NPY2R Agonist-Induced Gastric Effects Leading to Intestinal Dysbiosis and Secondary Intestinal Pathology in CD1 Mice

Obesity research has identified several drug targets, including the neuropeptide Y receptor 2 (NPY2R), which causes anorexigenic effects and delays gastric emptying. Test Peptide, an NPY2R agonist, was tested for toxicity in CD1 mice. Following unexpected mortality in a 4-week study, a 4-day study was conducted to determine the cause. The examination included clinical observations, pathology, and microbiome analysis of jejunal samples. Histopathologic lesions were primarily observed in animals showing clinical signs of toxicity ("responders"), including vacuolation of gastric parietal cells, inflammation, ulcers, and bacterial overgrowth in the small intestine. Occasionally, vacuolation of parietal cells was noted in clinically asymptomatic animals ("non-responders") terminated after 4 days, but not in nonresponders treated for 4 weeks. Microbiome analysis revealed in responders a significantly increased abundance of pathogenic bacteria like Shigella and a significant decrease in probiotic bacteria like Lactobacillus. The altered intestinal microflora resulted in overt dysbiosis, leading to intestinal inflammation, sepsis, and death. The intestinal microbiome appears to be an important factor determining differences in the interindividual susceptibility of mice to Test Peptide treatment. The human relevance of these murine findings is considered low, owing to substantial anatomical and physiological gastrointestinal differences, and the absence of comparable observations in nonhuman primates.