Plasma ghrelin following cure of Helicobacter pylori

C U Nwokolo; D A Freshwater; P O’Hare; H S Randeva

doi:10.1136/gut.52.5.637

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Plasma ghrelin following cure of Helicobacter pylori

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Ghrelin and Helicobacter pylori
Charles DR Murray
Published on: 18 April 2016
Author's reply
Chuka U Nwokolo
Published on: 18 April 2016
Helicobacter Pylori, ghrelin and obesity.
Robert C Macadam
Published on: 18 April 2016
Authors' reply
Chuka U Nwokolo
Published on: 18 April 2016

Published on: 18 April 2016
Ghrelin and Helicobacter pylori
- Charles DR Murray, Research Fellow
- Other Contributors:
  Anton V Emmanuel
Dear Editor
We read with interest the article by Nwokolo et al reporting raised serum ghrelin levels following helicobacter pylori eradication.[1] There are some exceptions to the interpretation of the data that we would take.
The authors state that the increase in ghrelin levels seen in their study “lends support to the view that ghrelin could be involved in the long term regulation of body w...
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Dear Editor
We read with interest the article by Nwokolo et al reporting raised serum ghrelin levels following helicobacter pylori eradication.[1] There are some exceptions to the interpretation of the data that we would take.
The authors state that the increase in ghrelin levels seen in their study “lends support to the view that ghrelin could be involved in the long term regulation of body weight”. Whilst there is growing evidence to support this in the literature,[2-4] this study does not present any such data and is not methodologically geared towards addressing this question. The proposal that eradication of H. pylori leads to an increase in ghrelin levels, which in turn leads to an increase in obesity, is also without foundation. The only known situation in which hyper-ghrelinaemia is associated with obesity is in the Prader-Willi syndrome.[5] In all other studies ghrelin levels correlate inversely with measures of body adiposity, and are altered in a compensatory manner by changes in body weight.[6] To suggest therefore that H. pylori eradication leads to a hyper-ghrelinaemic state that drives increased appetite is not physiologically feasible, since any transient appetite increase would be expected to be countered by any increase in adiposity, which in turn would suppress ghrelin levels.
The authors’ proposal that “children with H. pylori may have relatively low ghrelin concentrations contributing to growth retardation” is also without foundation. A recent study has shown H. pylori status to have no effect on ghrelin levels.[7] The role of ghrelin on the growth of children remains unclear. Ghrelin is an endogenous ligand to the growth hormone secretagogue receptor (GHS-R), and potently stimulates growth hormone release. It may indeed have a role to play in growth, since in patients with a genetic GHRH deficiency nocturnal enhancement of GH secretion remains,[8] an effect that may be mediated by ghrelin.
One other proposal of the authors is that H. pylori eradication increases 24 hour gastric acidity by a ghrelin dependent mechanism. Whilst central and peripheral ghrelin administration has been shown to increase stomach acidity when given to rats,[9] data is lacking in humans. The small, but statistically significant increase in acidity seen here would be expected after H. pylori eradication, and is likely to be secondary to parietal cell recovery following resolution of inflammation. The suggestion that hypergastrinaemia leads to lower ghrelin levels, and vice versa, is not supported in the literature.[10]
References
(1) Nwokolo CU, Freshwater DA, O'Hare P, Randeva HS. Plasma ghrelin following cure of Helicobacter pylori. Gut 2003; 52(5):637-640.
(2) Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346(21):1623-1630.
(3) Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409(6817):194-198.
(4) Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86(12):5992.
(5) Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med 2002; 8(7):643-644.
(6) Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Christiansen JS et al. Weight loss increases circulating levels of ghrelin in human obesity. Clin Endocrinol (Oxf) 2002; 56(2):203-206.
(7) Gokcel A, Gumurdulu Y, Kayaselcuk F, Serin E, Ozer B, Ozsahin AK et al. Helicobacter pylori has no effect on plasma ghrelin levels. Eur J Endocrinol 2003; 148(4):423-426.
(8) Maheshwari HG, Pezzoli SS, Rahim A, Shalet SM, Thorner MO, Baumann G. Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance. Am J Physiol Endocrinol Metab 2002; 282(4):E943-E951.
(9) Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 2000; 276(3):905-908.
(10) Dornonville dlC, Bjorkqvist M, Sandvik AK, Bakke I, Zhao CM, Chen D et al. A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control. Regul Pept 2001; 99(2-3):141-150.
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Conflict of Interest:
None declared.
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Published on: 18 April 2016
Author's reply
- Chuka U Nwokolo, Consultant Gastroenterologist
Dear Editor
Macadam et al. have rightly questioned whether our novel observation is merely epiphenomenal or of patho-physiological significance. Their “gut feeling” is that it is the former since the changes are “mild” and the ghrelin concentrations after Helicobacter pylori cure are no different from that seen in a non-obese western population. They also suggest that the “moderate” reduction of ghrelin...
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Dear Editor
Macadam et al. have rightly questioned whether our novel observation is merely epiphenomenal or of patho-physiological significance. Their “gut feeling” is that it is the former since the changes are “mild” and the ghrelin concentrations after Helicobacter pylori cure are no different from that seen in a non-obese western population. They also suggest that the “moderate” reduction of ghrelin in Helicobacter pylori +ve subjects (which they attribute to oxyntic gland atrophy) is unlikely to protect these individuals from obesity.
There is no doubt that cure of Helicobacter pylori increases plasma ghrelin in “healthy subjects”. The real questions are:
whether plasma ghrelin concentrations are higher in Helicobacter pylori –ve individuals and if so, whether the higher ghrelin concentration causes weight gain, whether any weight gained exacerbates gastroesophageal acid reflux enough to induce Barrett’s oesophagus and cancer. There are no satisfactory answers to these questions based on first class evidence but in our discussion we considered some indirect evidence. Firstly, populations with a high prevalence of Helicobacter pylori have a relatively high proportion of thin children and adults and those with a low prevalence have a higher proportion of obese individuals; we acknowledge the numerous other confounding factors in our paper.
Secondly, Furuta et al. showed that patients cured of Helicobacter pylori gained weight.[1] Lane A et al. continuing their reporting of the large Bristol Helicobacter project showed that at the end of 6 months, individuals who received treatment for Helicobacter pylori increased their weight by 0.6 kg over and above a matched group that received placebo.[2] Finally, in the only published study of its kind, infusion of ghrelin into healthy subjects was associated with increased appetite and food intake.[3]
In the presence of Helicobacter pylori, abnormalities in the function of the gastric neuro-endocrine cell population can be detected long before gastric atrophy occurs. “Inappropriate” hypergastrinaemia and disturbances in D-cell function have been described; these are fully reversible, returning to normal soon after Helicobacter pylori cure.[4,5] Similarly, gastric atrophy which is irreversible in the short-term is unlikely to be the mechanism that mediates hypoghrelinaemia in Helicobacter pylori positive subjects given that reversion to normal non-obese concentrations occurred 6-12 weeks after cure which was the time course of our study.[6] Also, the median age of our subjects was 36 years; the fact that they had normal gastrin concentrations and 24-hour intragastric acidity makes it unlikely that they had significant gastric atrophy.
In general, single factors rarely account for large epidemiological trends. We do not believe that everything can be explained by ghrelin; that would really be simplistic. However we believe that Helicobacter pylori +ve subjects with low ghrelin may have decreased appetite and food intake and are thinner than their Helicobacter pylori –ve counterparts in the western world. Their poor nutritional status would be exaggerated by co-existing dyspepsia due to peptic ulceration, concurrent infection and poor diet. They would have relatively lower intragastric acidity. Taken together these factors could protect these individuals from gastroesophageal reflux disease (GORD). Conversely, having normal ghrelin, a good appetite and normal intragastric acidity could make GORD more likely, possibly leading to Barrett’s oesophagus and oesophageal adenocarcinoma.
References
(1)Furuta T, Shirai N, Xiao F, et al. Effect of Helicobacter infection and its eradication on nutrition. Aliment Pharmacol Ther 2002; 4: 799-806
(2) Lane A, Harvey R, Murray L, et al. Effect of Helicobacter pylori eradication on body weight: the Bristol Helicobacter Project. Gastroenterology 2003; 124: 4 (suppl 1): A-622
(3) Wren A, Seal L, Cohen M, et al. Ghrelin enhances appetite and increases food intake in humans. Journal of Clinical Endocrinology & Metabolism 2001;86: 5992.
(4) Smith J, Pounder R, Nwokolo C, et al. Inappropriate hypergastrinaemia in asymptomatic healthy subjects infected with Helicobacter pylori. Gut0 1990; 31:522-5.
(5) Prewett E, Smith J, Nwokolo C, et al. Eradication of Helicobacter pylori abolishes 24-hour hypergastrinaemia: a prospective study in healthy subjects. Aliment Pharmacol Ther 1991;5:283-90.
(6) Nwokolo CU, Freshwater DA, O’Hare P, et al. Plasma ghrelin following cure of Helicobacter pylori. Gut 2003; 52: 637-640
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Conflict of Interest:
None declared.
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Published on: 18 April 2016
Helicobacter Pylori, ghrelin and obesity.
- Robert C Macadam, Surgeon
- Other Contributors:
  Vishal Borse, Ibrahim Dodo, Stephen G. Pollard
Dear Editor
Nwokolo et al. have demonstrated that following the eradication of Helicobacter pylori from asymptomatic patients, plasma ghrelin ‘ increases profoundly’.[1] Although we find these results interesting, we cannot agree with the conclusion that this may be causally linked to epidemiological observations of the rising incidence of obesity and oesophageal adenocarcinoma in Western populations....
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Dear Editor
Nwokolo et al. have demonstrated that following the eradication of Helicobacter pylori from asymptomatic patients, plasma ghrelin ‘ increases profoundly’.[1] Although we find these results interesting, we cannot agree with the conclusion that this may be causally linked to epidemiological observations of the rising incidence of obesity and oesophageal adenocarcinoma in Western populations. In particular the present study in fact demonstrates that after Helicobacter pylori eradication, ghrelin merely returns to levels detected in non-obese control patients using the same hormone assay.[2] It would seem likely that Helicobacter pylori infection, leading to oxyntic gland atrophy,[3] is associated with at most a mild suppression of plasma ghrelin, which recovers after treatment. This seems unlikely to have a profound effect on calorie intake, particularly as obese patients have a lower mean plasma ghrelin concentration than matched non-obese controls.[2] Whilst it is possible, though unproven, that the virtually abolition of plasma ghrelin seen after roux-en-Y gastric bypass surgery may contribute to the paradoxical reduction of hunger observed in these patients, it is simplistic to suggest that the moderate reduction in ghrelin as seen in the Helicobacter pylori - infected group in this study is protective against the development of obesity and its associated conditions.
References
(1) Nwokolo C, Freshwater D, O’Hare P, et al. Plasma ghrelin following cure of helicobacter pylori. Gut 2003;52:637-640.
(2) Cummings D, Weigle D, Frayo R, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346:1623-29.
(3) Date Y, Kojima M, Hosoda H, et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000;141:4255-61.
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Conflict of Interest:
None declared.
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Published on: 18 April 2016
Authors' reply
- Chuka U Nwokolo, Consultant Gastroenterologist
- Other Contributors:
  Harpal Randeva
Dear Editor
We would like to draw the attention of Murray et al.[1] to the objectives set out clearly in the introductory section of our paper.
Our study was not designed to address the question of whether ghrelin is involved in long-term regulation of body weight. Furthermore, the duration of the study was too short to see any change in BMI. More importantly, waist circumference would be a better...
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Dear Editor
We would like to draw the attention of Murray et al.[1] to the objectives set out clearly in the introductory section of our paper.
Our study was not designed to address the question of whether ghrelin is involved in long-term regulation of body weight. Furthermore, the duration of the study was too short to see any change in BMI. More importantly, waist circumference would be a better anthropometric measure of change in body fat composition supported by sequential dual energy Xray absorptiometry or MRI. The results of our study were unexpected and there was nothing in the literature that gave us forewarning. We would have designed the study to follow-up the subjects for at least one year, monitoring their plasma ghrelin and assessing changes in body composition using the techniques described above.
The authors refer to “physiological feasibility” and thereby miss the point that Helicobacter pylori-infected stomachs exhibit distortion of normal physiological mechanisms. For example, the tight reciprocal relationship between gastrin and intragastric acidity seen in Helicobacter pylori negative subjects is modified in Helicobacter pylori positive subjects. We believe that an Helicobacter pylori-infected stomach produces less ghrelin leading to decreased appetite and food intake. The physiological response should be that the resulting weight loss leads to a compensatory increase in ghrelin, increased appetite, and weight gain and so on. We believe that this “physiological” mechanism is altered by the presence of Helicobacter pylori, possibly by resetting a putative “ghrelin thermostat” at a lower level, allowing thinness and hypo-ghrelinaemia to occur together. Proof will come only from further experimentation.
The authors cite a study comparing spot measurements of plasma ghrelin in women with and without Helicobacter pylori gastritis;[2] this does not amount to a robust challenge to our hypothesis on Helicobacter pylori, ghrelin and children.
The authors repeat the widely-held, though unproven belief that the increase in intragastric acidity after Helicobacter pylori cure can be attributed to the recovery of parietal cells from inflammation. They ignore our observation of a positive correlation between ghrelin and 24- hour intragastric acidity.
We accept that the relationship between gastrin and ghrelin is unproven in man, but this emphasises the paucity of human data and the need for more studies.
References
(1) Murray CDR, Emmanuel AV. Ghrelin and Helicobacter pylori [electronic response to Nwokolo CU et al. Plasma ghrelin following cure of Helicobacter pylori] gutjnl.com 2003 http://gut.bmjjournals.com/cgi/eletters/52/5/637#94
(2) Gokcel A, Gumurdulu Y, Kayaselcuk F, et al. Helicobacter pylori has no effect on plasma ghrelin levels. Eur J Endocrinol 2003;148(4):423-6.
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Conflict of Interest:
None declared.
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