Primary Motility  Disorders of the  Esophagus
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OESO©2011
 
Volume: Barrett's Esophagus
Chapter: Adenocarcinomas
 

What is the role of bacterial overgrowth in the rising incidence of adenocarcinoma?

C.D. Morris, S.E.A. Attwood (Salford)

There are two areas where we can currently find clues about the contribution of bacteria in the pathogenesis of esophageal adenocarcinoma. These are the roles of Helicobacter pylori and bacterial overgrowth secondary to acid suppression.

Helicobacter pylori

Since Helicobacter pylori colonisation of Barrett's epithelium was first described in 1985, much interest has surrounded its possible contribution to the rising incidence of Barrett's adenocarcinoma. A recent review of the incidence of Helicobacter pylori colonisation of Barrett's epithelium found a 24% colonisation rate [1] of the Barrett's epithelium, which was not significantly different from the incidence of gastric infection in the same patients. However the incidence of gastric infection in controls was higher at 41% suggesting a lower rate of Helicobacter pylori infection in patients with Barrett's esophagus.

Despite initial fears that this Helicobacter pylori colonisation may contribute to esophageal carcinogenesis, the converse appears to be true. Chow et al. [2] found odds ratios for esophageal/gastric cardia adenocarcinoma of 0.4 (CI 0.2-0.8) in patients carrying cagA+ strains of Helicobacter pylori. This apparent protective effect not only applies to adenocarcinoma but also to other complications of reflux as the review by Bowrey suggests. In the study of Weston et al. [3] the prevalence of cagA+ strains was decreased in a stepwise manner in patients with gastroesophageal reflux disease (44.2%), Barrett's esophagus (35.1%) / low-grade dysplasia (36.2%) and high-grade dysplasia (14.3%) / adenocarcinoma (15.1%).

The controversy regarding the association between reflux and Helicobacter pylori infection may be explained by the pattern of gastric colonisation. Gastric antral infection tends to lead to increased acid production via hypergastrinaemia [4]. These patients will be at risk of duodenal ulceration and reflux disease, which would both improve on Helicobacter pylori eradication. However in the corpus predominant gastritis, glandular atrophy leads to hypochlorhydria [5] and these patients are therefore protected from reflux. These patients would have increased reflux on Helicobacter pylori eradication, and indeed there is evidence that severity of reflux increases in patients who have undergone Helicobacter pylori eradication as part of the management of conditions such as duodenal ulceration [6]. The nature of colonisation depends on a number of factors including CagA status, with cagA+ strains leading to greater Corpus gastritis. This would explain the apparent protective role for these organisms in reflux disease and adenocarcinoma. There is also some evidence that Helicobacter pylori colonisation increases the efficacy of acid suppression by H2 receptor antagonists or proton pump inhibitors (PPIs) leading to superior control of reflux [7].

In view of the accumulating evidence for a protective effect of Helicobacter pylori in reflux disease and esophageal adenocarcinoma, and the lack of data supporting Helicobacter pylori eradication in reducing gastric cancer, the policy of blanket Helicobacter pylori eradication in any patient found to be a carrier may turn out to be expensive both financially and medically.

Bacterial overgrowth

The ability for bacteria to colonize the stomach is largely dependent on the pH of the gastric content, with bacterial overgrowth frequently occurring in conditions with diminished acid output such as atrophic gastritis. As the pH rises to above 4, salivary organisms are able to survive, and once the pH reaches 5 a large flora develops including faecal organisms [8]. This can lead to diarrhoea, malabsorption [9] and the formation of potentially carcinogenic compounds [10]. Initial reports of the bacterial changes occurring during acid suppression therapy with H2 receptor antagonists were controversial with some but not all demonstrating elevations in bacteria levels on treatment [11]. However with the more profound acid suppression seen with PPIs there is little doubt that bacterial overgrowth of salivary and faecal organisms occurs, both in the stomach and duodenum [11]. These changes are reversed following the normalisation of acid levels.

Whether this bacterial overgrowth contributes to the rising incidence of adenocarcinoma of the esophagus and gastroesophageal junction is unknown, though there are a number of mechanisms by which it could promote carcinogenesis. Firstly many of the bacteria present in the stomach of acid suppressed patients, such as Enterococcus and Bacteroides are able to deconjugate bile acids [12]. Studies have demonstrated clear increases in deconjugated bile acids secondary to bacterial overgrowth in patients on PPI [12] and H2 receptor antagonist therapy [13]. These deconjugated bile acids are most damaging to the foregut mucosa at more neutral pH when they are unionized and are able to gain access into the cells. These pH changes are obviously encouraged by acid suppression therapy. The bile acids may cause cellular injury by disrupting cell membranes or accumulating within cells and disturbing cellular processes [14, 15].

A further possible damaging mechanism is the metabolism of salivary and dietary nitrates to nitrites by the bacteria. These can react with amides and amines to form carcinogens. Bile acids are a rich source of amides which react with nitrites in the stomach under the action of bacteria to form N-nitroso compounds such as N-nitrosotaurocholic acid and N-nitrosoglycocholic acid which have been shown to be carcinogenic [16]. Some studies have been able to demonstrate an elevation in the levels of nitrite and Nnitrosamine, associated with a fall in nitrate in gastric juice as bacterial levels increase due to profound acid suppression, these changes reverting to normal on discontinuing therapy [10]. Other studies however have been unable to confirm such changes in nitrosamines due to the overgrowth [11], and an element of doubt therefore remains concerning the production and contribution of these endogenous nitrosamines.

In summary, the mechanisms described above may be important in explaining the rising incidence of esophageal adenocarcinoma, and links bacterial overgrowth, bile reflux and Nnitroso carcinogens, all of which have been implicated in this disease. The rise in adenocarcinoma incidence has also occurred along a similar time scale to the rising use of acid suppression, though this may be a coincidental finding, due to treating an increasing prevalence of reflux disease.

References

1. Bowrey D, Williams G, Clark G. Interactions between Helicobacter pylori and gastrooesophageal reflux disease. Dis Esophagus 1998;11:203-209.

2. Chow WH, Blaser MJ, Blot WJ, Gammon MD, Vaughan TL, Risch HA, Perez Perez GI, Schoenberg JB, Stanford JL, Rotterdam H, West AB, Fraumeni JF Jr. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res 1998;58(4):588-590.

3. Weston AP, Badr AS, Topalovski M, Cherian R, Dixon A, Hassanein RS. Prospective evaluation of the prevalence of gastric Helicobacter pylori infection in patients with GERD, Barrett's esophagus, Barrett's dysplasia, and Barrett's adenocarcinoma. Am J Gastroenterol 2000;95(2):387-394.

4. Moss S, Legon S, Bishop A, et al. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease. Lancet 1992;340:930-932.

5. El-Omar E, Oien K, El-Nujumi A, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 1997;113:15-24.

6. Labenz J, Blum A, Bayerdorffer E, et al. Curing Helicobacter pylori in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997;112:1442-1447.

7. Koster E. Adverse events of HP eradication:long term negative consequences of HP eradication. Acta Gastroenterol-Belg 1998;61(3):350-351.

8. Stockbruegger R. Bacterial overgrowth as a consequence of reduced gastric acidity. Scand J Gastroenterol 1985;19:355364.

9. Saltzman J, Russell R. Nutritional consequences of intestinal bacterial overgrowth. Compr Ther 1994. 20(9):523-530.

10. Sharma B, Santana I, Wood E, Walt R, Pereira M, Noone P, Smith P, Walters C, Pounder R. Intragastric bacterial activity and nitrosation before, during and after treatment with omeprazole. Br Med J 1984;289:717-719.

11. Thorens J, Froehlich F, Schwizer W, Saraga E, Bille J, Gyr K, Duroux P, Nicolet M, Pignatelli B, Blum A, Gonvers J, Fried M. Bacterial overgrowth during treatment with omeprazole compared with cimetidine:a prospective randomized double blind study. Gut 1996;39(1):54-59.

12. Shindo K, Machida M, Fukumura M, Koide K, Yamazaki R. Omeprazole induces altered bile acid metabolism. Gut 1998;42(2):266-271.

13. Shindo K, Yamazaki R, Koide K, Fukumura M, Hirai Y. Alteration of bile acid metabolism by cimetidine in healthy humans. J Investig Med 1996;44(8):462-469.

14. Batzri S, Harmon JW, Schweitzer EJ, Toles R. Bile acid accumulation in gastric mucosal cells. Proc Soc Exp Biol Med 1991;197(4):393-399.

15. Thomas AJ, Nahrwold DL, Rose RC. Detergent action of sodium taurocholate on rat gastric mucosa. Biochim Biophys Acta 1972;282(1):210-213.

16. Busby W, Shuker D, Charnley G, Newberne P, Tanenbaum S, Wogan G. Carcinogenicity in rats of the nitrosated bile acid conjugates N-nitrosoglycocholic acid and N-nitrosotaurocholic acid. Cancer Res 1985;45:1367-1371.


Publication date: August 2003 OESO©2011