Abstract
The short chain fatty acids (SCFAs) acetate, butyrate and propionate, are produced by fermentation of non-digestible carbohydrates by the gut microbiota and regulate appetite, adiposity, metabolism, glycemic control, and immunity. SCFAs act at two distinct G protein coupled receptors (GPCRs), FFAR2 and FFAR3 and are expressed in intestinal enteroendocrine cells (EECs), where they mediate anorectic gut hormone release. EECs also express other GPCRs that act as nutrient sensors, thus SCFAs may elicit some of their health-promoting effects by altering GPCR expression in EECs and enhance gut sensitivity to dietary molecules. Here, we identify that exposure of the murine EEC STC-1 cell line or intestinal organoids to physiological concentrations of SCFAs enhances mRNA levels of the umami taste receptors TASR1 and TASR3, without altering levels of the SCFA GPCRs, FFAR2 and FFAR3. Treatment of EECs with propionate or butyrate, but not acetate, increased levels of umami receptor transcripts, while propionate also reduced CCK expression. This was reversed by inhibiting Gαi/o signaling with pertussis toxin, suggesting that SCFAs act through FFAR2/3 to alter gene expression. Surprisingly, neither a FFAR3 nor a FFAR2 selective ligand could increase TASR1/TASR3 mRNA levels. We assessed the functional impact of increased TASR1/TASR3 expression using unique pharmacological properties of the umami taste receptor; namely, the potentiation of signaling by inosine monophosphate. Activation of umami taste receptor induced inositol-1-phosphate and calcium signaling, and butyrate pretreatment significantly enhanced such signaling. Our study reveals that SCFAs may contribute to EEC adaptation and alter EEC sensitivity to bioactive nutrients.
Highlights
After ingestion, physical, and chemical processes digest food into a large and dynamic array of metabolites within the gastrointestinal (GI) tract
To determine whether short-chain fatty acids (SCFAs) can influence the expression of taste G protein coupled receptors (GPCRs), STC-1 cells were incubated for 2 h with SCFAs in a 3:1:1 molar ratio of acetate:propionate:butyrate at 5 or 10 mM chosen to reflect the physiological SCFA concentrations in the proximal and distal colon [3, 4]. qPCR was used to analyze the relative changes in expression of the transcripts of TAS1R1, TAS1R2, TAS1R2, TAS2 [108], and TAS2 [138]
Of particular note was the substantial upregulation of the umami taste receptor subunits, as the expression profile of these is significantly different in the GI tract of obese individuals when compared with lean controls [20, 21]
Summary
Physical, and chemical processes digest food into a large and dynamic array of metabolites within the gastrointestinal (GI) tract. Of particular note are colonic short-chain fatty acids (SCFAs), the anaerobic fermentation of non-digestible carbohydrates, components of high-fiber diets. These are carboxylic acids with fewer than six carbons (Cs), which can reach high luminal concentrations of 10−1 M [2, 3]. Ninety-five percent of the SCFAs produced in the GI tract are acetate (2Cs), propionate (3Cs) and butyrate (4Cs) [3, 4]. These SCFAs, in particular propionate, are currently of interest, because of their ability to regulate anorectic gut hormone release, and to promote weight loss, reduce abdominal adiposity and improve insulin sensitivity [5,6,7,8]
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