Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease

• DOI: 10.7554/elife.88051.2
• Publication Date: 2023-12-18T15:20:43Z
• Authors: Subhash Kulkarni; Monalee Saha; Jared Slosberg; Alpana Singh; Sushma Nagaraj; Laren Becker; Chengxiu Zhang; Alicia Bukowski; Zhuolun Wang; Guosheng Liu; Jenna M Leser; Mithra Kumar; Shriya Bakhshi; Matthew J Anderson; Mark Lewandoski; Elizabeth Vincent; Loyal A Goff; Pankaj Jay Pasricha
• Keywords: Enteric Nervous System; Lineage (genetic)

The enteric nervous system (ENS), a collection of neural cells contained in the wall gut, is fundamental importance to gastrointestinal and systemic health. According prevailing paradigm, ENS arises from progenitor migrating crest remains largely unchanged thereafter. Here, we show that lineage composition maturing changes with time, decline canonical neural-crest derived neurons their replacement by newly identified mesoderm-derived neurons. Single cell transcriptomics immunochemical approaches establish distinct expression profile dynamic balance between proportions these two different lineages post-natal gut dependent on availability respective trophic signals, GDNF-RET HGF-MET. With increasing age, become dominant form ENS, change associated significant functional effects intestinal motility which can be reversed GDNF supplementation. Transcriptomic analyses human tissues reduced signaling patients dysmotility reduction crest-derived neuronal markers concomitant increase transcriptional patterns specific Normal function adult tract therefore appears require an optimal within ENS.