Background
The healthful regulation of energy homeostasis in humans, depends on centrally-acting hormones such as ghrelin and leptin [
1,
2]. Serum ghrelin concentrations increase during fasting, and decrease after eating [
3]; ghrelin decreases energy expenditure and promotes weight gain [
4]. In contrast, leptin produced primarily by adipocytes, reduces appetite and increases energy utilization [
5]. The gastric epithelium expresses both ghrelin and leptin (and their receptors) [
6,
7]; inflammation can modify their production [
8,
9].
Helicobacter pylori, which colonizes the human stomach and interacts with host tissues [
10] may affect the regulation of ghrelin and leptin [
9]. However, ghrelin and leptin expression in
H. pylori-colonized hosts has been reported as reduced [
11], or increased. Similarly, body mass index (BMI) has been reported to be increased [
12] or reduced [
13] following
H. pylori eradication.
We hypothesized that gastric H. pylori colonization affects the physiologic regulation of gut hormones involved in food intake, energy expenditure, and body weight maintenance. The hormones that affect overall metabolic function include ghrelin, leptin, amylin, insulin, active glucagon-like peptide-1, gastric inhibitory polypeptide, peptide YY, and pancreatic polypeptide. We used clinically indicated H. pylori eradication to evaluate the effect of H. pylori on meal-associated changes in ghrelin, leptin, and the other specified insulinotropic and digestive hormones, and to assess post-eradication changes in body mass index.
Discussion
Appetite-reducing hormones, such as amylin, insulin, GIP, GLP-1, PP, and PYY, produced in the small intestine and pancreas are important in mammalian energy homeostasis, [
32‐
35], as is leptin which is produced mostly by adipocytes, but also by gastric chief cells [
6]. Importantly, gastric oxyntic endocrine cells [
36] account for 65-80% of the body's total ghrelin production.
H. pylori colonization status has been correlated with circulating and gastric mucosal leptin levels [
9], and with gastric mRNA expression and plasma levels of ghrelin [
9,
37]. We now identified substantial effects of
H. pylori eradication on meal-associated changes in gastric hormones and energy balance, confirming and extending prior studies in a more rigorous manner [
13,
38].
That
H. pylori-positive and
H. pylori-negative subjects had similar baseline digestive hormonal physiologies (Additional file
3, Table S4) may reflect the highly integrated cross-regulation of energy homeostasis, [
39] and the long-term equilibria between
H. pylori and individual hosts [
10,
40]. Our observations of high pre-meal levels of acylated (acyl-) ghrelin that then fell post-prandially were as expected [
3]. However, several months after
H. pylori eradication, the extent of physiologic meal-associated reduction in circulating acyl-ghrelin was much diminished. These findings are consistent with other studies of subjects who underwent
H. pylori eradication and then had increased plasma ghrelin [
13,
30,
38] and gastric ghrelin mRNA levels [
29]. Alterations in ghrelin regulation following
H. pylori eradication may reflect the extent of baseline gastric inflammation [
8]. Similarly, plasma levels of acyl-ghrelin may be significantly elevated post-
H. pylori eradication, and vary reflecting the severity of atrophic gastritis [
30], but atrophic gastritis is uncommon in the population we studied (data not shown). Methodological issues across studies, such as the length of follow-up post-
H. pylori treatment [
11,
29] and differences in populations examined [
11] may partially account for differing metabolic and anthropometric findings. We now provide evidence that the extent and location of
H. pylori-induced inflammation at baseline is associated with the differences in ghrelin physiology that develop due to
H. pylori eradication. Although our data must be considered preliminary with small numbers of subjects, baseline antral gastritis appears to affect responses to eradication.
Although ghrelin is known to induce weight gain, in a study with six weeks of follow-up after
H. pylori eradication, plasma ghrelin was increased, but median BMI was unchanged [
13]. In another study, 12 weeks following
H. pylori eradication, plasma ghrelin was increased in some subjects and reduced in others [
29].
Our study now shows that following
H. pylori eradication, there is blunting of the meal-associated physiologic reduction in circulating acyl-ghrelin, and there is long-term weight gain; in addition, changes in baseline acyl-ghrelin values and changes in BMI were linked (Additional file
2, Figure S3). Reflecting the observed weight gain, leptin levels pre-meal and post-meal ghrelin levels were significantly elevated after eradication and differed significantly from baseline values. We also observed that
H. pylori eradication was associated with preservation of the expected [
26,
41‐
43] meal-associated increases in amylin, insulin, GIP, PP, and PYY. Post-meal levels of the incretin GLP-1 were significantly increased following eradication compared to baseline, perhaps reflecting the need for a meal-termination signal in the setting of persistently elevated ghrelin levels. We found no evidence that the weight gain associated with
H. pylori eradication reflected improvement of dyspeptic symptoms as suggested previously [
44]. Although in our study group, the
H. pylori-positive subjects had higher BMIs at baseline compared to
H. pylori-negative, the study was not designed to compare BMI between
H. pylori-negative and
H. pylori-positive groups. Rather, we sought to compare the change in BMI over time within the groups.
Our findings are limited by the study setting at a veteran's hospital where most of the evaluated patients were older men. Measurement of ghrelin is not standardized, [
45] and may account for the substantial inter-individual variation that we report. However, comparing each subject to himself before and after the standard test meal, and repeating the same measurements at baseline and during follow-up reduces the effects of inter-individual variation, as well as any potential effect of the endoscopic evaluation performed on all patients. We also verified measurements in the same individuals in duplicate on separate occasions. Since all patients (
H. pylori-negative and
H. pylori-positive) had an endoscopic evaluation prior to the first postprandial measurement of hormones, and not prior to the second postprandial measurement, the observed post-eradication changes could not be explained by the potential effect of the endoscopic examination alone. We measured acyl-ghrelin, which also may be relevant in energy homeostasis following
H. pylori eradication, as opposed to total ghrelin as others have done [
11,
29]. We did not address changes in the ratio of circulating active versus inactive ghrelin before and after eradication. Other strengths of the study include the collection of detailed demographic, clinical, and histologic data from a prospectively enrolled group using validated instruments,
H. pylori status determination using multiple methods for all patients that improve sensitivity and diminish falsely negative categorization [
46], measurement of eight gut hormones to ascertain the meal-associated metabolic profile of each subject at baseline, and following up an
H. pylori-negative group for comparison. We planned to analyze patients who were not successfully treated to eradicate
H. pylori, however few individuals failed eradication therapy and thus that control group was not sufficiently populated. In addition, our ability to further analyze
H. pylori-negative patients was limited by the fact that only 7 completed follow-up evaluations.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All authors read and approved the final manuscript. FF participated in the design of the study, patient recruitment, sample procurement, statistical analysis, and manuscript preparation. JR participated in patient recruitment, sample processing, and manuscript preparation. NJ contributed with patient recruitment and with manuscript preparation. ZP was involved in review of pathology samples and manuscript. AC participated in patient recruitment and manuscript review. JRS participated in sample processing and manuscript preparation. AZO was involved in sample procurement and processing as well as manuscript review. GIP participated in sample processing and manuscript preparation. MJB participated in study design, analysis, and manuscript preparation.