Increased colonic bile acid (BA) exposure, frequent in diarrhea‐predominant irritable bowel syndrome (IBS‐D), can affect gut function. Nerve growth factor (NGF) is implicated in the development of visceral hyper‐sensitivity (VH). In this study, we tested the hypothesis that BAs cause VH via mucosal mast cell (MMC)‐to‐nociceptor signaling, which involves the farnesoid X receptor (FXR)/NGF/transient receptor potential vanilloid (TRPV)1 axis. BAs were intracolonically administered to rats for 15 d. Visceral sensitivity to colorectal distention and colonic NGF expression were examined. BAs caused VH, an effect that involved MMC‐derived NGF and was accompanied by enhanced TRPV1 expression in the dorsal root ganglia. Anti‐NGF treatment and TRPV1 antagonism inhibited BA‐induced VH. BAs induced NGF mRNA and protein expression and release in cultured mast cells. Colonic supernatants from patients with IBS‐D with elevated colonic BA content transcriptionally induced NGF expression. In FXR−/− mice, visceral sensitivity and colonic NGF expression were unaltered after BA treatment. Pharmacological antagonism and FXR silencing suppressed BA‐induced NGF expression and release in mast cells. Mitogen‐activated protein kinase kinase (MKK) 3/6/p38 MAPK/NF‐κB signaling was mechanistically responsible for FXR‐mediated NGF expression and secretion. The findings show an MMC‐dependent and FXR‐mediated pronociceptive effect of BAs and identify the BA/FXR/NGF/TRPV1 axis as a key player in MMC‐to‐neuron communication during pain processing in IBS.—Li, W.‐T., Luo, Q.‐Q., Wang, B., Chen, X., Yan, X.‐J., Qiu, H.‐Y., Chen, S.‐L. Bile acids induce visceral hypersensitivity via mucosal mast cell–to–nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis. FASEB J. 33, 2435–2450 (2019). http://www.fasebj.org

This study was carried out to investigate the effects of tributyrin (TB) on the growth performance, pro-inflammatory cytokines, intestinal morphology, energy status, disaccharidase activity, and antioxidative capacity of broilers challenged with lipopolysaccharide (LPS). A total of 160 one-day-old Cobb broilers were allocated to 1 of 4 treatments, with 4 replicated pens per treatment and 10 birds per pen. The experiment consisted of a 2×2 factorial arrangements of treatments with TB supplementation (0 or 500 mg/kg) and LPS challenge (0 or 500 μg/kg body weight [BW]). On days 22, 24, and 26 of the trial, broilers received an intraperitoneal administration of 500 μg/kg BW LPS or saline. Dietary TB showed no effect on growth performance. However, LPS challenge decreased the average daily gain of broilers from day 22 to day 26 of the trial. Dietary TB supplementation inhibited the increase of interleukin-1β (in the jejunum and ileum), interleukin-6 (in the duodenum and jejunum), and prostaglandin E2 (in the duodenum) of LPS-challenged broilers. Similar inhibitory effects of TB in the activities of total nitric oxide synthase (in the ileum) and inducible nitric oxide synthase (in the jejunum) were also observed in birds challenged with LPS. Additionally, TB supplementation mitigated the decrease of ileal adenosine triphosphate, adenosine diphosphate and total adenine nucleotide and the reduction of jejunal catalase activity induced by LPS. Taken together, these results suggest that the TB supplementation was able to reduce the release of pro-inflammatory cytokines and improve the energy status and anti-oxidative capacity in the small intestine of LPS-challenged broilers.

Background Psychological factors contribute to the pathogenesis of functional dyspepsia (FD). Antidepressant agents are beneficial in treatment of refractory FD. However, their efficacy is greatly hindered by the poor treatment adherence. Stigma is present in patients with chronic diseases or mental disorders and could affect adherence. The present study was aimed to evaluate stigma prevalence in FD patients and to explore the impact of stigma on treatment adherence to antidepressants. Methods Functional dyspepsia patients unsatisfied with the regular first‐line treatment and received newly initiated antidepressant medicine were recruited and subjected to antidepressant treatment for 8 weeks. Stigma scales and symptom scores of dyspepsia, depression, and anxiety were analyzed before and after treatment. Associations between stigma and medication adherence were evaluated. Key results One hundred and ten of the enrolled 138 participants reported minimal disease‐related internalized stigma, and 28 reported mild stigma before antidepressant therapy. Male gender, lower education, and higher scores of dyspepsia, depression, and anxiety were predictors of stigma before treatment. The mean stigma scores increased after 8‐week antidepressant treatment. A proportion (36.4%‐89.9%) of patients showed stigma attached to antidepressant therapy in the 4‐question survey. Post‐treatment stigma scores negatively correlated with treatment adherence and efficacy. Patients with decreased post‐treatment stigma scores displayed better medication adherence and symptom improvement compared to those with elevated or unaltered post‐treatment stigma scores. Conclusions Patients with refractory FD report stigma attached to the disease and antidepressants. It is an obstacle to treatment adherence and efficacy of antidepressant medication in FD therapy.

Background Psychological stress is an important factor for the development and recurrence of irritable bowel syndrome (IBS). The mechanisms underlying stress‐induced visceral hypersensitivity (VH), a key pathophysiological component in IBS, are still incompletely understood. We aimed to test whether transient receptor potential melastatin 8 (TRPM8) participates in acute stress–induced VH. Methods Rats were subjected to 1‐hour water avoidance stress (WAS). Visceral sensitivity was measured with visceromotor response to colorectal distension. Western blot and immunofluorescence were applied to evaluate the expression of GR and TRPM8 and activation of PKA, Akt, and PKC pathways. Results WAS‐caused VH depended on glucocorticoid receptors (GRs) and TRPM8 channels. In a dorsal root ganglion (DRG)–derived cell line, corticosterone rapidly (within 30 minutes) induced membrane expression of TRPM8. This effect was inhibited by GR antagonism and was mimicked by membrane‐impermeable corticosterone. PKA, PI3K/Akt, and PKC pathways, which lied downstream of GR and acted in parallel to promote membrane expression of TRPM8, contributed to WAS‐induced VH. The non‐receptor tyrosine kinase Pyk2, which may serve as a convergence point for PKA, PI3K/Akt, and PKC pathways, facilitated membrane insertion of TRPM8 via tyrosine‐phosphorylating TRPM8 in L6‐S2 DRGs and participated in WAS‐induced VH. Conclusions Collectively, acute stress–induced VH could involve membrane‐bound GR‐dependent enhancement of TRPM8 function in nociceptive DRG neurons. Mechanistically, Pyk2 could act as a key mediator that coordinates multiple protein kinase signaling and triggers phosphorylation and membrane insertion of TRPM8.

Appropriate clinician-patient communication regarding the reasons for prescribing psychoactive drugs that emphasizes both the psychological and GI mechanisms might improve adherence to FM in patients with FD.

BackgroundEvidence suggests that circadian rhythm disorder is associated with a variety of gastrointestinal diseases, and the circadian rhythm plays a key role in maintaining the homeostasis of intestinal flora. The underlying mechanisms are still not completely identified. This study was aimed to explore whether jet lag-caused circadian disruption influences gut microbiome and its metabolites.MethodsMice were synchronized with 12-h light/dark cycles (control group) or subjected to daily 8-h advance of the light/dark cycle for every 3 days (jet-lagged group). Four months later, fecal samples and jejunal contents were collected and analyzed by 16S rRNA gene sequencing. In addition, fecal samples were subjected to metabolome analysis with ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS).ResultsThe results of 16s rRNA sequencing showed that chronic jet lag led to decreased microbial abundance, richness, and diversity in both feces and jejunal contents. ANOSIM analysis revealed significant difference between control and jet-lagged groups. As the colonic microbiome, the abundance of Bacteroidetes phylum was significantly decreased and that of Actinobacteria phylum was increased in jet-lagged mice. Jet lag increased the ratio of Firmicutes to Bacteroidetes, an indicator for the imbalance of gut microbiota. Metabolome analysis of fecal samples showed that the levels of tryptophan and its derivatives were decreased in jet-lagged mice. In addition, fecal levels of secondary bile acids changed under jet lag conditions. Correlation analysis identified associations between tryptophan (and its derivatives) levels and colonic microbiota.ConclusionsThis study presents a comprehensive landscape of gut microbiota and its metabolites in mice subjected to chronic jet lag. The results suggest that circadian disruption may lead to changes in fecal and jejunal microbiota and fecal metabolites. Moreover, our results demonstrate a novel interplay between the gut microbiome and metabolome.

Background/AimsAntidepressants are effective in patients with functional dyspepsia (FD). However, stigma associated with FD and antidepressants may affect treatment adherence. This study aims to explore possible communication strategies to alleviate stigma and improve adherence in patients with FD. MethodsIn this randomized, single-center, and single-blind trial, 160 patients with FD initiating antidepressant treatment were recruited. Different communication strategies were performed when prescribing antidepressants. Participants in Group 1 were told that brain is the "headquarters" of gut, and that antidepressants could act as neuromodulators to relieve symptoms of FD through regulating the functions of gut and brain. Participants in Group 2 were told that antidepressants were empirically effective for FD. Stigma scores, medication-related stigma, treatment compliance, and efficacy were analyzed. ResultsAfter 8-week antidepressant treatment, the proportion of patients with FD with decreased stigma scores in Group 1 was significantly higher than in Group 2 (internalized stigma: 64.10% vs 12.00%; perceived stigma: 55.13% vs 13.33%; P < 0.01). Medication-related stigma was lower in Group 1 than in Group 2 (P < 0.05 for 3 of 4 questions). Concurrently, patients in Group 1 had better treatment compliance (0.71 ± 0.25 vs 0.60 ± 0.25, P < 0.01) and efficacy. In Group 1, participants with decreased post-treatment stigma scores showed better treatment compliance and efficacy than those with non-decreased scores. Decrease in stigma scores positively correlated with treatment compliance. ConclusionImproving knowledge of patients with FD of the disease and antidepressants via proper communication may be an effective way to alleviate stigma and promote adherence.

Background: Bowel preparation is essential to the success of colonoscopy. However, many patients cannot finish the preparation due to nausea and vomiting when taking polyethylene glycol (PEG). Dopamine-2 receptor antagonists, such as domperidone and sulpiride, are classical antiemetic drugs. This study aimed to explore the effect of domperidone and sulpiride on reducing the discomforts associated with PEG. Methods: Patients scheduled for colonoscopy were enrolled and randomly allocated into 3 groups. Patients in the domperidone group (Dom group) or sulpiride group (Sul group) took 2 doses of domperidone or sulpiride before PEG. Patients in the control group (Con group) followed the regular routine of PEG. Discomforts during bowel preparation and the quality of bowel preparation were assessed. Results: A total of 306 patients were enrolled. The participants in the Dom group and Sul group completed PEG better and had fewer abdominal discomforts than those in the Con group. The severity of nausea and abdominal fullness was lower in the Dom group and Sul group. The quality of bowel preparation was better in the Dom group and Sul group than Con group. Conclusions: Domperidone and sulpiride could reduce the PEG-related discomfort and improve the quality of bowel preparation. This method may be a promising way to improve the satisfaction of bowel preparation for both patients and endoscopists.