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Deciphering the pathogenesis of small intestinal damage caused by non-steroidal antiinflammatory drugs – the role of microbes, bile acids, and other luminal factors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide. Their mucosal damaging effect in the stomach and duodenum is well-recognized and can be effectively prevented and treated by antisecretory drugs. However, NSAIDs also injure the lower gastrointestinal tract, and the development and introduction of new diagnostic tools (e.g. video capsule endoscopy) have revealed that small intestinal ulcers are much more common and serious than previously recognized (Bjarnason et al., 2018).

In the last two decades, much effort has been put into understanding the complex pathogenesis of NSAID enteropathy (Figure 1), but it still remains insufficiently understood.

Figure 1. Some factors involved in the pathogenesis of NSAID enteropathy: 1. Enterohepatic recirculation of NSAIDs; 2. Inhibition of prostaglandin synthesis and „topical effect”; 3. Enteric bacteria and dysbiosis; 4. Bile acids.

Our studies aim to identify novel mechanisms and targets in a rat model of NSAID enteropathy, which could potentially be useful for the design of new therapeutic interventions. After treating the animals with different NSAIDs, they are euthanized and their small intestines are removed. The severity of mucosal injury is evaluated macroscopically, histologically, and by various molecular biological techniques (Western blotting, ELISA, enzyme activity assays, etc.) (Figure 2).

Figure 2. Flow chart of experimental design. NSAID-induced mucosal damage is determined by measuring the tissue levels of pro- and anti-inflammatory cytokines, reactive oxygen species, tight junction proteins.

Considering the pivotal role of enteric bacteria and bile acids in the pathogenesis of enteropathy, we also aim to determine the composition of intestinal microflora in NSAID-treated animals (Figure 3), as well as the concentrations of primary and secondary bile acids.

Figure 3. Microbial composition of the jejunal microbiota in a Wistar rat, determined by deep sequencing of 16S rRNA.

Acquirable skills: drug treatment of animals, macroscopic evaluation of enteropathy, histology, Western blot, ELISA

Tutor: Dr. Zoltán Zádori, associate professor