The Enteric Nervous System Primes Systemic Immunity in Response to Mucosal Infection 2258662

Abstract Introduction The enteric nervous system (ENS) is essential for gastrointestinal (GI) function and has recently been implicated in regulating immune activity at mucosal sites. However, its broader contributions to systemic immunity remain unclear. Because the ENS interfaces with extrinsic neural circuits, it is well-positioned to relay information between the gut and peripheral tissues. We hypothesized that enteric neurons detect disturbances in intestinal immune homeostasis and transmit signals that coordinate systemic defenses. Methods To test this, we combined an in vivo infection-challenge paradigm in mice with manipulations of ENS activity and measured downstream immune readouts. We also used ex vivo cultures to assess how enteric neurons respond to microbial cues. Results Our findings indicate that activating the ENS promotes rapid protective responses in distal organs. Upon stimulation, enteric neurons released inflammatory mediators, supporting the mobilization of innate immune cells to both intestinal and peripheral sites. Modulating ENS activity altered host susceptibility to a subsequent systemic challenge. Conclusion Together, these results suggest that the ENS functions as a sensor-effector hub, linking local GI infection to rapid, body-wide immune responses, and highlighting a previously understudied role for the ENS in systemic host defenses. Funding Source n/a Topic Categories Neuroimmunology (NEUR)