Helicobacter Pylori Journal Article

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Review Article

An Ecological Study

Abstract and Introduction

Abstract

Background. There is emerging debate over the effect of Helicobacter pyloriinfection on body mass index (BMI). A

recent study demonstrated that individuals who underwent H. pylorieradication developed significant weight gain as

compared to subjects with untreated H. pyloricolonisation.

Aim. To elucidate the association between H. pyloricolonisation and the prevalence of overweight and obesity in

developed countries.

Methods. The literature was searched for publications reporting data on H. pyloriprevalence rates and obesity

prevalence rates. Studies selected reported H. pyloriprevalence in random population samples with sample sizes of

more than 100 subjects in developed countries (GDP >25 000 US$/person/year). Corresponding BMI distributions for

corresponding countries and regions were identified. Nonparametric tests were used to compare the association

between H. pyloriand overweight and obesity rates.

Results. Forty-nine studies with data from 10 European countries, Japan, the US and Australia were identified. The

mean H. pylorirate was 44.1% (range 1775%), the mean rates for obesity and overweight were 46.6 (16)% and

14.2 (8.9)%. The rate of obesity and overweight were inversely and significantly (r= 0.29, P< 0.001) correlated with

the prevalence of H. pyloriinfection.

Conclusions. There is an inverse correlation between H. pyloriprevalence and rate of overweight/obesity in countries

of the developed world. Thus, the gradual decrease of the H. pyloricolonisation that has been observed in recent

decades (or factors associated with decrease of) could be causally related to the obesity endemic observed in the

Western world.

Introduction

In Western countries, the prevalence of those people classified as overweight (BMI >25 > 30) and obese (BMI >30)

has substantially increased.[1,2]The WHO in 2008 estimated that over 500 million adults have obesity, representing

1014% of the world's population. [2]In this context, there is emerging debate over the effect of Helicobacter pylori(H.pylori)infection on body mass index (BMI). While several cross-sectional studies have observed an association of H.

pyloriinfection with BMI,[3,4]the National Health and Nutrition Examination Survey (NHANES III) did not find an

association.[5]Other studies have evaluated the impact of H. pylorieradication on BMI. Kamada et al. demonstrated

that Japanese patients who underwent H. pylorieradication developed significant weight gain as compared to

subjects with untreated H. pyloricolonisation.[6]This has since been confirmed in a larger population-based

randomised controlled trial in England where people gained more than 3 kg of weight in the intervention (19%) as

compared to placebo (13%), although follow-up of this study was limited to 6 months. [7]In addition, animal studies

have shown that H. pyloricolonisation decreased fasting blood glucose levels, increased levels of leptin, improved

glucose tolerance, and suppressed weight gain.[8]All this may indeed suggest a role of the reduction of the H. pylori

Review Article: Associations Between Helicobacter PyloriandObesity - An Ecological Study

N. Lender, N. J. Talley, P. Enck, S. Haag, S. Zipfel, M. Morrison, G. J. Holtmann

Aliment Pharmacol Ther. 2014;40(1):24-31.
http://www.medscape.com/http://www.medscape.com/http://www.medscape.com/


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prevalence as a contributing factor for the obesity endemic.

It is widely accepted that environmental factors such as the availability and the characteristics of food and dietary

habits[9]play a role, while there are also genetic factors [10]that influence the manifestation of obesity. On the other

hand, it is interesting to note that some cohort studies do not find an association between nutrition and obesity[11]

suggesting that factors other than caloric intake are important for the obesity endemic. Nevertheless, there are

overwhelming data supporting that the endemic of obese patients is linked to an increased incidence of cancer[12]

and liver disease.[13]

While the obesity epidemic has been observed for prolonged periods of time in the Western World, there is now

emerging evidence that the obesity epidemic is spreading to the developing world.[14]Interestingly, there is now a

substantial decrease in the H. pyloriprevalence. However, it is as yet unknown if on a larger scale (e.g. across

different populations and countries) there might be an association between H. pyloriand obesitas. In the Western

World, the prevalence of H. pyloriis decreasing.[15]H. pyloriinfection is prevalent worldwide, with a large disparity

between developed and developing countries.[2]This decreasing prevalence of H. pylorimay represent a risk or

contributing factor to the world-wide endemic of obesity with all its complications. However, as yet there are no

systematic analyses that aim to assess a potential association between the prevalence of H. pyloriand the

prevalence of obesity across various geographical regions of the world. Thus, this study aimed to elucidate the

potential link between H. pyloriand the prevalence of obesity and people who are overweight in developed countries.

Methods

Helicobacter PyloriPrevalence

The literature was searched for publications reporting H. pyloriprevalence rates between 1990 and 2012. Two

researchers (NL & GH) conducted searches independently. Literature keyword searches included 'Helicobacter pylori

and 'prevalence' and retrieved 6945 articles. This was narrowed down on the basis of the outlined inclusion and

exclusion criteria including adult population, random (population) samples of both gender, H. pyloriinfection assessed

via serology, urea breath test or stool samples and sample size >100 subjects. Studies focussing on nonrandom

samples or patient cohorts with H. pyloriassociated disease were excluded. In addition, only studies from countries

with a GDP >$ 25,000 were included. Based upon this, 196 publications were identified. Full text articles werereviewed to ensure that all inclusion and exclusion criteria were met. Finally, 50 studies with data from 10 European

countries, Japan, USA, Canada and Australia were identified that were suitable for further analysis ( ). WHO and

other databases were then searched for overweight and obesity prevalence rates. Data from the relevant countries and

years corresponding (5 years) with the H. pyloridata were selected ( ).

Table 1. Studies reporting of H. pyloriprevalence (proportion of subjects with H. pyloriinfection) and WHO data on body

mass index (proportion of overweight (BMI 2530) and obese (BMI >30) subjects in the various countries

Study

Sample

size Methods Country Year

Prevalence

H. pylori

Prevalence

overweight

Prevalence

obesity

Shapira et al.31 100 Serology Italy 2011 0.3 0.44 0.098

Peleteiro et al34 649 Serology Portugal 2011 0.85 0.535 0.142

Lane et al.7 10 537 UBT UK 2011 0.155 0.61 0.227

Adamu et al.33 5229 Serology Germany 2011 0.4984 0.665 0.129

Whiteman et

al.351346 Serology Australia 2010 0.23 0.49 0.164

Telaranta-Keerie 4256 Serology, Finland 2010 0.19 0.488 0.157


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et al.36 ELISA

Sasazuki et al.37 494 Serology Japan 2010 0.751 0.232 0.031

Salomaa-

Rasanen et al.38504 Serology Finland 1994 0.36 0.42 0.106

Risch et al.32 690 Serology;

ELISA

USA 2010 0.17391 0.669 0.339

Kawai et al.39 418 Serology,IgG

Japan 2010 0.337 0.232 0.031

Fullerton et al.40 2437 Serology England 2009 0.264 0.61 0.227

Moujaber et al.41 2413 Serology Australia 2002 0.151 0.462 0.151

De Bastiani et

al.43104 Urea breath

test

Italy 2008 0.54 0.44 0.098

Stettin et al.44 563 Stool

samples

Germany 2007 0.21 0.665 0.129

SanchezCeballos et al.45

481 Urea breathtest

Spain 2007 0.603 0.534 0.156

Naja et al.46 1306 Serology Canada 2007 0.231 0.591 0.231

Sharara et al.47 104

(males

only)

Serology Italy 2006 0.683 0.44 0.098

Macenlle Garcia

et al.48383 Urea breath

test

Spain 2006 0.691 0.534 0.156

Cardenas et al.49 7462 Serology USA 2000 0.271 0.583 0.307

Kuepper-Nybelen

et al.496545 Serology Germany 1999 0.407 0.60 0.203

Ioannou et al.26 3130 Serology USA 2005 0.35 0.669 0.339

Ang et al.50 595 Serology Japan 2005 0.463 0.325 0.069

Cho et al.5 7003 Serology USA 2005 0.38 0.669 0.339

Simon et al.51 6746 Serology USA 2003 0.32 0.545 0.307

Robertson et

al.52

500 Serology Australia 2003 0.32 0.49 0.164

Nishise et al.53 695 Serology Japan 2003 0.6 0.232 0.031

Iszlai et al.54 756 ELISA Hungary 2000 0.586 0.532 0.177

Moayyedi et

al.558429 13C urea

breath test

England 2002 0.276 0.61 0.227

Bode et al.56 474 Serology Germany 2001 0.308 0.606 0.194

Bazzoli et al.57 1533 13C Urea

breath test

Italy 2001 0.679 0.42 0.085


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Rosenstock et

al.582527 Serology Denmark 1983

1994

0.247 0.417 0.094

Everhart et al.59 5465 Serology USA 1988

1991

0.325 0.55 0.227

Russo et al.60 2598 Serology Italy 1995

1997

0.45 0.385 0.064

Peach et al.61 324 Serology Australia 1999 0.3 0.573 0.193

Collett et al.62 1060 Serology Australia 1999 0.24 0.573 0.193

Senra-Varel et

al.63332 Serology Spain 1998 0.43 0.36 0.121

Martin de Argila

et al.64301 Serology UK 1998 0.522 0.669 0.11

Lin et al.65 273 Serology Australia 1998 0.38 0.598 0.193

Dite et al.66 309 Serology Czech

republic

1998 0.588 0.46 0.114

Babus et al.67 456 Serology Croatia 1998 0.5105 0.644 0.231

Rodrigo Saez et



Murray et al.69 4742 Serology Northern

Ireland

1997 0.505 0.669 0.11


Martin-de-Argila

et al.71381 Serology Spain 1996 0.53 0.488 0.121

Breuer et al.72 260 Serology Germany 1996 0.392 0.606 0.194

Asaka et al.73 109 Serology Japan 1995 0.743 0.224 0.022

Holtmann et al.74 180 Serology Germany 1994 0.317 0.606 0.186

Graham et al.75 485 13C Urea

breath test

USA 1991 0.502 0.55 0.227

The table includes only data from countries with a gross domestic product >US$ 17 000 (purchasing power parity

(PPP) adjusted).



Study

Sample


Prevalence

H. pylori

Prevalence

overweight

Prevalence

obesity




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Lane et al.7 10 537 UBT UK 2011 0.155 0.61 0.227


Whiteman et


Telaranta-Keerie

et al.364256 Serology,

ELISA

Finland 2010 0.19 0.488 0.157


Salomaa-



ELISA

USA 2010 0.17391 0.669 0.339

Kawai et al.39 418 Serology,

IgG

Japan 2010 0.337 0.232 0.031



De Bastiani et


test

Italy 2008 0.54 0.44 0.098


samples

Germany 2007 0.21 0.665 0.129

Sanchez

Ceballos et al.45481 Urea breath

test

Spain 2007 0.603 0.534 0.156



(males

only)

Serology Italy 2006 0.683 0.44 0.098

Macenlle Garcia


test

Spain 2006 0.691 0.534 0.156


Kuepper-Nybelen






Robertson et




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Moayyedi et

al.558429 13C urea

breath test

England 2002 0.276 0.61 0.227



breath test

Italy 2001 0.679 0.42 0.085

Rosenstock etal.58

2527 Serology Denmark 19831994

0.247 0.417 0.094


1991

0.325 0.55 0.227


1997

0.45 0.385 0.064



Senra-Varel etal.63

332 Serology Spain 1998 0.43 0.36 0.121

Martin de Argila

et al.64301 Serology UK 1998 0.522 0.669 0.11



republic

1998 0.588 0.46 0.114


Rodrigo Saez etal.68

480 Serology Spain 1997 0.492 0.488 0.121



Ireland

1997 0.505 0.669 0.11


Martin-de-Argila

et al.71381 Serology Spain 1996 0.53 0.488 0.121

Breuer et al.72

260 Serology Germany 1996 0.392 0.606 0.194




breath test

USA 1991 0.502 0.55 0.227


(PPP) adjusted).

Overweight and Obesity Prevalence


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Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. Based upon

the WHO definitions, we used the body mass index (BMI). It is defined as a person's weight in kilograms divided by

the square of his height in metres (kg/m2). A BMI greater than or equal to 25 is overweight and a BMI greater than or

equal to 30 defines obesity.[16]

Data Analysis

Mean prevalence rates for the different countries and different methods for the assessment were calculated. In a

second step, the correlations between the H. pyloriprevalence and overweight and obesity rates in the respective

geographical regions were calculated. To ensure that the association between H. pyloriand obesity/overweight

prevalence rates were not due to an effect of GDP per capita an additional partial correlation analysis that removed

the effect of the purchase power parity (PPP) adjusted GDP per capita was performed. All analysis statistical

analysis were done utilising spss version 22.

Results

Forty-nine studies with a total of 99,463 subjects were identified ( ). There were significant differences in H. pylori

prevalence rates for different countries. The lowest H. pylorirates were reported from Australia (15.1%), the highest fo

Portugal (85%) with a mean H. pylorirate of 41.9%. Similarly, there was considerable variability in prevalence rates

for overweight and obesity ranging from 22.4 to 66.9% (mean 51.9) and 2.2 to 33.9% (mean 16.2), respectively. As

shown in Figure 1 the prevalence of obesity and overweight were inversely and significantly ( r= 0.43, P< 0.01 and r= 0.292, P< 0.05) correlated with the prevalence of H. pyloriinfection (Figure 1). The association between H. pylori

prevalence and overweight or obesity remained significant after adjusting for GDP per capita (r= 0.352, P< 0.02 and

r= 0.291, P< 0.05). Interestingly, GDP per capita and H. pyloriprevalence were inversely correlated (r= 0.387, P

< 0.01).



Study

Sample


Prevalence

H. pylori

Prevalence

overweight

Prevalence

obesity



Lane et al.7 10 537 UBT UK 2011 0.155 0.61 0.227


Whiteman et


Telaranta-Keerie

et al.

364256 Serology,

ELISA

Finland 2010 0.19 0.488 0.157


Salomaa-



ELISA

USA 2010 0.17391 0.669 0.339

Kawai et al.39 418 Serology,

IgG

Japan 2010 0.337 0.232 0.031


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De Bastiani et


test

Italy 2008 0.54 0.44 0.098


samples

Germany 2007 0.21 0.665 0.129

SanchezCeballos et al.45

481 Urea breathtest

Spain 2007 0.603 0.534 0.156



(males

only)

Serology Italy 2006 0.683 0.44 0.098

Macenlle Garcia


test

Spain 2006 0.691 0.534 0.156


Kuepper-Nybelen






Robertson et

al.52

500 Serology Australia 2003 0.32 0.49 0.164



Moayyedi et

al.558429 13C urea

breath test

England 2002 0.276 0.61 0.227



breath test

Italy 2001 0.679 0.42 0.085

Rosenstock et

al.582527 Serology Denmark 1983

1994

0.247 0.417 0.094


1991

0.325 0.55 0.227


1997

0.45 0.385 0.064




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Senra-Varel et


Martin de Argila

et al.64301 Serology UK 1998 0.522 0.669 0.11



republic

1998 0.588 0.46 0.114


Rodrigo Saez et




Ireland

1997 0.505 0.669 0.11


Martin-de-Argilaet al.71

381 Serology Spain 1996 0.53 0.488 0.121

Breuer et al.72 260 Serology Germany 1996 0.392 0.606 0.194




breath test

USA 1991 0.502 0.55 0.227


(PPP) adjusted).


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Figure 1.

Association between the prevalence of H. pylori(%) and prevalence of obesity in countries with a gross domestic

product (GDP) per capita >US$ 25 000 (purchasing power parity (PPP) adjusted). The prevalence of obesity in a givenpopulation is inversely correlated with the H. pyloriprevalence in the same population (r= 0.46, P< 0.01).

Discussion

The key finding of this study is a striking inverse association between the H. pyloriprevalence in various countries and

the prevalence of overweight or obesity in these countries. This finding is consistent with previous observations in

controlled trials that after successful H. pylorieradication patients experience a significant increase in weight that

was not observed in control subjects who had placebo instead of H. pylorieradication.[7]Along the same lines, a

cohort study observed that children who were never infected with H. pylorior cleared the infection grew significantly

faster (gained weight) than those with persistent H. pyloriinfection.[18]Another intervention study demonstrated in H.

pylori-infected children growth retardation and low serum acylated ghrelin. [16]In these children, H. pylorieradication

restored ghrelin levels and increased body weight gains and growth.

Weight gain following H. pylorieradication could be attributed to improvement of postprandial symptoms such as

early satiety that may affect some people. However, the efficiency of H. pylorieradication with regard to symptoms is

very small[17]and other large well controlled studies were not able to demonstrate any effect. [19]More importantly, a

positive trial[6]conducted in a geographical region that had a high peptic ulcer prevalence and long waiting times for

endoscopic procedures suggests that the beneficial effect might be due to undiagnosed peptic ulcer disease. There is

also some evidence that H. pylorimay protect against symptoms of gastro-oesophageal reflux while obesity is a risk

factor for the manifestation of GERD. [20]Thus, it might be speculated that the manifestation of GERD symptoms


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affects behaviour and thus may have an impact on weight gain.

Among other factors, the hormone ghrelin is relevant for the regulation of appetite and food intake.[21]Interestingly, in

one study, plasma ghrelin increased profoundly in asymptomatic subjects after H. pyloricure.[22]This could lead to

increased appetite and consequently weight gain, and contribute to the increasing obesity seen in Western

populations where H. pyloriprevalence is low. Interestingly, other studies have shown that circulating meal-associated

leptin and ghrelin levels change significantly after H. pylorieradication, providing further direct evidence that H. pylori

colonisation is involved in ghrelin and leptin regulation, with consequent effects on body morphometry. [23]In another

study of 156 patients, who were undergoing laparoscopic vertical-banded gastroplasty for obesity, the density ofghrelin-positive cells was significantly lower for H. pylori-infected patients. Moreover, there was a significant stepwise

decrease in density of ghrelin-positive cells, with progression of histological severity of chronic inflammation,

neutrophil activity and glandular atrophy in the corpus.[24]H. pyloriinfection was also associated with a reduction in

circulating ghrelin levels independent of sex and BMI.[25]In contrast, in a cohort study with nearly 7000 subjects, H.

pyloriseropositivity and CagA antibody status were not associated with body mass index or fasting serum leptin

level.[26]

It might be argued that the inverse relation between H. pyloriand obesity that was found in our study is mediated by

the development status of the various countries which is reflected by the GDP. In our study, we have only included

countries with a (PPP adjusted) GDP per capita >US$ 25 000 to ensure that only developed countries were included.

In addition, in a separate analysis on the association between H. pyloriand the prevalence of overweight and obesity,we even adjusted for the GDP per capita in a partial correlation analysis. Even after this adjustment, the association

between H. pyloriand overweight/obesity remained significant across these developed countries. Thus, our data

clearly support the assumption that the association is not simply mediated by the income or the development status

of the populations included in this analysis.

While our data may suggest that the decrease in H. pyloriprevalence observed in many countries in recent decades

could be a contributing factor to the obesity endemic of the Western world, our study cannot rule out that other

factors that are correlated with the risk of a H. pyloriinfection are causal for the observed association. Indeed this

ecological study does not provide individual-level analysis. This can be seen as an advantage since an ecological

study might not be affected by some of the biases that may affect individual-level analysis. However, there are other

potential limitations such as ecological fallacy of the ecological approach that require a careful interpretation of the

data. In an ecologic study, the correlation between individual variables is deduced from the correlation of the variables

collected for the group to which those individuals belong. As a consequence, the correlation of aggregate quantities

may not be equal to the correlation of individual quantities. On the other hand, the ecological correlation (correlation o

aggregate quantities) may avoid specific selection biases (e.g. the patient cohorts may have received antibiotic

treatment for the management of obesity related diseases that may have affected the H. pylroistatus). It also needs

to be considered that there might be a temporal association between H. pyloriand obesity. i.e. while H. pylori

decreases over time, there is a parallel increase of obesity. However, it is unlikely that this effect is the explanation

for our results since during the time period between 1991 (oldest study) and 2011 (most recent study included) there

was no significant reduction of the H. pyloriprevalence over time (P> 0.20). Thus, a temporal association is unlikely

to explain the link between H. pyloriand obesity. Another potential error could be some kind of selection bias.However, a very comprehensive review of the published literature plus strict inclusion criteria should help to avoid this

error. It is important in this context to note that independent of our study other case control studies found very similar

results.[3,4]

However, other potential factors need to be considered. e.g. the gastrointestinal microbiome might be different in

subjects with or without H. pyloriinfection. Subjects with an H. pyloriinfection might have been exposed to

substantially more bacteria that ultimately may colonise the gastrointestinal mucosa. Thus subjects with H. pylori

infection may have been exposed to more bacteria as compared topylori-negative subject and thus may have a

different gastrointestinal microbiome. In addition, the patient's gastrointestinal microbiome may respond to antibiotic

therapy.[27]Thus while this ecological study clearly supports a link between H. pyloriand obesity it cannot be


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excluded that this is an indirect relationship. It might not be the H. pyloriinfection but other factors linked to H. pylori

that are causal for the observed association between H. pyloriand obesitas. Thus the role that the gastrointestinal

microbiome may play needs to be properly addressed. It is well established that there is an interplay between diet,

microbiome and health.[28]Recent evidence suggests that the gut microbiome may be related to the development of

obesity. This includes evidence of associations between obesity phenotypes and microbial class representation in

the gut[29]although further studies are needed. Studies looking at the effects of eradication treatment for H. pylori

infections on the intest inal microflora[27,30]have been plagued by methodological weakness and more research is

needed in order to fully understand the role that the microbiome may play in the observed relationship between

decreasing H. pyloriprevalence and the increasing rate of overweight/obesity.

While this study has several strengths including the focus on developed countries to avoid potential confounders, it

should be noted that the same obesity epidemic is taking place in developing countries[14]and not necessarily driven

by changes of H. pyloriprevalence. As we conducted an ecological study, we were not able to provide individual-level

analysis and it is therefore critical to carefully interpret the data. However, with regard to the association between H.

pyloriand obesity besides direct effects of the H. pylori infect ionalso potential confounders such as the influence of

antibiotic use and the gastrointestinal microbiome should be examined in future studies in this area.

In summary, while previous data already have suggested that weight gain may occur after antibiotic therapy targeting

H. pylorieradication, our data demonstrate that the prevalence of gastric H. pyloricolonisation in various countries is

inversely related to the prevalence of obesity. The obesity endemic observed in the Western world thus may partly belinked to a reduction of the prevalence of H. pylori. Alternatively, it might be speculated that hygiene factors that

favour a high H. pyloriprevalence have a protective role with regard to the manifestation of obesity e.g. via effects on

the gastrointestinal microbiome. Thus the H. pyloriprevalence could be a marker for these protective factors. While

these observations require further studies, they may provide important novel insights into the mechanisms that are

relevant for the obesity endemic in the developed world.

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