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.
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ABSTRACT |
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body mass index; body weight; cagA protein, Helicobacter pylori; Helicobacter pylori; obesity
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INTRODUCTION |
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Leptin is a protein secreted by fat cells that plays a role in the regulation of body weight through effects on food intake (5). Serum leptin levels show a positive linear relation with body mass index (6
). Leptin is also produced by chief cells in the human stomach, and levels are affected by Helicobacter pylori-associated gastritis (7
, 8
). H. pylori are gram-negative bacteria that colonize the human stomach and increase the risk of peptic ulcer disease and gastric cancer (9
, 10
). Gastric inflammation is highest with cytotoxin-associated gene A (cagA) strains of H. pylori (11
, 12
). Much evidence indicates that H. pylori is an ancient colonizer of humans (13
, 14
) that is highly prevalent in developing countries but is disappearing in developed countries, including the United States (15
). 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 (16
). 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.
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MATERIALS AND METHODS |
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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 (4). 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 00.90, equivocal if the immune status ratio was 0.911.09, 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 (17
). Serologic testing for cagA was done using a noncommercial assay developed and standardized at Vanderbilt University, as previously described (12
).
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) (18). 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 (18
).
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 (19). 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, 1.313.49, 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 (20) 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.
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RESULTS |
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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.
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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, 0.5145.0)) and the 501 H. pylori+cagA participants (8.1 µg/liter (range, 0.894.6)) than in the 1,178 H. pylori participants (7.3 µg/liter (range, 0.767.9)). 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).
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DISCUSSION |
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Serum leptin, which is primarily synthesized by adipose tissue, regulates food intake and body weight homeostasis (21). Leptin is now known to be synthesized in the stomach as well (22
), and this source may also be involved in the regulation of food intake and satiety (23
). Gastric inflammation, such as that induced by H. pylori (10
), 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. (8
) 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. (24
) 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 (8
, 25
). In addition, our findings agree with those of several smaller studies that have found no association between H. pylori colonization and risk of obesity (26
, 27
).
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 (28). 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 (29
). 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.
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ACKNOWLEDGMENTS |
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References |
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