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Bitter taste receptors (taste 2 receptors, TAS2Rs) serve as warning sensors in the lingual system against the ingestion of potentially poisonous food. Here, we investigated the functional role of TAS2Rs in the human gut and focused on their potential to trigger an additional host defense pathway in the intestine. Human jejunal crypts, especially those from individuals with obesity, responded to bitter agonists by inducing the release of antimicrobial peptides ([alpha]-defensin 5 and regenerating islet-derived protein 3 [alpha] [REG3A]) but also regulated the expression of other innate immune factors (mucins, chemokines) that affected E. coli growth. We found that the effect of aloin on E. coli growth and on the release of the mucus glycoprotein CLCA1, identified via proteomics, was affected by TAS2R43 deletion polymorphisms and thus confirmed a role for TAS2R43. RNA-Seq revealed that denatonium benzoate induced an NRF2-mediated nutrient stress response and an unfolded protein response that increased the expression of the mitokine GDF15 but also ADM2 and LDLR, genes that are involved in anorectic signaling and lipid homeostasis. In conclusion, TAS2Rs in the intestine constitute a promising target for treating diseases that involve disturbances in the innate immune system and body weight control. TAS2R polymorphisms may be valuable genetic markers to predict therapeutic responses., Introduction Bitter is an aversive taste perceived on the tongue that acts as the first defense mechanism to protect our body against the ingestion of potentially poisonous compounds (1). Bitter [...]

Background: Secondary bile acids entrain peripheral circadian clocks and inhibit colonic motility via the bile acid receptor GPBAR1. We aimed to investigate whether chronodisruption affected the rhythm in serum bile acid levels and whether this was associated with alterations in clock gene and Gpbar1 mRNA expression in the colonic smooth muscle layer. We hypothesized that this in turn may affect the rhythm in the inhibitory effect of secondary bile acids on colonic contractility. Methods: Mice were exposed to 4 weeks of chronic jetlag induction. The expression of Gpbar1 and clock genes was measured in colonic smooth muscle tissue using RT‐qPCR over 24 h (4 h time interval). The effect of secondary bile acids on electrical field‐induced neural contractions was measured isometrically in colonic smooth muscle strips. Key Results: Chronic jetlag abolished the rhythmicity in serum bile acid levels. This was associated with a phase‐shift in diurnal clock gene mRNA fluctuations in smooth muscle tissue. Chronic jetlag induced a rhythm in Gpbar1 expression in the colonic smooth muscle layer. In parallel, a rhythm was induced in the inhibitory effect of taurodeoxycholic acid (TDCA), but not deoxycholic acid, on neural colonic contractions that peaked together with Gpbar1 expression. Conclusions & Inferences: Chronodisruption abolished the rhythm in bile acid levels which might contribute to a shift in smooth muscle clock gene expression. Our findings suggest that chronodisruption caused a transcriptional reprogramming in the colonic smooth layer thereby inducing a rhythm in the expression of Gpbar1 and in the inhibitory effect of TDCA on colonic contractility. [ABSTRACT FROM AUTHOR]

Research was conducted to examine the hypothesis that the changes in intestinal contractility that accompanies inflammation of the gut are agonist specific. A comparison of the response of inflamed strips to substance P(SP), motilin, ACh and K+ as a function of time was performed. Results reveals that TNBS-induced colitis in the rabbit alters the contractile response of circular colonic smooth muscle tissue. However, the extent of the change and its time course depends on the stimulus.

Abstract: Ghrelin is an orexigenic peptide present in the stomach with gastroprokinetic properties. Previous in vivo studies have shown that the ghrelin receptor antagonist, D-Lys3-GHRP-6, reduced food intake and delayed gastric emptying in rodents but these effects are at variance with the normal phenotype of the ghrelin knockout mice. To verify the specificity of the effects observed with D-Lys3-GHRP-6 this study aimed to investigate the pharmacology of D-Lys3-GHRP-6 in vitro. Rat fundic strips were suspended in a tissue bath and the contraction of strips to 10−5 M of ghrelin, GHRP-6 or D-Lys3-GHRP-6 was measured isometrically in the absence and presence of blockers. Neither ghrelin, nor GHRP-6, induced significant contractions in the absence of electrical field stimulation thereby excluding the presence of ghrelin receptors on smooth muscle cells. In contrast D-Lys3-GHRP-6, induced a pronounced biphasic contraction of 13.9±1.8% and 40.5±3.2% relative to the response to 60 mM KCl. The contraction was blocked by the 5-HT1,2 receptor antagonist methysergide and was markedly reduced by the 5-HT2B receptor antagonist, yohimbine, which also profoundly affected 5-HT induced contractions in fundic strips. The existence of 5-HT2B receptors in the fundus was confirmed by use of the 5-HT2B receptor agonist, BW 723C86. In contrast to ghrelin and GHRP-6, the ghrelin receptor antagonist, D-Lys3-GHRP-6, induced pronounced smooth muscle contractions in the rat fundus by interacting with 5-HT2B receptors. This may question the role of endogenous ghrelin in the effects observed with D-Lys3-GHRP-6 on food intake and gastric emptying in vivo. [Copyright &y& Elsevier]

Aim: The microbiota shows diurnal oscillations that are synchronized by the host's circadian clock and feeding rhythms. Short‐chain fatty acids (SCFAs) produced by the microbiota are possible synchronizers of peripheral circadian clocks. We aimed to investigate whether faecal SCFAs show a diurnal rhythm that regulates the rhythm of SCFA receptor expression (FFAR2/3, OLFR78, HCAR2) and SCFA‐induced colonic contractility. The role of the circadian clock was studied in mice lacking the core clock gene Bmal1. Methods: Mice were sacrificed at 4‐hour intervals. Faecal SCFA concentrations and SCFA receptor expression were determined. The effect of increasing concentrations of a SCFA mix on electrical field‐induced neural responses in colon strips was measured isometrically. Results: Diurnal fluctuations in faecal SCFA concentrations (peak 4 hours after lights on) were observed that were in phase with the rhythm of Ffar2/3 expression in the colonic muscle layer. Olfr78 expression was not diurnal and Hcar2 was not detectable. The inhibitory effect of a SCFA mix on neural contractions in colonic smooth muscle strips showed a diurnal rhythm and oscillated in phase with faecal SCFA concentrations and Ffar2/3 expression. In contrast, neither excitatory neural responses nor acetylcholine‐induced smooth muscle contractions showed a diurnal rhythm. In Bmal1−/− mice, no fluctuations in faecal SCFA levels, Ffar3 expression and neural responses to SCFAs were observed. Conclusion: Diurnal microbial SCFA levels regulate the rhythm of Ffar3 expression in the colonic myenteric plexus, which causes rhythmicity in SCFA‐induced colonic motility. Deletion of Bmal1 abolishes rhythmicity of SCFA levels and their downstream effects. [ABSTRACT FROM AUTHOR]

Background & Aims: Circadian disturbances result in adverse health effects, including gastrointestinal symptoms. We investigated which physiological pathways in jejunal mucosa were disrupted during chronic jetlag and prevented during time-restricted feeding (TRF). Enteroids from Bmal1 +/+ and Bmal1 -/- mice were used to replicate the processes that were affected by chronic jetlag and rescued by TRF., Methods: C57BL/6J male mice were subjected to chronic jetlag or night-TRF for 4 weeks. An around-the-clock bulk-RNA sequencing study was performed on the jejunal mucosa. Bmal1 +/+ and Bmal1 -/- mouse enteroids were generated to study the jejunal epithelial clock dependency of rhythmic jejunal processes., Results: Chronic jetlag disrupted the rhythmicity of jejunal clock genes and the jejunal transcriptome which was partially rescued by TRF. Genes whose rhythm was altered by chronic jetlag but prevented by TRF were primarily associated with nutrient transport, lipid metabolism, ketogenesis and cellular organization. In vivo, chronic jetlag caused a phase shift in the rhythmic accumulation of neutral lipids and induced a diurnal rhythm in the number of crypt epithelial cells, both of which were prevented by TRF. In vitro, enteroids replicated the in vivo rhythmic accumulation of neutral lipids in a clock-dependent manner, while the rhythm of S phase proliferation was ultradian in both genotypes of enteroids., Conclusions: This pioneering transcriptomic study demonstrates that TRF acts as a robust entrainer during chronic jetlag, realigning disturbances in the circadian clock and the transcriptome involved in metabolic functions in the jejunal mucosa. Enteroids can replicate the rhythmic accumulation of neutral lipids dependent on the jejunal epithelial clock, enabling these functions to be studied in vitro., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)