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ChREBP deficiency leads to diarrhea-predominant irritable bowel syndrome.

ABSTRACT: OBJECTIVE:Fructose malabsorption is a common digestive disorder in which absorption of fructose in the small intestine is impaired. An abnormality of the main intestinal fructose transporter proteins has been proposed as a cause for fructose malabsorption. However the underlying molecular mechanism for this remains unclear. In this study, we investigated whether carbohydrate response element-binding protein (ChREBP) plays a role in intestinal fructose absorption through the regulation of genes involved in fructose transport and metabolism and ion transport. METHODS:Wild type (WT) and Chrebp knockout (KO) mice (6 or 8?weeks old) were fed a control diet (55% starch, 15% maltodextrin 10) or high-fructose diet (HFrD, 60% fructose, 10% starch) for 3-12?days. Body weight and food intake were measured, signs of fructose malabsorption were monitored, and the expression of genes involved in fructose transport/metabolism and ion transport was evaluated. Furthermore, transient transfection and chromatin immunoprecipitation were performed to show the direct interaction between ChREBP and carbohydrate response elements in the promoter of Slc2A5, which encodes the fructose transporter GLUT5. RESULTS:Chrebp KO mice fed the control diet maintained a constant body weight, whereas those fed a HFrD showed significant weight loss within 3-5?days. In addition, Chrebp KO mice fed the HFrD exhibited a markedly distended cecum and proximal colon containing both fluid and gas, suggesting incomplete fructose absorption. Fructose-induced increases of genes involved in fructose transport (GLUT5), fructose metabolism (fructokinase, aldolase B, triokinase, and lactate dehydrogenase), and gluconeogenesis (glucose-6-phosphatase and fructose-1,6-bisphosphatase) were observed in the intestine of WT but not of Chrebp KO mice. Moreover the Na+/H+ exchanger NHE3, which is involved in Na+ and water absorption in the intestine, was significantly decreased in HFrD-fed Chrebp KO mice. Consistent with this finding, the high-fructose diet-fed Chrebp KO mice developed severe diarrhea. Results of chromatin immunoprecipitation assays showed a direct interaction of ChREBP with the Glut5 promoter, but not the Nhe3 promoter, in the small intestine. Ectopic co-expression of ChREBP and its heterodimer partner Max-like protein X activated the Glut5 promoter in Caco-2BBE cells. CONCLUSIONS:ChREBP plays a key role in the dietary fructose transport as well as conversion into lactate and glucose through direct transcriptional control of genes involved in fructose transport, fructolysis, and gluconeogenesis. Moreover, ablation of Chrebp results in a severe diarrhea in mice fed a high-fructose diet, which is associated with the insufficient induction of GLUT5 in the intestine.

SUBMITTER: Oh AR

PROVIDER: S-EPMC7400734 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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ChREBP deficiency leads to diarrhea-predominant irritable bowel syndrome.

Oh Ah-Reum AR Sohn Seonyong S Lee Junghoon J Park Jong-Min JM Nam Ki Taek KT Hahm Ki-Baik KB Kim Young-Bum YB Lee Ho-Jae HJ Cha Ji-Young JY

Metabolism: clinical and experimental 20180415

<h4>Objective</h4>Fructose malabsorption is a common digestive disorder in which absorption of fructose in the small intestine is impaired. An abnormality of the main intestinal fructose transporter proteins has been proposed as a cause for fructose malabsorption. However the underlying molecular mechanism for this remains unclear. In this study, we investigated whether carbohydrate response element-binding protein (ChREBP) plays a role in intestinal fructose absorption through the regulation of ...[more]

PMID: 29669261

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Project description:Altered gut microbiota are assumed to be involved in the pathogenesis of irritable bowel syndrome (IBS). However, gut microbiota alterations reported in different studies are divergent and sometimes even contradictory. To better elucidate the relationship between altered gut microbiota and IBS, we characterized fecal microbiota of diarrhea-predominant IBS (IBS-D) patients and further explored the effect of rifaximin on gut microbiota using bacterial 16S rRNA gene-targeted pyrosequencing. In our study, IBS-D patients defined by Rome III criteria and age-and-gender matched healthy controls (HC) were enrolled to investigate the fecal microbiota alterations. These IBS-D patients were then treated with rifaximin for 2 weeks and followed up for 10 weeks. Fecal microbiota alterations, small intestine bacterial overgrowth (SIBO) and gastrointestinal (GI) symptoms of IBS-D patients were analyzed before and after treatment. Our results showed fecal microbiota richness but not diversity was decreased in IBS-D patients as compared to HC and there were alterations of fecal microbiota at different taxonomy levels. The abundant phyla Firmicutes was significantly decreased and Bacteroidetes was increased in IBS-D patients. Moreover, the alterations of predominant fermenting bacteria such as Bacteroidales and Clostridiales might be involved in the pathophysiology of IBS-D. In addition, rifaximin was effective in terms of SIBO eradication and even GI symptoms of IBS-D patients achieved at least 10-week improvement after treatment. Furthermore, rifaximin induced alterations of some special bacteria rather than affected the overall composition of microbiota in IBS-D patients. Meanwhile, a potential decrease in propanoate and butanoate metabolism was found in these IBS-D patients after rifaximin treatment. Taken together, there were alterations of gut microbiota in IBS-D patients as compared to HC. Rifaximin could relieve GI symptoms, modify gut microbiota in IBS-D patients and eradicate SIBO in those patients with SIBO, suggesting an additional therapeutic mechanism of rifaximin in the treatment of IBS-D. Our findings of compositional gut microbiota alterations in IBS-D and the effect of rifaximin on the gut microbiota implied that altered gut microbiota were associated with the pathogenesis of IBS.

Project description:BackgroundOral serum-derived bovine immunoglobulin (SBI)/protein isolate is a medical food intended to manage chronic diarrhea. It has been shown to improve pain and diarrhea in adults with diarrhea-predominant irritable bowel syndrome (d-IBS).AimTo determine if SBI can improve symptoms in children with d-IBS.MethodsWe performed a randomized, double-blind, placebo-controlled, pilot study (NCT02609529) to evaluate the effectiveness of SBI in children 8-18 years with d-IBS. We recorded stool number, abdominal pain, and stool form in all patients for 1 week and then assigned the patients at a ratio of 2:1 to treatment with SBI 5 g BID or placebo for 3 weeks. The patients and their parents completed the Pediatric Quality of Life Inventory™ for Gastrointestinal Symptoms (PedsQOL) and the Pediatric Functional Disability Index (FDI). In addition, complete blood counts and serum chemistries were recorded at the start and end of treatment to evaluate safety.ResultsFifteen patients (nine SBI, six placebo) completed the study. Both SBI and placebo groups reported nonstatistical reductions in stool frequency per week. The SBI group showed a significant reduction in stool frequency at weeks 1 and 2 but not at the end of treatment. The SBI group also demonstrated statistical improvements in abdominal pain and stool form by 3 weeks. The placebo group did not achieve similar improvements. The overall FDI and PedsQOL scores, as well as PedsQOL subscale scores for pain, discomfort when eating, diarrhea, worry about stomach aches, and communication, improved significantly in the SBI group, but not in the placebo group. No serious adverse events occurred. Serum chemistries and hemograms were normal at baseline and at the end of study in all patients.ConclusionIn this single-center, exploratory pilot study, we demonstrated that 10 g SBI per day was safe in children with d-IBS and improved symptoms. Larger studies, with longer treatment duration, seem warranted based on these initial positive results.

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Project description:Diarrhea-predominant irritable bowel syndrome (IBS-D) and functional diarrhea (FD) are highly prevalent, and the effectiveness of acupuncture for managing IBS-D and FD is still unknown.The aim of this study was to compare the effectiveness of electroacupuncture with loperamide.It was a prospective, randomized, parallel group controlled trial.A total of 448 participants were randomly assigned to He electroacupuncture group (n = 113), Shu-Mu electroacupuncture group (n = 111), He-Shu-Mu electroacupuncture group (n = 112), or loperamide group (n = 112). Participants in the 3 acupuncture groups received 16 sessions of electroacupuncture during a 4-week treatment phase, whereas participants in the loperamide group received oral loperamide 2 mg thrice daily. The primary outcome was the change from baseline in stool frequency at the end of the 4-weeks treatment. The secondary outcomes were the Bristol scale, the MOS 36-item short form health survey (SF-36), the weekly average number of days with normal defecations and the proportion of adverse events.Stool frequency was significantly reduced at the end of the 4-week treatment in the 4 groups (mean change from baseline, 5.35 times/week). No significant difference was found between the 3 electroacupuncture groups and the loperamide group in the primary outcome (He vs. loperamide group [mean difference 0.6, 95% CI, -1.2 to 2.4]; Shu-Mu vs. loperamide group [0.4, 95% CI, -1.4 to 2.3]; He-Shu-Mu vs. loperamide group [0.0, 95% CI, -1.8 to 1.8]). Both electroacupuncture and loperamide significantly improved the mean score of Bristol scale and increased the weekly average number of days with normal defecations and the mean scores of SF-36; they were equivalent in these outcomes. However, the participants in electroacupuncture groups did not report fewer adverse events than those in the loperamide group. Similar results were found in a subgroup analysis of separating patients with IBS-D and FD patients.Electroacupuncture is equivalent to loperamide for reducing stool frequency in IBS-D and FD patients. Further studies on cost effectiveness of acupuncture are warranted.

Dataset Information

ChREBP deficiency leads to diarrhea-predominant irritable bowel syndrome.

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ChREBP deficiency leads to diarrhea-predominant irritable bowel syndrome.

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