Irritable bowel syndrome: Epidemiology, overlap disorders, pathophysiology and treatment.

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disease with a significant impact on patients' quality of life and a high socioeconomic burden. And the understanding of IBS has changed since the release of the Rome IV diagnosis in 2016. With the upcoming Rome V revision, it is necessary to review the results of IBS research in recent years. In this review of IBS, we can highlight future concerns by reviewing the results of IBS research on epidemiology, overlap disorders, pathophysiology, and treatment over the past decade and summarizing the latest research.

Small noncoding vault RNA2-1 disrupts gut epithelial barrier function via interaction with HuR.

Vault RNAs (vtRNAs) are small noncoding RNAs and highly expressed in many eukaryotes. Here, we identified vtRNA2-1 as a novel regulator of the intestinal barrier via interaction with RNA-binding protein HuR. Intestinal mucosal tissues from patients with inflammatory bowel diseases and from mice with colitis or sepsis express increased levels of vtRNAs relative to controls. Ectopically expressed vtRNA2-1 decreases the levels of intercellular junction (IJ) proteins claudin 1, occludin, and E-cadherin and causes intestinal epithelial barrier dysfunction in vitro, whereas vtRNA2-1 silencing promotes barrier function. Increased vtRNA2-1 also decreases IJs in intestinal organoid, inhibits epithelial renewal, and causes Paneth cell defects ex vivo. Elevating the levels of tissue vtRNA2-1 in the intestinal mucosa increases the vulnerability of the gut barrier to septic stress in mice. vtRNA2-1 interacts with HuR and prevents HuR binding to claudin 1 and occludin mRNAs, thus decreasing their translation. These results indicate that vtRNA2-1 impairs intestinal barrier function by repressing HuR-facilitated translation of claudin 1 and occludin.

A Breakthrough Point in Integrative Medical Research: Challenge of Treating Overlapping Symptoms in Functional Gastrointestinal Disorders.

Functional gastrointestinal disorders (FGIDs) are common disorders that are characterized by persistent and recurring gastrointestinal symptoms. Many patients with FGIDs have overlapping symptoms, which impaired the quality of life and ability to work of patients, and left a considerable impact on health-care systems and society. Chinese medicines (CMs) are commonly utilized by many patients with FGIDs. This article discusses the current status of diagnosis and treatment of FGIDs, the advantages and characteristics of CM treatment, and how integrated medicine can make a breakthrough in FGIDs diagnosis and treatment.

Circular RNA CircHIPK3 Promotes Homeostasis of the Intestinal Epithelium by Reducing MicroRNA 29b Function.

BACKGROUND & AIMS: Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that form covalently closed circles. Although circRNAs influence many biological processes, little is known about their role in intestinal epithelium homeostasis. We surveyed circRNAs required to maintain intestinal epithelial integrity and identified circular homeodomain-interacting protein kinase 3 (circHIPK3) as a major regulator of intestinal epithelial repair after acute injury. METHODS: Intestinal mucosal tissues were collected from mice exposed to cecal ligation and puncture for 48 hours and patients with inflammatory bowel diseases and sepsis. We isolated primary enterocytes from the small intestine of mice and derived intestinal organoids. The levels of circHIPK3 were silenced in intestinal epithelial cells (IECs) by transfection with small interfering RNAs targeting the circularization junction of circHIPK3 or elevated using a plasmid vector that overexpressed circHIPK3. Intestinal epithelial repair was examined in an in vitro injury model by removing part of the monolayer. The association of circHIPK3 with microRNA 29b (miR-29b) was determined by biotinylated RNA pull-down assays. RESULTS: Genome-wide profile analyses identified ∼300 circRNAs, including circHIPK3, differentially expressed in the intestinal mucosa of mice after cecal ligation and puncture relative to sham mice. Intestinal mucosa from patients with inflammatory bowel diseases and sepsis had reduced levels of circHIPK3. Increasing the levels of circHIPK3 enhanced intestinal epithelium repair after wounding, whereas circHIPK3 silencing repressed epithelial recovery. CircHIPK3 silencing also inhibited growth of IECs and intestinal organoids, and circHIPK3 overexpression promoted intestinal epithelium renewal in mice. Mechanistic studies revealed that circHIPK3 directly bound to miR-29b and inhibited miR-29 activity, thus increasing expression of Rac1, Cdc42, and cyclin B1 in IECs after wounding. CONCLUSIONS: In studies of mice, IECs, and human tissues, our results indicate that circHIPK3 improves repair of the intestinal epithelium at least in part by reducing miR-29b availability.

Tojapride Reverses Esophageal Epithelial Inflammatory Responses on Reflux Esophagitis Model Rats.

OBJECTIVE: To investigate the mechanism of Tojapride, a Chinese herbal formula extract, on strengthening the barrier function of esophageal epithelium in rats with reflux esophagitis (RE). METHODS: Ten out of 85 SD rats were randomly selected as the sham group (n10), and 75 rats were developed a reflux esophagitis model (RE) by the esophageal and duodenal side-to-side anastomosis. Fifty successful modeling rats were divided into different medicated groups through a random number table including the model, low-, medium-, and high-dose of Tojapride as well as omeprazole groups (n10). Three doses of Tojapride [5.73, 11.46, 22.92 g/(kg•d)] and omeprazole [4.17 mg/(kg•d)] were administrated intragastrically twice daily for 3 weeks. And the rats in the sham and model groups were administered 10 mL/kg distilled water. Gastric fluid was collected and the supernatant was kept to measure for volume, pH value and acidity. Esophageal tissues were isolated to monitor the morphological changes through hematoxylin-eosin (HE) staining, and esophageal epithelial ultrastructure was observed by transmission electron microscopy. The expressions of nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-KBp65), κB kinase beta (IKKß), occludin, and zonula occludens-1 (ZO-1) in the esophageal tissues were measured by immunohistochemistry and Western blot, respectively. RESULTS: The gastric pH value in the model group was significantly lower than the sham group (P<0.05). Compared with the model group, gastric pH value in the omeprazole and medium-dose of Tojapride groups were significantly higher (P<0.05). A large area of ulceration was found on the esophageal mucosa from the model rats, while varying degrees of congestion and partially visible erosion was observed in the remaining groups. Remarkable increase in cell gap width and decrease in desmosome count was seen in RE rats and the effect was reversed by Tojapride treatment. Compared with the sham group, the IKKß levels were significantly higher in the model group (P<0.05). However, the IKKß levels were down-regulated after treatment by all doses of Tojapride (P<0.01 or P<0.05). The occluding and ZO-1 levels decreased in the model group compared with the sham group (Ps0.01 or Ps0.05), while both indices were significantly up-regulated in the Tojapride-treated groups (P<0.01 or P<0.05). CONCLUSIONS: Tojapride could improve the pathological conditions of esophageal epithelium in RE rats. The underlying mechanisms may involve in down-regulating the IKKß expression and elevating ZO-1 and occludin expression, thereby alleviating the inflammation of the esophagus and strengthening the barrier function of the esophageal epithelium.

RNA-binding protein HuR regulates translation of vitamin D receptor modulating rapid epithelial restitution after wounding.

Homeostasis of the intestinal epithelium is tightly regulated by numerous extracellular and intracellular factors including vitamin D and the vitamin D receptor (VDR). VDR is highly expressed in the intestinal epithelium and is implicated in many aspects of gut mucosal pathophysiology, but the exact mechanism that controls VDR expression remains largely unknown. The RNA-binding protein human antigen R (HuR) regulates the stability and translation of target mRNAs and thus modulates various cellular processes and functions. Here we report a novel role of HuR in the posttranscriptional control of VDR expression in the intestinal epithelium. The levels of VDR in the intestinal mucosa decreased significantly in mice with ablated HuR, compared with control mice. HuR silencing in cultured intestinal epithelial cells (IECs) also reduced VDR levels, whereas HuR overexpression increased VDR abundance; neither intervention changed cellular Vdr mRNA content. Mechanistically, HuR bound to Vdr mRNA via its 3'-untranslated region (UTR) and enhanced VDR translation in IECs. Moreover, VDR silencing not only inhibited IEC migration over the wounded area in control cells but also prevented the increased migration in cells overexpressing HuR, although it did not alter IEC proliferation in vitro and growth of intestinal organoids ex vivo. The human intestinal mucosa from patients with inflammatory bowel diseases exhibited decreased levels of both HuR and VDR. These results indicate that HuR enhances VDR translation by directly interacting with its mRNA via 3'-UTR and that induced VDR by HuR is crucial for rapid intestinal epithelial restitution after wounding.

Interaction between HuR and circPABPN1 Modulates Autophagy in the Intestinal Epithelium by Altering ATG16L1 Translation.

Intestinal epithelial autophagy is crucial for host defense against invasive pathogens, and defects in this process occur frequently in patients with inflammatory bowel disease (IBD) and other mucosal disorders, but the exact mechanism that activates autophagy is poorly defined. Here, we investigated the role of RNA-binding protein HuR (human antigen R) in the posttranscriptional control of autophagy-related genes (ATGs) in the intestinal epithelium. We found that targeted deletion of HuR in intestinal epithelial cells (IECs) specifically decreased the levels of ATG16L1 in the intestinal mucosa. Intestinal mucosa from patients with IBD exhibited reduced levels of both HuR and ATG16L1. HuR directly interacted with Atg16l1 mRNA via its 3' untranslated region and enhanced ATG16L1 translation, without affecting Atg16l1 mRNA stability. Circular RNA circPABPN1 blocked HuR binding to Atg16l1 mRNA and lowered ATG16L1 production. HuR silencing in cultured IECs also prevented rapamycin-induced autophagy, which was abolished by overexpressing ATG16L1. These findings indicate that HuR regulates autophagy by modulating ATG16L1 translation via interaction with circPABPN1 in the intestinal epithelium.

Tojapride prevents CaSR-mediated NLRP3 inflammasome activation in oesophageal epithelium irritated by acidic bile salts.

Impairment of the oesophageal epithelium in patients with reflux oesophagitis (RE) is a cytokine-mediated injury rather than a chemical burn. The present study was conducted to explore CaSR/NLRP3 inflammasome pathway activation and cytokines IL-1ß and IL-18 release in oesophageal epithelia injured by refluxates and the effects of Tojapride on that signal regulation. Using a modified RE rat model with Tojapride administration and Tojapride-pretreated SV40-immortalized human oesophageal epithelial cells (HET-1A) exposed to acidic bile salts pretreated with Tojapride, we evaluated the therapeutic effects of Tojapride on oesophageal epithelial barrier function, the expression of CaSR/NLRP3 inflammasome pathway-related proteins and the release of downstream cytokines in response to acidic bile salt irritation. In vivo, Tojapride treatment ameliorated the general condition and pathological lesions of the oesophageal epithelium in modified RE rats. In addition, Tojapride effectively blocked the CaSR-mediated NLRP3 inflammasome activation in modified RE rats. In vitro, Tojapride treatment can reverse the harmful effect of acidic bile salts, which reduced transepithelial electrical resistance (TEER), up-regulated the CaSR-mediated NLRP3 inflammasome pathway and increased caspase-1 activity, LDH release and cytokines secretion. Taken together, these data show that Tojapride can prevent CaSR-mediated NLRP3 inflammasome activation and alleviate oesophageal epithelial injury induced by acidic bile salt exposure.

Shen-ling-bai-zhu-san, a spleen-tonifying Chinese herbal formula, alleviates lactose-induced chronic diarrhea in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Shen-ling-bai-zhu-san (SLBZS) was firstly documented in ancient Chinese medical works "Tai Ping Hui Min He Ji Ju Fang" in Song-dynasty. It has been widely used for treating gastrointestinal disorders such as diarrhea with poor appetite for about 900 years. The present study is to observe the effects of SLBZS on high lactose diet-induced chronic diarrhea. MATERIALS AND METHODS: Rats were subjected to a high lactose diet to induce chronic diarrhea, which were then administrated with SLBZS or smecta. General symptom, body weight, food consumption, water intake and fecal fluid content were recorded every day. The intestinal absorption function was determined by d-xylose uptake assay. The ultrastructures of intestine segments including jejunum, ileum, proximal and distal colon were observed by transmission electron microscopy. Additionally, sodium transport proteins including γ-epithelial sodium channel (ENAC-γ) and sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1) in distal colon were detected by immunohistochemistry and western blotting. RESULTS: Diarrheal rats produced watery or loose, sticky feces, and presented inactiveness and grouping. A high lactose diet caused a significant decline in body weight, serum d-xylose level as well as food consumption rather than water intake. In contrast, general symptoms were improved to a certain extent and body weight loss was alleviated in the rats treated by SLBZS for one week. Fecal fluid content in diarrheal rats treated by SLBZS presented a gradual decrease trend with about 55% in the end, which was significantly less than the model group with about 81%. Meanwhile, SLBZS significantly improved the serum d-xylose level and reversed abnormal changes of tight junctions and microvilli in intestine. Additionally, SLBZS significantly modulated the abnormal expressions of ENAC-γ and ATP1A1 in distal colon of diarrheal rats. CONCLUSIONS: These findings suggested that SLBZS exhibited ameliorating effects against lactose-induced diarrhea, which might be attributed to its modulations on intestinal absorption function as well as mucosal ultrastructure.

Efficacy and safety of Xiangsha Liujunzi granules for functional dyspepsia: A multi-center randomized double-blind placebo-controlled clinical study.

AIM: To assess the efficacy and safety of a Chinese herbal medicine (CHM), Xiangsha Liujunzi granules, in the treatment of patients with functional dyspepsia (FD). METHODS: We performed a randomized, double-blind, placebo-controlled trial with patients from three centers. Two hundred and sixteen subjects diagnosed with FD according to ROME III criteria and confirmed by upper gastrointestinal endoscopy and spleen-deficiency and Qi-stagnation syndrome were selected to receive Xiangsha Liujunzi granules or placebo for 4 wk in a 2:1 ratio by blocked randomization. The subjects also received follow-up after the 4-wk intervention. Herbal or placebo granules were dissolved in 300 mL of water. Participants in both groups were administered 130 mL (45 °C) three times a day. Participants were evaluated prior to and following 4 wk of the intervention in terms of changes in the postprandial discomfort severity scale (PDSS) score, clinical global impression (CGI) scale score, hospital anxiety and depression scale (HADS) score, traditional Chinese medicine symptoms score (SS), scores of various domains of the 36-item short form health survey (SF-36), gastric emptying (GE) and any observed adverse effects. RESULTS: Compared with the placebo group, patients in the CHM group showed significant improvements in the scores of PDSS, HADS, SS, SF-36 and CGI scale (P < 0.05 or P < 0.01). They also showed the amelioration in the GE rates of the proximal stomach and distal stomach (P < 0.05 or P < 0.01). CONCLUSION: Xiangsha Liujunzi granules offered significant symptomatic improvement in patients with FD.