A transcriptional atlas of gut-innervating neurons reveals activation of interferon signaling and ferroptosis during intestinal inflammation.

Enteric infections often cause long-term sequelae, including persistent gastrointestinal symptoms, such as pain, discomfort, or irritable bowel syndrome. The plethora of sensory symptoms indicates that gut-innervating neurons might be directly affected by inflammation. However, sequencing studies of neurons in the gastrointestinal tract are hampered by difficulties in purifying neurons, especially during inflammation. Activating a nuclear GFP tag selectively in neurons enabled sort purification of intrinsic and extrinsic neurons of the gastrointestinal tract in models of intestinal inflammation. Using bulk and single-nucleus RNA sequencing, we mapped the whole transcriptomic landscape and identified a conserved neuronal response to inflammation, which included the interferon signaling and ferroptosis pathway. Deletion of the interferon receptor 1 in neurons regulated ferroptosis, neuronal loss, and consequently gut-transit time. Collectively, this study offers a resource documenting neuronal adaptation to inflammatory conditions and exposes the interferon and ferroptosis pathways as signaling cascades activated in neurons during inflammation.