Bini, E. J.