Cinnamaldehyde Induces Release of Cholecystokinin and Glucagon-Like Peptide 1 by Interacting with Transient Receptor Potential Ankyrin 1 in a Porcine Ex-Vivo Intestinal Segment Model

SIMPLE SUMMARY: The gut is able to “sense” nutrients and release gut hormones to regulate digestive processes. Accordingly, various gastrointestinal cell types possess transient receptor potential channels, cation channels involved in somatosensation, thermoregulation and the sensing of pungent and spicy substances. Recent research shows that both channels are expressed in enteroendocrine cell types responsible for the release of gut peptide hormones such as Cholecystokinin (CCK) and Glucagon-like Peptide-1 (GLP-1). A large array of herbal compounds, used in pig nutrition mostly for their antibacterial and antioxidant properties, are able to activate these channels. Cinnamaldehyde, occurring in the bark of cinnamon trees, acts as an agonist of Transient Receptor Potential Ankyrin 1 (TRPA1)-channel. Capsaicin, the active component of chili peppers, acts as an agonist of Transient Receptor Potential Vanilloid 1 (TRPV1)-channel. This study explored the ability of both compounds to stimulate the release of CCK and GLP-1, and whether this response was mediated by TRP channels, using an ex-vivo intestinal segment model. Results showed mainly the potential of cinnamaldehyde to interact with TRPA1 and trigger CCK and GLP-1 release, while yet being dependent on the location in the small intestine. ABSTRACT: Cinnamaldehyde and capsaicin have been reported to exert effects on the gastric function, mediated by the interaction with transient receptor potential ankyrin channel 1 (TRPA1) and transient receptor potential vanilloid channel 1 (TRPV1), respectively. This study examined whether these compounds could trigger the release of cholecystokinin (CCK) and/or glucagon-like peptide 1 (GLP-1) in the pig’s gut in a porcine ex-vivo intestinal segment model. Furthermore, it was verified whether this response was mediated by TRPA1 or TRPV1 by using the channel’s antagonist. These gut peptides play a key role in the “intestinal brake”, a feedback mechanism that influences the function of proximal parts of the gut. Structural analogues of cinnamaldehyde were screened as well, to explore structure-dependent activation. Results showed a significant effect of capsaicin on GLP-1 release in the proximal small intestine, TRPV1 independent. TRPA1 showed to be strongly activated by cinnamaldehyde, both in proximal and distal small intestine, evidenced by the release of CCK and GLP-1, respectively. Out of all structural derivates, cinnamaldehyde showed the highest affinity for TRPA1, which elucidates the importance of the α,β-unsaturated aldehyde moiety. In conclusion, cinnamaldehyde as a TRPA1 agonist, is a promising candidate to modulate gastric function, by activating intestinal brake mechanisms.