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 (α-defensin 5 and regenerating islet–derived protein 3 α [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.

We used time-restricted feeding (TRF) to investigate whether microbial metabolites and the hunger hormone ghrelin can become the dominant entraining factor during chronic jetlag to prevent disruption of the master and peripheral clocks, in order to promote health. Therefore, hypothalamic clock gene and Agrp/Npy mRNA expression were measured in mice that were either chronically jetlagged and fed ad libitum, jetlagged and fed a TRF diet, or not jetlagged and fed a TRF diet. Fecal short-chain fatty acid (SCFA) concentrations, plasma ghrelin and corticosterone levels, and colonic clock gene mRNA expression were measured. Preventing the disruption of the food intake pattern during chronic jetlag using TRF restored the rhythmicity in hypothalamic clock gene mRNA expression of Reverbα but not of Arntl. TRF countered the changes in plasma ghrelin levels and in hypothalamic Npy mRNA expression induced by chronic jetlag, thereby reestablishing the food intake pattern. Increase in body mass induced by chronic jetlag was prevented. Alterations in diurnal fluctuations in fecal SCFAs during chronic jetlag were prevented thereby re-entraining the rhythmic expression of peripheral clock genes. In conclusion, TRF during chronodisruption re-entrains the rhythms in clock gene expression and signals from the gut that regulate food intake to normalize body homeostasis.

The direct infusion of bitter solutions in the gastrointestinal tract can reduce the secretion of orexigenic hormones and influence appetite and food intake. We aimed to explore whether oral ingestion of the bitter tastant hydroxychloroquine sulfate can exert similar effects. Ten lean adult women were included in this double-blind, randomized, two-visit, crossover study. After an overnight fast, each volunteer received film-coated tablets containing 400 mg of hydroxychloroquine sulfate (Plaquenil^®) or placebo. Plasma-ghrelin, -motilin, -insulin and blood-glucose concentrations were determined every 10 min before and 30 min after feeding; appetite was scored every 10 min. Hunger scores were investigated with a special interest 50–60 min after the ingestion of hydroxychloroquine sulfate, right before a rewarding chocolate milkshake was offered to drink ad libitum. Compared with the placebo, hydroxychloroquine sulfate tended to reduce hunger at the time of interest (p = 0.10). No effect was found upon subsequent milkshake intake. Motilin plasma concentrations were unaltered, but acyl-ghrelin plasma concentrations decreased after the ingestion of hydroxychloroquine sulfate (t = 40–50; p < 0.05). These data suggest that the oral intake of hydroxychloroquine sulfate tablets reduces subjective hunger via a ghrelin-dependent mechanism but does not affect motilin release, hedonic food intake or insulin levels in healthy women.

Objectives: To determine whether a fetal lamb model reproducibly induces complex gastroschisis at term with its associated structural and functional bowel changes, and to compare its occurrence and associated bowel findings at different post-induction intervals. Methods: Gastroschisis was surgically induced in fetal lambs at gestational day 75 by creating a standardized abdominal wall defect stabilized with a silicone ring. Fetuses were assessed at term or at mid-gestation (13–21 days after induction), using non-operated littermates as controls. The primary outcome was occurrence of complex gastroschisis (bowel stenosis, atresia, volvulus, perforation, or necrosis) in survivors. At mid-gestation, this was compared between early (13–16 days) and late (17–21 days) groups, using Fisher’s exact test. Sample size for the primary outcome at term was determined a priori (α=0.05, 80% power). Mid-gestation sample size was determined using the same statistical assumptions, informed by an initial exploratory cohort. Secondary outcomes included prenatal and in vivo imaging, ex vivo bowel contractility, amniotic fluid composition, and histology. Results: Gastroschisis was induced in 32 fetuses. In the term cohort (n=14), 50% survived (7/14); all survivors had complex gastroschisis, with impaired bowel motility, altered enteric neural contractile responses, and smooth muscle remodeling compared with controls. Among fetuses assessed at mid-gestation (n=18), two died in utero; complex gastroschisis occurred more frequently in the late (5/7, 71%) than in the early (1/9, 11%; p =.04) group. Mid-gestation fetuses with gastroschisis had greater intra-abdominal bowel dilation on ultrasound and higher amniotic fluid digestive enzyme levels than controls, with the greatest dilation in fetuses with complex gastroschisis. Conclusions: This fetal lamb model reproducibly induced complex gastroschisis with structural and functional bowel changes in surviving lambs at term. Complex gastroschisis occurred more frequently at 17–21 than at 13–16 days after induction. At mid-gestation, fetuses with gastroschisis showed greater bowel dilation and differences in amniotic fluid composition than controls, whereas structural and functional bowel changes were not detected.

We would like to thank Erren et al.