Depression of tryptophan may contribute to adverse effects of naproxen

Non-steroidal anti-inflammatory drugs are popular choices for the mitigation of pain and inflammation; however, they are accompanied by adverse effects in the gastrointestinal and cardiovascular systems. Identifying biomarkers and mechanisms for early gastrointestinal or cardiovascular disease detection is desirable. Here we compare the effects of placebo, naproxen, a traditional NSAID, and celecoxib, a cyclooxygenase 2 inhibitor and find a decrease in tryptophan and kynurenine levels in the plasma of healthy volunteers who receive naproxen. We further validate this result in mice. Depression of tryptophan is independent of inhibition of either cyclooxygenase but rather, is due to the displacement of bound tryptophan by naproxen. Supplementation of tryptophan in naproxen-treated mice rescues fecal blood loss and inflammatory gene expression driven by IL-1β in the heart. Furthermore, tryptophan also rescues changes in genes that are reflective of inflammation and tissue damage in the gut.