Activation of endocrine and innate immune responses by tastants in the human gut epithelium: impact of obesity

Activation of endocrine and innate immune responses by tastants in the human gut epithelium: impact of obesity

The expression of taste receptors similar to those in the lingual system has been demonstrated in several cell types with distinct functions in the gastrointestinal tract. In obesity, the expression of these receptors in the gut is altered, which may affect their functional response to tastants. We aimed to unravel the role of bitter (hTAS2Rs) and sweet taste receptors in regulating the secretion of the hunger hormone ghrelin and in the induction of innate immune responses (mucins from goblet cells and antimicrobial peptides (AMPs) such as defensins from Paneth cells) at the cellular level in the human gut epithelium of lean and obese subjects. We showed that obesity is characterized by impaired basal ghrelin protein production and adrenalin-induced ghrelin secretion in primary fundic cultures. Bitter agonists selective for hTAS2R5 and hTAS2R10 stimulated ghrelin secretion in fundic cells, while glucose inhibited ghrelin secretion via SGLT1 and sweet taste receptors. Obesity altered the mRNA expression of some TAS2Rs and glucose sensors in the gut mucosa and affected the sensitivity of the ghrelin cell to tastants in a region-dependent manner. Sweet taste receptor activation inhibited bitter taste signaling of the ghrelin cell. In innate immune cells, bitter agonists regulated the mRNA and/or protein expression of some innate immune markers such as defensins and mucins in the human jejunal crypts, especially in obese subjects. The effect of the bitter agonist denatonium benzoate (DB) on α-defensin 6 mRNA expression was hTAS2R43-dependent, and hTAS2R10 was demonstrated in Paneth cells. The supernatant of jejunal crypts stimulated with phenylthiocarbamide (hTAS2R38) and 1,10-phenanthroline (hTAS2R5) inhibited E. coli growth and biofilm formation respectively, indicating a role of bitter agonists in the release of AMPs from Paneth cells. In contrast, some bitter agonists enhanced E. coli growth, suggesting the release of molecules from other epithelial cells such as mucins from goblet cells.

In conclusion, bitter and/or sweet taste receptors regulate not only gut hormone secretion but also innate immune responses in the human gut epithelium and may provide new therapeutic targets for the regulation of appetite and immune disorders.