Three hypotheses linking bile to carcinogenesis in the gastrointestinal tract: certain bile salts have properties that may be used to complement chemotherapy☆

The literature for the proliferative effect of bile acids on the GI tract has been reviewed and three hypotheses developed regarding their carcinogenicity. Considered as a unit, the GI tract is protected from this carcinogenicity in different ways in the esophagus, stomach, small bowel and colon. Uncharged BAs can enter the esophageal epithelial cells by reflux of gastroduodenal juices in humans, and in animals by surgical alteration of the GI tract or by adding bile concentrate to the diets, and this can initiate GERD and eventually cancer. Acid suppressant therapy used to treat GERD patients, converts stomach pH to >4. This will remove the charges on conjugated bile acids allowing them entry into the epithelium thus casting doubt on the efficacy of acid suppression. From these observations, we postulate that (a) uncharged BA in daily contact with the esophagus can cause GERD and eventually cancer. This might explain the cancers obtained by Fein et al. (1). (b) Clinical trials designed to test the effectiveness of acid suppressants will be meaningless since up to ∼87% of these patients (in one study) have bile in their refluxate, and this, combined with acid suppressants, will initiate carcinogenesis. (c) Bile reaching a colon made sterile by antibiotics or other means, will not be deconjugated and so, with pKa's of 2 and 4, will be uncharged and therefore can easily enter the colonic cells where the pH is >6. This should be of some concern, especially on a high-fat diet when more bile enters the colon. A group of physicians noted that ∼47% of patients with esophageal cancers also had some form of colon cancer and postulated that an etiological factor in the environment was responsible. Could this factor be bile? Reactions of certain bile salts with epithelial cells suggest a useful role for them in chemotherapy. Experiments to test hypotheses a, b and c are presented in the addendum.