Review Article An Ecological Study Abstract and Introduction Abstract Background. There is emerging debate over the effect of Helicobacter pylori infection on body mass index (BMI). A recent study demonstrated that individuals who underwent H. pylori eradication developed significant weight gain as compared to subjects with untreated H. pylori colonisation. Aim. To elucidate the association between H. pylori colonisation and the prevalence of overweight and obesity in developed countries. Methods. The literature was searched for publications reporting data on H. pylori prevalence rates and obesity prevalence rates. Studies selected reported H. pylori prevalence 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. pylori and overweight and obesity rates. Results. Forty-nine studies with data from 10 European countries, Japan, the US and Australia were identified. The mean H. pylori rate 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. pylori infection. Conclusions. There is an inverse correlation between H. pylori prevalence and rate of overweight/obesity in countries of the developed world. Thus, the gradual decrease of the H. pylori colonisation 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. pylori infection 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. pylori eradication on BMI. Kamada et al. demonstrated that Japanese patients who underwent H. pylori eradication developed significant weight gain as compared to subjects with untreated H. pylori colonisation. [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. pylori colonisation 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 Pylori and Obesity - 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. 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 2/17 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. pylori prevalence. 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. pylori and obesitas. In the Western World, the prevalence of H. pylori is decreasing. [15] H. pylori infection is prevalent worldwide, with a large disparity between developed and developing countries. [2] This decreasing prevalence of H. pylori may 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. pylori and the prevalence of obesity across various geographical regions of the world. Thus, this study aimed to elucidate the potential link between H. pylori and the prevalence of obesity and people who are overweight in developed countries. Methods Helicobacter Pylori Prevalence The literature was searched for publications reporting H. pylori prevalence 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. pylori infection assessed via serology, urea breath test or stool samples and sample size >100 subjects. Studies focussing on nonrandom samples or patient cohorts with H. pylori associated 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 were reviewed 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. pylori data were selected ( ). Table 1. Studies reporting of H. pylori prevalence (proportion of subjects with H. pylori infection) 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 al 34 649 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. 35 1346 Serology Australia 2010 0.23 0.49 0.164 Telaranta-Keerie 4256 Serology, Finland 2010 0.19 0.488 0.157 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 3/17 et al. 36 ELISA Sasazuki et al. 37 494 Serology Japan 2010 0.751 0.232 0.031 Salomaa- Rasanen et al. 38 504 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. 43 104 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 Sanchez Ceballos et al. 45 481 Urea breath test 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. 48 383 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. 49 6545 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. 55 8429 13 C 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 13 C Urea breath test Italy 2001 0.679 0.42 0.085 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 4/17 Rosenstock et al. 58 2527 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. 63 332 Serology Spain 1998 0.43 0.36 0.121 Martin de Argila et al. 64 301 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 al. 68 480 Serology Spain 1997 0.492 0.488 0.121 Peach et al. 61 217 Serology Australia 1995 0.306 0.573 0.193 Murray et al. 69 4742 Serology Northern Ireland 1997 0.505 0.669 0.11 Babus et al. 70 3082 Serology Croatia 1997 0.604 0.644 0.231 Martin-de-Argila et 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 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 13 C 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). Table 1. Studies reporting of H. pylori prevalence (proportion of subjects with H. pylori infection) 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 al 34 649 Serology Portugal 2011 0.85 0.535 0.142 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 5/17 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. 35 1346 Serology Australia 2010 0.23 0.49 0.164 Telaranta-Keerie et al. 36 4256 Serology, ELISA Finland 2010 0.19 0.488 0.157 Sasazuki et al. 37 494 Serology Japan 2010 0.751 0.232 0.031 Salomaa- Rasanen et al. 38 504 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. 43 104 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 Sanchez Ceballos et al. 45 481 Urea breath test 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. 48 383 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. 49 6545 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 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 6/17 Iszlai et al. 54 756 ELISA Hungary 2000 0.586 0.532 0.177 Moayyedi et al. 55 8429 13 C 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 13 C Urea breath test Italy 2001 0.679 0.42 0.085 Rosenstock et al. 58 2527 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. 63 332 Serology Spain 1998 0.43 0.36 0.121 Martin de Argila et al. 64 301 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 al. 68 480 Serology Spain 1997 0.492 0.488 0.121 Peach et al. 61 217 Serology Australia 1995 0.306 0.573 0.193 Murray et al. 69 4742 Serology Northern Ireland 1997 0.505 0.669 0.11 Babus et al. 70 3082 Serology Croatia 1997 0.604 0.644 0.231 Martin-de-Argila et 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 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 13 C 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). Overweight and Obesity Prevalence 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 7/17 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/m 2 ). 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. pylori prevalence and overweight and obesity rates in the respective geographical regions were calculated. To ensure that the association between H. pylori and 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. pylori rates were reported from Australia (15.1%), the highest for Portugal (85%) with a mean H. pylori rate 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. pylori infection (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. pylori prevalence were inversely correlated (r = 0.387, P < 0.01). Table 1. Studies reporting of H. pylori prevalence (proportion of subjects with H. pylori infection) 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 al 34 649 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. 35 1346 Serology Australia 2010 0.23 0.49 0.164 Telaranta-Keerie et al. 36 4256 Serology, ELISA Finland 2010 0.19 0.488 0.157 Sasazuki et al. 37 494 Serology Japan 2010 0.751 0.232 0.031 Salomaa- Rasanen et al. 38 504 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 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 8/17 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. 43 104 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 Sanchez Ceballos et al. 45 481 Urea breath test 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. 48 383 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. 49 6545 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. 55 8429 13 C 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 13 C Urea breath test Italy 2001 0.679 0.42 0.085 Rosenstock et al. 58 2527 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 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 9/17 Senra-Varel et al. 63 332 Serology Spain 1998 0.43 0.36 0.121 Martin de Argila et al. 64 301 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 al. 68 480 Serology Spain 1997 0.492 0.488 0.121 Peach et al. 61 217 Serology Australia 1995 0.306 0.573 0.193 Murray et al. 69 4742 Serology Northern Ireland 1997 0.505 0.669 0.11 Babus et al. 70 3082 Serology Croatia 1997 0.604 0.644 0.231 Martin-de-Argila et 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 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 13 C 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). 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 10/17 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 given population is inversely correlated with the H. pylori prevalence 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. pylori prevalence 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. pylori eradication patients experience a significant increase in weight that was not observed in control subjects who had placebo instead of H. pylori eradication. [7] Along the same lines, a cohort study observed that children who were never infected with H. pylori or cleared the infection grew significantly faster (gained weight) than those with persistent H. pylori infection. [18] Another intervention study demonstrated in H. pylori-infected children growth retardation and low serum acylated ghrelin. [16] In these children, H. pylori eradication restored ghrelin levels and increased body weight gains and growth. Weight gain following H. pylori eradication could be attributed to improvement of postprandial symptoms such as early satiety that may affect some people. However, the efficiency of H. pylori eradication 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. pylori may 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 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 11/17 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. pylori cure. [22] This could lead to increased appetite and consequently weight gain, and contribute to the increasing obesity seen in Western populations where H. pylori prevalence is low. Interestingly, other studies have shown that circulating meal-associated leptin and ghrelin levels change significantly after H. pylori eradication, 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 of ghrelin-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. pylori infection 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. pylori seropositivity 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. pylori and 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. pylori and 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. pylori and 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. pylori prevalence 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. pylori infection 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 of 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. pylroi status). It also needs to be considered that there might be a temporal association between H. pylori and 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. pylori prevalence over time (P > 0.20). Thus, a temporal association is unlikely to explain the link between H. pylori and 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. pylori infection. Subjects with an H. pylori infection 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 to pylori-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. pylori and obesity it cannot be 9/11/2014 http://www.medscape.com/viewarticle/827210_print is not available http://www.medscape.com/viewarticle/827210_print 12/17 excluded that this is an indirect relationship. It might not be the H. pylori infection but other factors linked to H. pylori that are causal for the observed association between H. pylori and 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 intestinal 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. pylori prevalence 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. pylori prevalence. 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. pylori and obesity besides direct effects of the H. pylori infection also 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. pylori eradication, our data demonstrate that the prevalence of gastric H. pylori colonisation in various countries is inversely related to the prevalence of obesity. The obesity endemic observed in the Western world thus may partly be linked to a reduction of the prevalence of H. pylori. Alternatively, it might be speculated that hygiene factors that favour a high H. pylori prevalence have a protective role with regard to the manifestation of obesity e.g. via effects on the gastrointestinal microbiome. Thus the H. pylori prevalence could be a marker for these protective factors. 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