Abstract
Innervation of the intestinal mucosa has gained more attention with demonstrations of tuft and enteroendocrine cell innervation. However, the role(s) these fibers play in maintaining the epithelial and mucus barriers are still poorly understood. This study therefore examines the proximity of mouse ileal goblet cells to neuronal fibers, and the regulation of goblet cell production by vasoactive intestinal peptide (VIP). An organotypic intestinal slice model that maintains the cellular diversity of the intestinal wall ex vivo was used. An ex vivo copper‐free click‐reaction to label glycosaminoglycans was used to identify goblet cells. Pharmacological treatment of slices was used to assess the influence of VIP receptor antagonism on goblet cell production and neuronal fiber proximity. Goblet cells were counted and shown to have at least one peripherin immunoreactive fiber within 3 µm of the cell, 51% of the time. Treatment with a VIP receptor type I and II antagonist (VPACa) resulted in an increase in the percentage of goblet cells with peripherin fibers. Pharmacological treatments altered goblet cell counts in intestinal crypts and villi, with tetrodotoxin and VPACa substantially decreasing goblet cell counts. When cultured with 5‐Ethynyl‐2’‐deoxyuridine (EdU) as an indicator of cell proliferation, colocalization of labeled goblet cells and EdU in ileal crypts was decreased by 77% when treated with VPACa. This study demonstrates a close relationship of intestinal goblet cells to neuronal fibers. By using organotypic slices from mouse ileum, vasoactive intestinal peptide receptor regulation of gut wall goblet cell production was revealed.
Highlights
Gut luminal microbiota are separated from the small intestinal epithelial barrier by an nonadherent mucus layer in the small intestine (Kaelberer et al, 2018)
The current study addresses the impact of neural regulation on gut wall goblet cells in an organotypic model of gut physiology that maintains numerous cell types ex vivo, including goblet cells and neurons
This study provides an anatomical basis for neural signaling to enteric goblet cells of the epithelial layer and shows the selective impact of vasoactive intestinal peptide (VIP) receptors on goblet cell production
Summary
Gut luminal microbiota are separated from the small intestinal epithelial barrier by an nonadherent mucus layer in the small intestine (Kaelberer et al, 2018). This is partially due to investigations using monolayer epithelial culture models that until recently did not contain a mucus layer (Wang, Kim, Sims, & Allbritton, 2019) While this is an advance, epithelial culture systems miss the cellular diversity of the gut wall, a critical aspect of in vivo physiologic function (McLean, Schwerdtfeger, Tobet, & Henry, 2018; Schwerdtfeger & Tobet, 2019). The sodium ion channel blocker tetrodotoxin (TTX), which blocks large amounts of enteric neuronal signaling (Osorio, Korogod, & Delmas, 2014), and VPACa, an antagonist for both VIP receptors (Pandol et al, 1986) These ex vivo pharmacological treatments were coupled with molecular visualization tools to reveal anatomical bases for neuronal fiber signaling with ileal goblet cells. This study suggests a specific role for neuronal fibers containing VIP to play in regulating intestinal goblet cell production
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