Studies on role of neuronalandnon neuronaltrpa1 channels in the action of prebiotics derived short chain fatty acids

Abstract

The TRPA1 channel, expressed on non-neuronal enteroendocrine cells, has been extensively studied for stimulating gut hormone secretion. Studies have shown that saturated fatty acids (SCFAs) potentiate gut hormone release, induce satiety, and prevent obesity. However, the involvement of non-neuronal TRPA1 channels in SCFA-induced gut hormone secretion has not been explored. In the first objective, we aimed to study the effect of SCFAs on TRPA1 channel activity and its involvement in intra cellular calcium signaling and vesicular exocytosis of gut hormones. Results showed that TRPA1 partially mediates SCFA-induced elevation in intracellular calcium levels, increases protein expression of TRPA1 in STC-1 enteroendocrine L-cells, and regulates changes in genes involved in calcineurin signaling, preproglucagon-derived gut hormone production, and vesicular exocytosis of gut hormones. In conclusion, non- neuronal TRPA1 acts as additional sensor for SCFA and mediates stimulatory effect of SCFAs on gut hormone synthesis and release. newlineTRPA1 sensory neurons in the gut are implicated in intestinal pain and inflammatory conditions like IBD and colitis. Inhibition of these neurons has been proposed as a therapeutic strategy. Capsazepine, a selective TRPV1 antagonist, desensitizes TRPA1/TRPV1 expressing sensory neurons, ameliorating pain and colitis in mice. However, their physiological role in intestinal mucosal health remains unexplored. newlineThis thesis explores the role of non-neuronal and neuronal TRPA1 channels in maintaining gut homeostasis. Non-neuronal TRPA1 in the STC-1 cell line partially regulates SCFA-induced gut hormone release, while neuronal nociceptive TRPA1 channels play a role in colonic mucosal health. Functional modulation of these channels influences the negative consequences of HFD and the protective actions of prebiotic-derived SCFAs. These findings have clinical significance and caution should be exercised when using TRP-based strategies for colitis-induced pain. newline newline