The discovery of cholera - like enterotoxins produced by Escherichia coli causing secretory diarrhoea in humans

Abstract

Non-vibrio cholera has been recognized as a clinical entity for as long as cholera was known to be caused by Vibrio cholerae. Until 1968, the aetiologic agent of this syndrome was not known. Following a series of studies in patients with non-vibrio cholera it was found that these patients had large concentrations of Escherichia coli in the small bowel and stools which produced cholera toxin-like enterotoxins, and had fluid and electrolyte transport abnormalities in the small bowel similar to patients with documented cholera. Furthermore, these patients developed antibodies to the cholera-like enterotoxin. Later studies showed that these strains, when fed to volunteers produced a cholera-like disease and that two enterotoxins were found to be produced by these organisms: a heat-labile enterotoxin (LT) which is nearly identical to cholera toxin, and a heat-stable enterotoxin (ST), a small molecular weight polypeptide. E. coli that produced one or both of these enterotoxins were designated enterotoxigenic E. coli (ETEC). ETEC are now known not only to cause a severe cholera-like illness, but to be the most common bacterial cause of acute diarrhoea in children in the developing world, and to be the most common cause of travellers' diarrhoea in persons who visit the developing world.

Fig. 1

Gross appearance of ligated loops of small intestine from rabbits 24 h after injection with cultures of Bacterium coli grown at pH 8.4. Upper loop injection with a culture of pathogenic Bact. coli; lower loop with non-pathogenic Bact. coli. Reproduced from reference 3 with permission.

Fig. 2

Titrations of E. coli culture filtrates in the RIL assay. Loops 1 and 2 represent positive (V. cholerae enterotoxin) and negative (saline) controls, respectively. Loops 6, 5, 4, and 3 show results obtained with increasing dilutions of the ETEC culture filtrates. Done in author’s laboratory.

Fig. 3

Titration of crude preparation of enterotoxin from three strains of ETEC and V. cholerae in the RIL. See reference 14 for details.

Fig. 4

Production of fluid in the RIL at various times after inoculations with different enterotoxin preparations. ECT, crude E. coli enterotoxin; LT, heat-labile enterotoxin; ST, heat-stable enterotoxin; and the results are compared with that obtained with V. cholerae enterotoxin (CT). Reproduced from reference 18 with permission.

Fig. 5

Fluid output from the small intestine using Thiry-Vella loops in dogs with either crude E. coli enterotoxin or V. cholerae enterotoxin. See references 14 and 19 for details.

Fig. 6

Titration of V. cholerae or E. coli enterotoxins by using the permeability factor assay in rabbit skin. The rabbit on the right had been injected about one month earlier and had rapid re-growth of hair at the site of injections. Done in author’s laboratory.

Fig. 7

Photomicrograph of E. coli (ETEC) showing fimbria/pili (A). × 60,000. The inset (B) shows a thin filament lying next to a flagellum. × 100,000. Flagella (C) as the only visible surface structure. × 100,000. Reproduced from reference 30 with permission.