Besides the brain, the gastrointestinal tract has the highest number of neurons in the entire body. The enteric nervous system (ENS) is often referred to as the second brain as it commands all manner of intestinal function, from nutrient absorption to defecation control. In patients suffering from Inflammatory Bowel Disease (IBD), the ENS undergoes major disruption resulting in many debilitating complications impacting the quality of life. We have recently uncovered that the ENS also controls intestinal inflammation and regulates the balance of “good” vs. “bad” bacteria in the gut. As the ENS has the unique capacity to rapidly relay signals from the gut directly to the brain and, by extension, to all other organs, we hypothesized that ENS might act as front-line sensors of gut inflammation to warn the body of impending infections. Our preliminary data indicate that when intestinal neurons are activated, they can trigger inflammation in other organs to protect against bacterial invasion. This novel protective mechanism has never been reported before and in this project, we aim to elucidate this unknown pathway of inflammation. Going forward, we will further explore if this axis is aberrantly activated during chronic intestinal inflammation and if it directly contributes to non-intestinal inflammatory complications exhibited in patients with IBD to aid in novel therapeutic design.