Neural FFA3 Negatively Regulates Cholinergic Secretory Function in Rat Proximal Colon

Abstract

The lumen of the proximal colon is continuously exposed to high concentrations of short‐chain fatty acids (SCFAs). Although propionate evokes transient anion secretion via neural and non‐neural cholinergic pathways in the colon, the involvement of FFA3 (GPR41) and its absorptive pathway have not been clarified. We investigated the expression of FFA3 and its contribution towards propionate‐ and carbachol (CCh)‐induced secretory responses in rat proximal colon. FFA3 immunolocalized to the enteroendocrine cells and to the enteric neural plexuses. Most of the FFA3‐immunoreactive nerve fibers were cholinergic, based on staining with ChAT, a vesicular ACh transporter, and the high affinity choline transporter CHT1. In Ussing chambered proximal colon, luminal propionate induced anion secretion in fasted, but not fed conditions. TTX or atropine reduced the response to propionate by 60% or 94%, respectively. In the presence of indomethacin, the non‐substrate sodium‐dependent monocarboxylate transporter (SMCT)1 inhibitor ibuprofen or fenoprofen abolished the response to propionate, without inhibition on CCh‐evoked secretion. CCh‐induced secretion was decreased by TTX or serosal propionate by 40%. Serosal application of the FFA3 agonist decreased the response to propionate and CCh, indicating that FFA3 negatively regulates cholinergic neural reflexes. These results suggest that luminal propionate‐induced anion secretion is dependent on SMCT1‐mediated SCFA absorption, which in turn varies cholinergic nerve activity.Supported by VA Merit Review, NIH R01 DK54221