Disease-specific alterations of the enteric nervous system in precancerous colonic mucosa and their implications for mucin regulation.

The dynamics of enteric glial cells (EGCs), the most prevalent cell type of the enteric nervous system (ENS), remain to be fully elucidated. Here, we analyzed the number and spatial distribution of Sox10 + mucosal EGCs in the human lower gastrointestinal tract. In the histologically normal mucosa, an average of 3.5 EGCs were present in each intercrypt region, with a higher concentration near the crypt base. Sex and anatomical location significantly influenced EGC numbers, while aging altered their intramucosal distribution. In both conventional adenomas (CAs) and sessile serrated lesions/polyps (SSLs), two main types of colonic precancerous lesions, EGC numbers were reduced by 80% compared with adjacent mucosa; however, the distribution of residual EGCs differed between these lesions. Neurite density analysis revealed that CAs exhibited overall depletion of ENS components, whereas SSLs showed selective loss of EGCs accompanied by increased vasoactive intestinal peptide (VIP) -positive neurites. In vitro co-culture experiments demonstrated that EGCs attenuate VIP- and its downstream effector cAMP-induced mucin gene expression in colonic epithelial cells via activating the PDK1-RSK pathway. These findings reveal differential alterations of the mucosal ENS between the two precancerous lesions, potentially creating unique microenvironments that contribute to their pathological features, such as mucin overproduction in SSLs.