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Resistance of germfree rats to indomethacin-induced intestinal lesions
Abstract:
Indomethacin given orally to conventional rats produced in three days a syndrome, often fatal, of intestinal lesions characterized by multiple ulcers and peritonitis. Male germfree rats were found to be resistant to this effect of indomethacin, while female germfree rats developed very mild lesions. Germfree rats became sensitive again to such lesions when monocontaminated with E. coli. In such animals, however, the lesions were less severe than in conventional animals, presumably because more than one microorganism is necessary for the full syndrome to develop. These results suggest that microorganisms are necessary for the development of indomethacin-induced intestinal lesions. Secondary bile acids, absent in germfree animals, may also be necessary. The prostaglandin deficiency caused by indomethacin appears to weaken the resistance of the intestinal mucosa to microorganisms and/or their toxins. The latter may then penetrate the mucosa, damage the cells and produce ulcers and perforations. Since several prostaglandins also protect against indomethacin-induced lesions, the hypothesis is advanced that certain prostaglandins may protect the mucosa ("cytoprotection") by preventing the spread of microorganisms and/or their toxin through the intestinal wall.
Insights
Microorganisms are essential for indomethacin to cause fatal intestinal lesions in rats. Germfree rats are resistant, but E. coli infection restores sensitivity, suggesting a role for gut bacteria in drug-induced injury.
Area of Science:
- Gastroenterology
- Microbiology
- Pharmacology
Background:
- Indomethacin, a nonsteroidal anti-inflammatory drug, can induce intestinal lesions.
- The role of the gut microbiota in the pathogenesis of drug-induced gastrointestinal injury is not fully understood.
Purpose of the Study:
- To investigate the role of microorganisms in the development of indomethacin-induced intestinal lesions.
- To explore the potential protective mechanisms of the intestinal mucosa against indomethacin toxicity.
Main Methods:
- Oral administration of indomethacin to conventional and germfree rats.
- Monocontamination of germfree rats with Escherichia coli (E. coli).
- Assessment of intestinal lesion severity and peritonitis.
Main Results:
- Conventional rats developed severe, often fatal, intestinal lesions and peritonitis after indomethacin administration.
- Male germfree rats were resistant, while female germfree rats showed only mild lesions.
- Monocontamination with E. coli rendered germfree rats sensitive to indomethacin, but lesions were less severe than in conventional rats.
- Secondary bile acids, absent in germfree animals, may also be necessary for lesion development.
Conclusions:
- Microorganisms are necessary for the development of indomethacin-induced intestinal lesions.
- Prostaglandin deficiency induced by indomethacin may compromise mucosal resistance to microbial invasion.
- Prostaglandins might exert a "cytoprotective" effect by preventing microbial and/or toxin translocation across the intestinal wall.