Serotonin attenuates tumor necrosis factor-induced intestinal inflammation by interacting with human mucosal tissue

The intestine hosts the largest immune system and peripheral nervous system in the human body. The gut‒brain axis orchestrates communication between the central and enteric nervous systems, playing a pivotal role in regulating overall body function and intestinal homeostasis. Here, using a human three-dimensional in vitro culture model, we investigated the effects of serotonin, a neuromodulator produced in the gut, on immune cell and intestinal tissue interactions. Serotonin attenuated the tumor necrosis factor-induced proinflammatory response, mostly by affecting the expression of chemokines. Serotonin affected the phenotype and distribution of tissue-migrating monocytes, without direct contact with the cells, by remodeling the intestinal tissue. Collectively, our results show that serotonin plays a crucial role in communication among gut–brain axis components and regulates monocyte migration and plasticity, thereby contributing to gut homeostasis and the progression of inflammation. In vivo studies focused on the role of neuromodulators in gut inflammation have shown controversial results, highlighting the importance of human experimental models. Moreover, our results emphasize the importance of human health research in human cell-based models and suggest that the serotonin signaling pathway is a new therapeutic target for inflammatory bowel disease. The gut–brain axis involves communication between the brain and the gut, which is important for maintaining gut health. Here the authors explored this by studying serotonin’s role in gut inflammation using a three-dimensional human cell model. They used intestinal organoids to mimic human gut conditions. These organoids were treated with serotonin and TNF to study their effects on gut cells and immune responses. The researchers found that serotonin reduced TNF-induced inflammation by altering gene expression related to immune cell movement. The study showed that serotonin can decrease the production of certain inflammatory signals in the gut, potentially reducing inflammation. This suggests that targeting serotonin could help treat inflammatory bowel disease (IBD). In conclusion, serotonin plays a role in controlling gut inflammation, offering insights into new treatments for IBD. Future research could explore serotonin’s broader impact on other inflammatory diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.