Helicobacter ISSN 1523-5378 doi: 10.1111/hel.12157
REVIEW ARTICLE
Helicobacter pylori and Nonmalignant Diseases Enzo Ierardi,* Elisabetta Goni,† Giuseppe Losurdo* and Francesco Di Mario† *Department of Emergency and Organ Transplantation, University of Bari – AOU Policlinico, Piazza Giulio Cesare 10, 70124, Bari, Italy, † Department of Clinical and Experimental Medicine, University of Parma - Ospedale Maggiore, Via A. Gramsci 14, 43126, Parma, Italy
Keywords Peptic ulcer, dyspepsia, oral cavity, intestinal disorders. Reprint requests to: Enzo Ierardi, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 10, 70124, Bari, Italy. E-mail: [email protected]
Abstract Peptic ulcer bleeding and recurrence rate are strongly linked to Helicobacter pylori infection even if nonsteroidal anti-inflammatory drugs (NSAIDs) play a relevant role in this setting. Further studies confirm that H. pylori eradication lowers the risk of recurrent peptic ulcer bleeding. Therefore, a test-and-treat strategy appears to be mandatory for patients with a history of ulcer bleeding and NSAIDs and/or aspirin use. Concerning gastroesophageal reflux disease (GERD), evidence clearly shows that H. pylori status has no effect on symptoms and treatment. Therefore, H. pylori treatment is not contraindicated in patients with GERD. The exact role of H. pylori in functional dyspepsia (FD) remains controversial. Novel possible mechanisms by which H. pylori may elicit dyspeptic symptoms include alterations of gastric motility, as well as endocrine and acid-secretory abnormalities. Hunger sensations, acid secretion, and gastrointestinal motility are regulated by ghrelin, particularly produced by the gastric enteroendocrine cell compartment. The improvement of symptoms correlates with enhanced plasma ghrelin levels. Apart from the need for more trials on this topic, these findings may give insight into the underlying pathophysiology of FD symptoms. Recent reports suggest that the presence of bacterial DNA in the oral cavity may be relevant to its transmission. A potential protective role of H. pylori on inflammatory bowel diseases needs to be better elucidated.
Helicobacter pylori has been the subject of intense investigation since its culture from a gastric biopsy in 1982. Declining H. pylori prevalence rates resulted in a decrease of peptic ulcer bleeding incidence. Moreover, eradication reduces peptic ulcer recurrence rate. New studies confirm that H. pylori eradication lowers the risk of recurrent peptic ulcer bleeding. Guidelines therefore advocate a test-and-treat strategy for patients with a history of ulcer bleeding and nonsteroidal anti-inflammatory drugs (NSAIDs) and/or aspirin use. There is mounting evidence that H. pylori status has no effect on symptoms and treatment efficacy in patients with gastroesophageal reflux disease (GERD). Some studies observed an improvement of GERD complaints after H. pylori eradication, which underlines that H. pylori treatment is not contraindicated in patients with GERD. The exact role of H. pylori in functional dyspepsia (FD) remains controversial. However, there is growing consensus that H. pylori-positive FD should be assessed
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 27–31
as a separate entity. In these patients, eradication can be beneficial and appropriate. At least several studies suggest that H. pylori infection may also be associated with beneficial effects for the host [1]. In this article, we will analyze the main data published between April 2013 and March 2014 on this topic including a potential relationship of the bacterium with oral cavity environment and a possible interference with intestinal diseases.
Peptic Ulcer Disease The relationship between H. pylori infection and peptic ulcer disease (PUD) and also peptic ulcer bleeding (PUB) has been extensively studied. Recently, Boylan et al. conducted a prospective cohort study of 47,120 men enrolled in the Health Professionals Follow-up Study (mean age of 54 years at
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baseline). Authors concluded that in a large prospective cohort of male health professionals, central and total obesity were associated with increased risk of peptic ulcer, and in particular gastric and H. pylori-negative ulcers [2]. Prahbu and Shivani analyzed 14,036 references concerning PUD, of which 1000 references were kept [3]. Authors concluded that in an area where general practitioners are the first contact for the patients, a substantial reduction or judicious use of NSAIDs helps in reducing gastroduodenal ulcers. In endoscopically proven cases of gastroduodenal ulcers, therapy for H. pylori eradication is mandatory. Even recent studies therefore confirm that the pathogenesis of PUD may be considered as a combination scenario involving an imbalance between defensive factors (mucus–bicarbonate layer, prostaglandins, cellular regeneration, mucosal blood flow) and aggressive factors (hydrochloric acid, pepsin, ethanol, bile salts, drugs). In this setting, NSAIDs play an important role in the pathogenesis as well, as there is a strong association between H. pylori infection and gastroduodenal ulcers [4–7]. Finally, cytokines play an important role in regulation of the mucosal immune system. Inflammation of gastroduodenal mucosa leads to the release of IL 1b, IL 2, IL 6, IL 8, and TNF alpha that damages mucosal tissue. The IL 1b levels are elevated in a subset of H. pylori cases which causes inhibition of gastric acid and pepsinogen secretion. Smolovic et al. analyzed the high risk of bleeding in H. pylori-negative, NSAID-negative ulcers, highlighting the clinical importance of analysis of the changing trends of PUD. They concluded that abnormal platelet function, aspirin use, and antral atrophy were the risk factors for ulcer bleeding in non-H. pylori, non-NSAID ulcer disease [8]. Kim et al. examined the proportion of patients with bleeding ulcers who had H. pylori testing and identified predictors associated with H. pylori testing. Among patients hospitalized with bleeding ulcers, less than a half received H. pylori testing and less than a third received the more accurate direct testing. Most of the direct H. pylori testing was biopsy-based with very few being tested after the index hospitalization. Efforts to increase H. pylori testing in patients with bleeding ulcers are needed to improve outcomes [9]. Hojsak et al. recently described an inverse relationship of H. pylori infection and gastroesophageal reflux disease. Furthermore, it has been hypothesized that an increased prevalence of allergic diseases could be, at least partially, explained by the decreased incidence of H. pylori infection. H. pylori can, to some degree, influence immunologic response. It has the ability to pro-
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mote high pro-inflammatory cytokine expression in the gastric mucosa shifting immunity toward Th1 response, which could be a plausible explanation for the downregulated clinical expression of allergies (including asthma) in patients with H. pylori gastritis [10].
Functional Dyspepsia Functional dyspepsia (FD) is currently defined as symptoms of epigastric pain, epigastric burning, postprandial fullness, or early satiation, in the absence of any organic, systemic, or metabolic disease that is more likely to explain the symptoms [5]. This chronic, relapsing, and remitting disorder is commonly seen in individuals from all around the world. Data from a large population-based study demonstrated no effect on life expectancy and no differences in the numbers of gastrointestinal-related deaths between subjects with or without dyspepsia [6]. The exact role of H. pylori in FD is still under debate. Some investigators have argued that if H. pylori gastritis is considered an organic disease, H. pylori-associated FD should not be considered as a functional disorder [11,12]. Possible mechanisms by which H. pylori may elicit dyspeptic symptoms include alterations of gastric motility, as well as endocrine and acid-secretory abnormalities [7]. Hunger sensations, acid secretion, and gastrointestinal motility are regulated by ghrelin, particularly produced by the gastric enteroendocrine cell compartment [7]. The improvement of symptoms correlated with enhanced plasma ghrelin levels. Apart from the need for more trials on this topic, these findings may give insight into the underlying pathophysiology of FD symptoms. Moreover, there is a trend of higher symptom response by H. pylori eradication treatment in Asian patients. Hence, particularly in these patients, exclusion of H. pylori infection is necessary before diagnosing FD. As in the past, current studies do not always give support for this statement. Sodhi et al. found no effect of H. pylori eradication on FD symptoms [13]. In this trial from India, H. pylori-positive patients suffering from FD (Rome II criteria) were randomly allocated to triple therapy (n = 259) or PPI and placebo (n = 260) for 2 weeks. After a 12-month follow-up, no difference in symptom resolution was found between the triple therapy and placebo group (44 vs 37%, p = .13). It should be noted that despite the low eradication rate of 70%, all patients allocated to the triple therapy arm (i.e. even unsuccessfully treated subjects) were included in the comparison. This may be a relevant bias influencing the outcome.
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 27–31
Ierardi et al.
Helicobacter pylori in the Oral Cavity Helicobacter pylori has been investigated in the past as a relevant actor in the pathogenesis of several stomatologic diseases such as periodontitis [14], caries [15], halitosis [16], and inflammatory or neoplastic disorders of oral mucosa [17]. Furthermore, it has been debated whether an oral localization of this organism could be a route of transmission, reinfection, or a marker of treatment failure [18]. In the last year, many authors studied the role played by H. pylori in the oral cavity, underlining the frequent colonization of this surface and the concordance of the strains populating oral and gastric mucosa. Cai et al. [19] studied 46 patients positive for gastric H. pylori infection and found bacterial 16S rDNA by realtime polymerase chain reaction (RT-PCR) in oral biopsy samples in 26 cases. Of these 26 cases, 12 patients (46.1%) were positive for the cagA gene, which was significantly lower than in the gastric mucosa (80.8%; p = .010). The homology of the complete sequence alignment ranged from 74.0% to 92.1% in the oral and gastric samples. Roman-Roman et al. [20] reached a similar result by evaluating H. pylori DNA in saliva by PCR: H. pylori DNA was found in 24% of the enrolled patients in saliva and biopsies, in 52.5% in biopsies only, while in 6.6% it was only found in saliva, so the authors concluded that saliva could be a possible route of transmission. Moreover, two recent studies investigated symbiotic yeast in the mouth to prove the hypothesis that the oral cavity is an important reservoir and source of infection. Saniee et al. [21] used light microscopy and PCR for primary detection of nonculturable H. pylori in 11 Candida yeasts (six oral and five gastric) and showed that inside yeast, H. pylori expresses proteins and is viable. These proteins appear to serve as powerful tools to help H. pylori establish itself in the vacuole of yeast where it can reach nutrients and proliferate. Furthermore, the same group found evidence of H. pylori genes in the mother’s vaginal and oral yeasts [22], a discovery that provides additional clues to the hypothesis of delivery transmission of H. pylori presented some years ago [23,24]. The concomitant presence of the organism in several oral diseases has been reported in various studies, with discordant results. For example, Salehi et al. [25] determined and compared the prevalence of H. pylori in gingival crevicular fluid of patients with chronic periodontitis and healthy subjects using PCR, showing no statistical significant association between H. pylori and chronic periodontitis, thus concluding that infection of the oral cavity, even if it may act as a reservoir
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 27–31
H. pylori and Nonmalignant Diseases
for H. pylori, does not seem to be involved in periodontal disease. On the other hand, Boylan et al. found a slightly increased risk of H. pylori infection (hazard ratio HR 1.4), gastric ulcers (HR 1.75), and duodenal ulcers (HR 1.47) in people affected by chronic periodontal disease [26], although this event could be explained by the fact that these patients are often smokers and present risk factors for peptic ulcer other than H. pylori. Finally, we report the observation that caries are more frequent in H. pylori-positive subjects (73.52%) than in negative ones (35.21%) [27] and that this bacterium has been found in association with oral lesions such as ulcerative/inflammatory lesions, squamous cell carcinoma, and primary lymphoma [28]. A single report documented this association with alterations of taste and olfaction (cacosmia and cacogeusia) [29]. To bring more arguments for an oral reservoir of H. pylori, adding relevance for treatment, Song and Li designed an intervention study including mouth rinse and periodontal treatment. They obtained significantly higher eradication rates, among those with a positive oral H. pylori test, in those who received mouth rinse and/or periodontal treatment in addition to the triple therapy [30].
Helicobacter pylori: Intestinal Manifestations In the literature, data concerning possible intestinal manifestations of an H. pylori infection are scanty. However, in the last year, various researchers focussed their attention on the relationship of H. pylori with inflammatory bowel diseases (IBD). All of the studies showed a low incidence of H. pylori infection in patients with IBD compared with normal controls. In a study by Jin et al. [31], the infection rate in patients affected by ulcerative colitis was 30.5%, significantly lower than 57.0% in the control group. Xiang et al. described a similar trend in subjects affected by Crohn’s disease, who were positive at biopsy in 27.1% of cases, much less than in the control group (47.9%), with no particular difference in the extension of the disease [32]. Looking more closely, the prevalence of this infection appears to have declined over the last decade. Indeed Triantafillidis et al. estimated the prevalence of this infection at 35.5% in 2002, and 24% in 2012 in the IBD group [33]. Finally, Hansen et al. [34] investigated microaerophilic microbiota in the colon of a pediatric population affected by IBD at the onset, showing that Campylobacter appears to be surprisingly common (around 8% of pediatric colonic biopsies), while Helicobacter species are relatively rare. It has been hypothesized that H. pylori could exert an immunomodulatory
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action on the intestinal mucosa [35], thus protecting against IBD but, at the moment, there is only a speculative observation that H. pylori infection has a relative risk for IBD of 0.43–0.59 [36]. Therefore, in the absence of strong evidence, the most reasonable explanation is that this trend could be attributed to previous antibiotic treatments, very frequent in subjects suffering from IBD [33]. It is a debated topic whether H. pylori might induce direct damage on the intestinal mucosa. Kim et al. reported multiple small bowel ulcerative lesions associated with H. pylori in an 11-year-old girl without any systemic disease [37]. Authors justified this event due to a weak mucosal defense mechanism against the bacterium for a structural deformity of the duodenal bulb caused by a previous gastrotomy. Even though a clear relationship could not be found, basic research demonstrated that H. pylori can use its pathogenic action against colonic cells, when they produce a gastric mucin (MUC5AC) [38]. Finally, secretory antibodies can modulate the progress of H. pylori infection, particularly in the duodenum, as shown by Gorrell et al.: Knockout mice for polymeric immunoglobulin receptors had a very intense colonization of the duodenum [39].
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Acknowledgements Competing interests: The authors have no competing interests.
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without Helicobacter pylori infection and without exposure to non-steroidal anti-inflammatory drugs. Vojnosanit Pregl 2014;71:183–90. Kim JJ, Lee JS, Olafsson S, Laine L. Low Adherence to Helicobacter pylori testing in hospitalized patients with bleeding peptic ulcer disease. Helicobacter 2014;19:98–104. Hojsak I, Kolacek S. Is Helicobacter pylori always a “Bad Guy”? Curr Pharm Des 2014;20:4517–20. Sugano K. Should we still subcategorize Helicobacter pylori-associated dyspepsia as functional disease? J Neurogastroenterol Motil 2011;17:366–71. Suzuki H, Nishizawa T, Hibi T. Can Helicobacter pylori-associated dyspepsia be categorized as functional dyspepsia? J Gastroenterol Hepatol 2011;26(Suppl 3):42–5. Sodhi JS, Javid G, Zargar SA, Tufail S, Shah A, Khan B, et al. Prevalence of Helicobacter pylori infection and the effect of its eradication on symptoms of functional dyspepsia in Kashmir, India. J Gastroenterol Hepatol 2013;28:808–13. Al AM, Al Hamoudi N, Anil S, Al Jebreen A, Al-Hamoudi WK. Is the presence of Helicobacter pylori in dental plaque of patients with chronic periodontitis a risk factor for gastric infection? Can J Gastroenterol 2009;23:177–9. Liu Y, Lin H, Bai Y, Qin X, Zheng X, Sun Y, et al. Study on the relationship between Helicobacter pylori in the dental plaque and the occurrence of dental caries or oral hygiene index. Helicobacter 2008;13:256–60. Ierardi E, Amoruso A, La Notte T, Francavilla R, Castellaneta S, Marrazza E, et al. Halitosis and Helicobacter pylori: a possible relationship. Dig Dis Sci 1998;43:2733–7. Grimm M, Munz A, Exarchou A, Polligkeit J, Reinert S. Immunohistochemical detection of Helicobacter pylori without association of TLR5 expression in oral squamous cell carcinoma. J Oral Pathol Med 2014;43:35–44. G€ urb€ uz AK, Ozel AM, Yazgan Y, Celik M, Yildirim S. Oral colonization of Helicobacter pylori: risk factors and response to eradication therapy. South Med J 2003;96:244–7. Cai H, Li W, Shu X, Peng K, Zhang Y, Jiang M. Genetic variation of Helicobacter pylori in the oral cavity and stomach detected using thymine adenine cloning in children with chronic gastritis. Pediatr Infect Dis J 2014;33:e1–6. Rom an-Rom an A, Giono-Cerezo S, Camorlinga-Ponce M, Martınez-Carrillo DN, Loaiza-Loeza S, Fern andez-Tilapa G. vacA genotypes of Helicobacter pylori in the oral cavity and stomach of patients with chronic gastritis and gastric ulcer. Enferm Infecc Microbiol Clin 2013;31:130–5. Saniee P, Siavoshi F, Nikbakht Broujeni G, Khormali M, Sarrafnejad A, Malekzadeh R. Immunodetection of Helicobacter pylori-specific proteins in oral and gastric Candida yeasts. Arch Iran Med 2013;16:624–30. Siavoshi F, Taghikhani A, Malekzadeh R, Sarrafnejad A, Kashanian M, Jamal AS, et al. The role of mother’s oral and vaginal yeasts in transmission of Helicobacter pylori to neonates. Arch Iran Med 2013;16:288–94. Baldassarre ME, Monno R, Laforgia N, Fumarola L, Fanelli M, Sgobba C, et al. The source of Helicobacter pylori infection in the neonatal period. J Perinat Med 2009;37:288–92. Baldassarre ME, Monno R, Laforgia N, Fumarola L, Fanelli M, Sgobba C, et al. Helicobacter pylori detection by stool antigen test in the perinatal period: an inadequate approach to establish maternal transmission. J Pediatr Gastroenterol Nutr 2008;47:673– 4. Salehi MR, Shah Aboei M, Naghsh N, Hajisadeghi S, Ajami E. A Comparison in prevalence of Helicobacter pylori in the gingival
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crevicular fluid from subjects with periodontitis and healthy individuals using polymerase chain reaction. J Dent Res Dent Clin Dent Prospects 2013;7:238–43. Boylan MR, Khalili H, Huang ES, Michaud DS, Izard J, Joshipura KJ, et al. A prospective study of periodontal disease and risk of gastric and duodenal ulcer in male health professionals. Clin Transl Gastroenterol 2014;5:e49. Liu P, Yue J, Han S, Deng T, Fu C, Zhu G, et al. A cross-sectional survey of dental caries, oral hygiene, and Helicobacter pylori infection in adults. Asia Pac J Public Health 2013;25(4 Suppl):49S–56S. Irani S, Monsef Esfahani A, Bidari Zerehpoush F. Detection of Helicobacter pylori in oral lesions. J Dent Res Dent Clin Dent Prospects 2013;7:230–7. Cecchini MP, Pellegrini C, Bassetto MA, Osculati F, Sbarbati A, Marcolini L, et al. Might Helicobacter pylori infection be associated with distortion on taste perception? Med Hypotheses 2013;81:496–9. Song HY, Li Y. Can eradication rate of gastric Helicobacter pylori be improved by killing oral Helicobacter pylori? World J Gastroenterol 2013;19:6645–50. Jin X, Chen YP, Chen SH, Xiang Z. Association between Helicobacter pylori infection and ulcerative colitis–a case control study from China. Int J Med Sci 2013;10:1479–84. Xiang Z, Chen YP, Ye YF, Ma KF, Chen SH, Zheng L, et al. Helicobacter pylori and Crohn’s disease: a retrospective
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single-center study from China. World J Gastroenterol 2013;19:4576–81. Triantafillidis JK, Gikas A. Over-time changes of Helicobacter pylori infection rate in patients with inflammatory bowel disease. J Crohns Colitis 2013;7:681. Hansen R, Berry SH, Mukhopadhya I, Thomson JM, Saunders KA, Nicholl CE, et al. The microaerophilic microbiota of denovo paediatric inflammatory bowel disease: the BISCUIT study. PLoS ONE 2013;8:e58825. Owyang SY, Luther J, Owyang CC, Zhang M, Kao JY. Helicobacter pylori DNA’s anti-inflammatory effect on experimental colitis. Gut Microbes 2012;3:168–71. Sonnenberg A, Genta RM. Low prevalence of Helicobacter pylori infection among patients with inflammatory bowel disease. Aliment Pharmacol Ther 2012;35:469–76. Kim EY, Kim JH, Woo SB, Lee JW, Lee KH, Shin SR, et al. A case of small bowel ulcer associated with Helicobacter pylori. Pediatr Gastroenterol Hepatol Nutr 2012;15:266–71. Naughton JA, Mari~ no K, Dolan B, Reid C, Gough R, Gallagher ME, et al. Divergent mechanisms of interaction of Helicobacter pylori and Campylobacter jejuni with mucus and mucins. Infect Immun 2013;81:2838–50. Gorrell RJ, Wijburg OL, Pedersen JS, Walduck AK, Kwok T, Strugnell RA, Robins-Browne RM. Contribution of secretory antibodies to intestinal mucosal immunity against Helicobacter pylori. Infect Immun 2013;81:3880–93.
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REVIEW ARTICLE
Helicobacter pylori and Nonmalignant Diseases Enzo Ierardi,* Elisabetta Goni,† Giuseppe Losurdo* and Francesco Di Mario† *Department of Emergency and Organ Transplantation, University of Bari – AOU Policlinico, Piazza Giulio Cesare 10, 70124, Bari, Italy, † Department of Clinical and Experimental Medicine, University of Parma - Ospedale Maggiore, Via A. Gramsci 14, 43126, Parma, Italy
Keywords Peptic ulcer, dyspepsia, oral cavity, intestinal disorders. Reprint requests to: Enzo Ierardi, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 10, 70124, Bari, Italy. E-mail: [email protected]
Abstract Peptic ulcer bleeding and recurrence rate are strongly linked to Helicobacter pylori infection even if nonsteroidal anti-inflammatory drugs (NSAIDs) play a relevant role in this setting. Further studies confirm that H. pylori eradication lowers the risk of recurrent peptic ulcer bleeding. Therefore, a test-and-treat strategy appears to be mandatory for patients with a history of ulcer bleeding and NSAIDs and/or aspirin use. Concerning gastroesophageal reflux disease (GERD), evidence clearly shows that H. pylori status has no effect on symptoms and treatment. Therefore, H. pylori treatment is not contraindicated in patients with GERD. The exact role of H. pylori in functional dyspepsia (FD) remains controversial. Novel possible mechanisms by which H. pylori may elicit dyspeptic symptoms include alterations of gastric motility, as well as endocrine and acid-secretory abnormalities. Hunger sensations, acid secretion, and gastrointestinal motility are regulated by ghrelin, particularly produced by the gastric enteroendocrine cell compartment. The improvement of symptoms correlates with enhanced plasma ghrelin levels. Apart from the need for more trials on this topic, these findings may give insight into the underlying pathophysiology of FD symptoms. Recent reports suggest that the presence of bacterial DNA in the oral cavity may be relevant to its transmission. A potential protective role of H. pylori on inflammatory bowel diseases needs to be better elucidated.
Helicobacter pylori has been the subject of intense investigation since its culture from a gastric biopsy in 1982. Declining H. pylori prevalence rates resulted in a decrease of peptic ulcer bleeding incidence. Moreover, eradication reduces peptic ulcer recurrence rate. New studies confirm that H. pylori eradication lowers the risk of recurrent peptic ulcer bleeding. Guidelines therefore advocate a test-and-treat strategy for patients with a history of ulcer bleeding and nonsteroidal anti-inflammatory drugs (NSAIDs) and/or aspirin use. There is mounting evidence that H. pylori status has no effect on symptoms and treatment efficacy in patients with gastroesophageal reflux disease (GERD). Some studies observed an improvement of GERD complaints after H. pylori eradication, which underlines that H. pylori treatment is not contraindicated in patients with GERD. The exact role of H. pylori in functional dyspepsia (FD) remains controversial. However, there is growing consensus that H. pylori-positive FD should be assessed
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 27–31
as a separate entity. In these patients, eradication can be beneficial and appropriate. At least several studies suggest that H. pylori infection may also be associated with beneficial effects for the host [1]. In this article, we will analyze the main data published between April 2013 and March 2014 on this topic including a potential relationship of the bacterium with oral cavity environment and a possible interference with intestinal diseases.
Peptic Ulcer Disease The relationship between H. pylori infection and peptic ulcer disease (PUD) and also peptic ulcer bleeding (PUB) has been extensively studied. Recently, Boylan et al. conducted a prospective cohort study of 47,120 men enrolled in the Health Professionals Follow-up Study (mean age of 54 years at
27
H. pylori and Nonmalignant Diseases
baseline). Authors concluded that in a large prospective cohort of male health professionals, central and total obesity were associated with increased risk of peptic ulcer, and in particular gastric and H. pylori-negative ulcers [2]. Prahbu and Shivani analyzed 14,036 references concerning PUD, of which 1000 references were kept [3]. Authors concluded that in an area where general practitioners are the first contact for the patients, a substantial reduction or judicious use of NSAIDs helps in reducing gastroduodenal ulcers. In endoscopically proven cases of gastroduodenal ulcers, therapy for H. pylori eradication is mandatory. Even recent studies therefore confirm that the pathogenesis of PUD may be considered as a combination scenario involving an imbalance between defensive factors (mucus–bicarbonate layer, prostaglandins, cellular regeneration, mucosal blood flow) and aggressive factors (hydrochloric acid, pepsin, ethanol, bile salts, drugs). In this setting, NSAIDs play an important role in the pathogenesis as well, as there is a strong association between H. pylori infection and gastroduodenal ulcers [4–7]. Finally, cytokines play an important role in regulation of the mucosal immune system. Inflammation of gastroduodenal mucosa leads to the release of IL 1b, IL 2, IL 6, IL 8, and TNF alpha that damages mucosal tissue. The IL 1b levels are elevated in a subset of H. pylori cases which causes inhibition of gastric acid and pepsinogen secretion. Smolovic et al. analyzed the high risk of bleeding in H. pylori-negative, NSAID-negative ulcers, highlighting the clinical importance of analysis of the changing trends of PUD. They concluded that abnormal platelet function, aspirin use, and antral atrophy were the risk factors for ulcer bleeding in non-H. pylori, non-NSAID ulcer disease [8]. Kim et al. examined the proportion of patients with bleeding ulcers who had H. pylori testing and identified predictors associated with H. pylori testing. Among patients hospitalized with bleeding ulcers, less than a half received H. pylori testing and less than a third received the more accurate direct testing. Most of the direct H. pylori testing was biopsy-based with very few being tested after the index hospitalization. Efforts to increase H. pylori testing in patients with bleeding ulcers are needed to improve outcomes [9]. Hojsak et al. recently described an inverse relationship of H. pylori infection and gastroesophageal reflux disease. Furthermore, it has been hypothesized that an increased prevalence of allergic diseases could be, at least partially, explained by the decreased incidence of H. pylori infection. H. pylori can, to some degree, influence immunologic response. It has the ability to pro-
28
Ierardi et al.
mote high pro-inflammatory cytokine expression in the gastric mucosa shifting immunity toward Th1 response, which could be a plausible explanation for the downregulated clinical expression of allergies (including asthma) in patients with H. pylori gastritis [10].
Functional Dyspepsia Functional dyspepsia (FD) is currently defined as symptoms of epigastric pain, epigastric burning, postprandial fullness, or early satiation, in the absence of any organic, systemic, or metabolic disease that is more likely to explain the symptoms [5]. This chronic, relapsing, and remitting disorder is commonly seen in individuals from all around the world. Data from a large population-based study demonstrated no effect on life expectancy and no differences in the numbers of gastrointestinal-related deaths between subjects with or without dyspepsia [6]. The exact role of H. pylori in FD is still under debate. Some investigators have argued that if H. pylori gastritis is considered an organic disease, H. pylori-associated FD should not be considered as a functional disorder [11,12]. Possible mechanisms by which H. pylori may elicit dyspeptic symptoms include alterations of gastric motility, as well as endocrine and acid-secretory abnormalities [7]. Hunger sensations, acid secretion, and gastrointestinal motility are regulated by ghrelin, particularly produced by the gastric enteroendocrine cell compartment [7]. The improvement of symptoms correlated with enhanced plasma ghrelin levels. Apart from the need for more trials on this topic, these findings may give insight into the underlying pathophysiology of FD symptoms. Moreover, there is a trend of higher symptom response by H. pylori eradication treatment in Asian patients. Hence, particularly in these patients, exclusion of H. pylori infection is necessary before diagnosing FD. As in the past, current studies do not always give support for this statement. Sodhi et al. found no effect of H. pylori eradication on FD symptoms [13]. In this trial from India, H. pylori-positive patients suffering from FD (Rome II criteria) were randomly allocated to triple therapy (n = 259) or PPI and placebo (n = 260) for 2 weeks. After a 12-month follow-up, no difference in symptom resolution was found between the triple therapy and placebo group (44 vs 37%, p = .13). It should be noted that despite the low eradication rate of 70%, all patients allocated to the triple therapy arm (i.e. even unsuccessfully treated subjects) were included in the comparison. This may be a relevant bias influencing the outcome.
© 2014 John Wiley & Sons Ltd, Helicobacter 19 (Suppl. 1): 27–31
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Helicobacter pylori in the Oral Cavity Helicobacter pylori has been investigated in the past as a relevant actor in the pathogenesis of several stomatologic diseases such as periodontitis [14], caries [15], halitosis [16], and inflammatory or neoplastic disorders of oral mucosa [17]. Furthermore, it has been debated whether an oral localization of this organism could be a route of transmission, reinfection, or a marker of treatment failure [18]. In the last year, many authors studied the role played by H. pylori in the oral cavity, underlining the frequent colonization of this surface and the concordance of the strains populating oral and gastric mucosa. Cai et al. [19] studied 46 patients positive for gastric H. pylori infection and found bacterial 16S rDNA by realtime polymerase chain reaction (RT-PCR) in oral biopsy samples in 26 cases. Of these 26 cases, 12 patients (46.1%) were positive for the cagA gene, which was significantly lower than in the gastric mucosa (80.8%; p = .010). The homology of the complete sequence alignment ranged from 74.0% to 92.1% in the oral and gastric samples. Roman-Roman et al. [20] reached a similar result by evaluating H. pylori DNA in saliva by PCR: H. pylori DNA was found in 24% of the enrolled patients in saliva and biopsies, in 52.5% in biopsies only, while in 6.6% it was only found in saliva, so the authors concluded that saliva could be a possible route of transmission. Moreover, two recent studies investigated symbiotic yeast in the mouth to prove the hypothesis that the oral cavity is an important reservoir and source of infection. Saniee et al. [21] used light microscopy and PCR for primary detection of nonculturable H. pylori in 11 Candida yeasts (six oral and five gastric) and showed that inside yeast, H. pylori expresses proteins and is viable. These proteins appear to serve as powerful tools to help H. pylori establish itself in the vacuole of yeast where it can reach nutrients and proliferate. Furthermore, the same group found evidence of H. pylori genes in the mother’s vaginal and oral yeasts [22], a discovery that provides additional clues to the hypothesis of delivery transmission of H. pylori presented some years ago [23,24]. The concomitant presence of the organism in several oral diseases has been reported in various studies, with discordant results. For example, Salehi et al. [25] determined and compared the prevalence of H. pylori in gingival crevicular fluid of patients with chronic periodontitis and healthy subjects using PCR, showing no statistical significant association between H. pylori and chronic periodontitis, thus concluding that infection of the oral cavity, even if it may act as a reservoir
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for H. pylori, does not seem to be involved in periodontal disease. On the other hand, Boylan et al. found a slightly increased risk of H. pylori infection (hazard ratio HR 1.4), gastric ulcers (HR 1.75), and duodenal ulcers (HR 1.47) in people affected by chronic periodontal disease [26], although this event could be explained by the fact that these patients are often smokers and present risk factors for peptic ulcer other than H. pylori. Finally, we report the observation that caries are more frequent in H. pylori-positive subjects (73.52%) than in negative ones (35.21%) [27] and that this bacterium has been found in association with oral lesions such as ulcerative/inflammatory lesions, squamous cell carcinoma, and primary lymphoma [28]. A single report documented this association with alterations of taste and olfaction (cacosmia and cacogeusia) [29]. To bring more arguments for an oral reservoir of H. pylori, adding relevance for treatment, Song and Li designed an intervention study including mouth rinse and periodontal treatment. They obtained significantly higher eradication rates, among those with a positive oral H. pylori test, in those who received mouth rinse and/or periodontal treatment in addition to the triple therapy [30].
Helicobacter pylori: Intestinal Manifestations In the literature, data concerning possible intestinal manifestations of an H. pylori infection are scanty. However, in the last year, various researchers focussed their attention on the relationship of H. pylori with inflammatory bowel diseases (IBD). All of the studies showed a low incidence of H. pylori infection in patients with IBD compared with normal controls. In a study by Jin et al. [31], the infection rate in patients affected by ulcerative colitis was 30.5%, significantly lower than 57.0% in the control group. Xiang et al. described a similar trend in subjects affected by Crohn’s disease, who were positive at biopsy in 27.1% of cases, much less than in the control group (47.9%), with no particular difference in the extension of the disease [32]. Looking more closely, the prevalence of this infection appears to have declined over the last decade. Indeed Triantafillidis et al. estimated the prevalence of this infection at 35.5% in 2002, and 24% in 2012 in the IBD group [33]. Finally, Hansen et al. [34] investigated microaerophilic microbiota in the colon of a pediatric population affected by IBD at the onset, showing that Campylobacter appears to be surprisingly common (around 8% of pediatric colonic biopsies), while Helicobacter species are relatively rare. It has been hypothesized that H. pylori could exert an immunomodulatory
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action on the intestinal mucosa [35], thus protecting against IBD but, at the moment, there is only a speculative observation that H. pylori infection has a relative risk for IBD of 0.43–0.59 [36]. Therefore, in the absence of strong evidence, the most reasonable explanation is that this trend could be attributed to previous antibiotic treatments, very frequent in subjects suffering from IBD [33]. It is a debated topic whether H. pylori might induce direct damage on the intestinal mucosa. Kim et al. reported multiple small bowel ulcerative lesions associated with H. pylori in an 11-year-old girl without any systemic disease [37]. Authors justified this event due to a weak mucosal defense mechanism against the bacterium for a structural deformity of the duodenal bulb caused by a previous gastrotomy. Even though a clear relationship could not be found, basic research demonstrated that H. pylori can use its pathogenic action against colonic cells, when they produce a gastric mucin (MUC5AC) [38]. Finally, secretory antibodies can modulate the progress of H. pylori infection, particularly in the duodenum, as shown by Gorrell et al.: Knockout mice for polymeric immunoglobulin receptors had a very intense colonization of the duodenum [39].
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Acknowledgements Competing interests: The authors have no competing interests.
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