Chronic gastrointestinal inflammation in cats is a complex condition associated with an exaggerated immune re-sponse, but the exact cause of this condition is largely unknown. The diagnosis and differentiation from intestinal small-cell lymphoma (EATL) is challenging, and treatment options are currently limited to drugs with the potential to have significant adverse effects. S100A8/A9 (calprotectin) and S100A12 are signaling molecules of the innate immune response, and by binding to their immune receptors (Toll-like receptor-4 and the receptor for advanced glycation end-products) can perpetuate or even amplify inflammatory processes. These small molecules’ signaling pathways include attractive targets for developing disease-specific non-invasive biomarkers and new avenues to pathway-specific treatment of affected cats. In previous studies, we found fecal S100A8/A9 concentrations in-creased in cats with chronic gastrointestinal inflammation and very low in a large number of healthy cats. We have developed antibodies to detect S100A8/A9 and S100A12 in dogs and have shown that these antibodies cross-react with the analogous proteins in cats. In a multi-center effort, we will further explore the role of S100A8/A9 and S100A12 in the complex pathogenesis of feline chronic gastrointestinal inflammation. We will also evaluate whether the fecal S100A8/A9 concentration is a clinically useful non-invasive biomarker to diagnose and reflect the severity of chronic gastrointestinal inflammation in cats and distinguish chronic gastrointestinal inflammation from feline EATL. Our results will have important clinical implications by providing a non-invasive tool for the diagnosis and routes for developing novel disease-specific treatment options for cats with chronic gastrointestinal inflammation.