scholarly journals A Clostridia-rich microbiota contributes to increased excretion of bile acids in diarrhea-predominant irritable bowel syndrome

2019 ◽  
Author(s):  
Ling Zhao ◽  
Wei Yang ◽  
Yang Chen ◽  
Fengjie Huang ◽  
Lin Lu ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Bile Acids ◽  
Protein Levels ◽  
Human Microbiota ◽  
Fecal Bile Acids ◽  
Fgf19 Expression ◽  
Irritable Bowel ◽  
Fibroblast Growth Factor 19

ABSTRACTObjectiveAn excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remains unclear. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D.DesignMetabolomic and metagenomic analyses were performed of specimens from 290 IBS-D patients and 89 healthy volunteers. By transplanting human microbiota and manipulating specific microbiome species in mice, the effects of microbiota on host BA metabolism were assessed at metabolic, genetic and protein levels. Effects of individual and mixed BAs on enterohepatic feedback pathways were also tested in vitro and in vivo.ResultsTotal fecal BAs were excessively excreted in 24.5% of IBS-D patients. Their fecal metagenomes showed increased abundances of Clostridia and BA-transforming genes (hdhA and bais). The increases of Clostridia bacteria (e.g. C. scindens) were positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), while being negatively correlated with serum fibroblast growth factor 19 (FGF19). Both Clostridia-rich human microbiota and C. scindens enhanced levels of serum C4 and hepatic conjugated BAs in mice recipients and reduced ileal FGF19 expression. Inhibition of Clostridium species by vancomycin yielded opposite findings. Clostridia-derived BAs (e.g. conjugated and free ursodeoxycholic acid) significantly suppressed intestinal FGF19 expression.ConclusionThe Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients. This study provided the basis for more precise clinical diagnosis and management for IBS-D.

IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells

2007 ◽  
Vol 292 (3) ◽  
pp. G779-G784 ◽  
Author(s):  
Kevin F. Foley ◽  
Cristen Pantano ◽  
Allison Ciolino ◽  
Gary M. Mawe
Keyword(s):  
Ulcerative Colitis ◽  
Irritable Bowel Syndrome ◽  
Conditioned Medium ◽  
Human Lymphocytes ◽  
Protein Levels ◽  
Tnf Α ◽  
Ifn Γ ◽  
5 Ht Uptake ◽  
Irritable Bowel

Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [3H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE2 (10 μM), IFN-γ (500 ng/ml), TNF-α (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 μM). [3H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [3H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-α and IFN-γ elicited significant decreases in SERT function. Neither TNF-α nor IFN-γ were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-α and IFN-γ could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.

scholarly journals Fecal Bile Acids and Fecal Short Chain Fatty Acids in Patients with Irritable Bowel Syndrome and Control Volunteers

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Chirag Patel ◽  
Carolyn Lockett ◽  
Huiping Xu ◽  
Andrea Shin
Keyword(s):  
Fatty Acids ◽  
Irritable Bowel Syndrome ◽  
Organic Acids ◽  
Bile Acids ◽  
Short Chain Fatty Acids ◽  
Small Sample ◽  
Short Chain ◽  
Fecal Bile Acids ◽  
Irritable Bowel ◽  
Chain Fatty Acids

Background and Aims: Fecal bile acids (BAs), short chain fatty acids (SCFAs), and gut microbiome may be implicated in irritable bowel syndrome (IBS) pathophysiology. Our aim was to compare fecal organic acids between IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and controls.   Methods: Stool samples were collected from 17 controls, 5 IBS-C, and 5 IBS-D volunteers during a 4-day high fat diet. Aliquots were stored for future analysis of the fecal microbiota. Fecal SCFA and BA analyses were conducted at the Metabolite Profiling Facility at Purdue University and Laboratory Medicine and Pathology at Mayo Clinic. We compared SCFA and BA levels among groups using the Wilcoxon rank sum test. Gamma and linear regression were used to compare SCFAs and BAs adjusting for age and body mass index (BMI).  Results: Fecal acetate levels (mean+SD, µg/mg) were higher in IBS-C (11.3±7) than in controls (6.1±3.3) or IBS-D (7.7±2), although not statistically significant (p=0.19). Total fecal BAs (median [IQR], %) were higher in IBS-D (675 [484-778]) than in controls (342 [130-640]) or IBS-C (321.5 (34.5-718); however, differences were not significant. No significant differences were observed in BAs or SCFAs between groups in multivariate analyses.  Conclusion: We are unable to show significant differences in organic acid levels in IBS and controls. Lack of association may be due to small sample size. Future investigation of larger patient numbers with incorporation of transit and microbiome analyses may shed further light on the role of organic acids in IBS to identify new biomarkers and treatment targets.

scholarly journals Prokaryotic and Eukaryotic Fecal Microbiota in Irritable Bowel Syndrome Patients and Healthy Individuals Colonized With Blastocystis

2021 ◽  
Vol 12 ◽  
Author(s):  
Céline Nourrisson ◽  
Julien Scanzi ◽  
Julie Brunet ◽  
Frédéric Delbac ◽  
Michel Dapoigny ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
High Throughput Sequencing ◽  
Fecal Microbiota ◽  
Healthy Individuals ◽  
High Prevalence ◽  
Potential Link ◽  
Irritable Bowel

Blastocystis is the most frequently isolated protozoan from human stool. Its role in human health is still debated, and a high prevalence was reported in irritable bowel syndrome (IBS) subjects, suggesting a potential link with microbiota. In the present study, we aimed to investigate prokaryotic and eukaryotic microbiota in both IBS-C (constipated) and healthy individuals. We recruited 35 IBS-C patients and 23 healthy subjects, from which 12 and 11 carried Blastocystis, respectively. We performed 16S and 18S rRNA high-throughput sequencing on feces. Whereas we did not observe differences between infected and non-infected controls, several phyla were significantly modified in IBS-C patients according to the presence of Blastocystis. Tenericutes phylum and Ruminococcaceae family were especially increased in Blastocystis carriers. Furthermore, colonization with Blastocystis was associated with discrete changes in the microbial eukaryome, particularly among the Fungi taxa. Depending on the group of patients considered, the mycobiota changes do not go in the same direction and seem more deleterious in the IBS-C group. These results encourage further in vivo and in vitro investigations concerning the role of Blastocystis in the gut environment.

scholarly journals Suppression of PTRF Alleviates Post-Infectious Irritable Bowel Syndrome via Downregulation of the TLR4 Pathway in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui-hui Zhou ◽  
Ye-ming Zhang ◽  
Sheng-peng Zhang ◽  
Qi-xiang Xu ◽  
Ya-qing Tian ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Water Content ◽  
Inos Expression ◽  
Tlr4 Signaling ◽  
Fecal Water ◽  
Irritable Bowel ◽  
Post Infectious

Background: Accumulating evidence suggests that the polymerase I and transcript release factor (PTRF), a key component of the caveolae structure on the plasma membrane, plays a pivotal role in suppressing the progression of colorectal cancers. However, the role of PTRF in the development of functional gastrointestinal (GI) disorders remains unclear. Post-infectious irritable bowel syndrome (PI-IBS) is a common functional GI disorder that occurs after an acute GI infection. Here, we focused on the role of PTRF in the occurrence of PI-IBS and investigated the underlying mechanisms.Methods: Lipopolysaccharide (LPS) (5 μg/ml) was used to induce inflammatory injury in human primary colonic epithelial cells (HCoEpiCs). Furthermore, a rat model of PI-IBS was used to study the role of PTRF. Intestinal sensitivity was assessed based on the fecal water content. A two-bottle sucrose intake test was used to evaluate behavioral changes. Furthermore, shRNA-mediated knockdown of PTRF was performed both in vitro and in vivo. We detected the expression of PTRF in colonic mucosal tissues through immunohistochemistry (IHC), western blotting (WB), and immunofluorescence (IF) analysis. Luciferase activity was quantified using a luciferase assay. Co-localization of PTRF and Toll-like receptor 4 (TLR4) was detected using IF analysis. The activation of the signaling pathways downstream of TLR4, including the iNOs, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) pathways, was detected via WB. The levels of NO, IL-1β, IL-6, and TNF-α were measured using enzyme-linked immunosorbent assays.Results: LPS significantly induced PTRF expression and signaling downstream of TLR4, including p38, ERK, and JNK pathways, in HCoEpiCs. Moreover, shRNA-mediated knockdown of PTRF in HCoEpiCs significantly decreased the phosphorylation of JNK, ERK, and p38 and iNOS expression. In PI-IBS rats, the lack of PTRF not only reduced fecal water content and suppressed depressive behavior but also increased the body weight. Furthermore, we found a strong co-localization pattern for PTRF and TLR4. Consistently, the lack of PTRF impaired TLR4 signaling, as shown by the decreased levels of p-JNK, p-ERK, and p-p38, which are upstream factors involved in iNOS expression.Conclusion: PTRF promoted PI-IBS and stimulated TLR4 signaling both in vitro and in vivo. The results of this study not only enlighten the pathogenesis of PI-IBS but also help us understand the biological activity of PTRF and provide an important basis for the clinical treatment of PI-IBS by targeting PTRF.

Abnormal gallbladder motility in irritable bowel syndrome: evidence for target-organ defect

1991 ◽  
Vol 260 (6) ◽  
pp. G815-G819
Author(s):  
P. S. Kamath ◽  
H. Y. Gaisano ◽  
S. F. Phillips ◽  
L. J. Miller ◽  
J. W. Charboneau ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Peripheral Circulation ◽  
Target Organ ◽  
Gallbladder Motility ◽  
Cholecystokinin Octapeptide ◽  
Irritable Bowel

We have described previously that the gallbladder responds abnormally to infusions of cholecystokinin octapeptide (CCK-8) in patients with irritable bowel syndrome (IBS). To confirm these results and to examine the possible mechanisms, patients with IBS and predominant symptoms of diarrhea or constipation were compared with matched controls. During infusions of CCK-8 at one of three doses, the response of the gallbladder was measured ultrasonographically. The levels of CCK-8 reached in the peripheral circulation and degradation of the peptide in vitro and in vivo were used to evaluate metabolism of cholecystokinin. We confirmed that the gallbladders of patients with IBS responded abnormally to CCK-8; however, the differences were not due to any prereceptor event. Instead, this abnormality in IBS must be explained by an atypical response at the level of the target tissues.

scholarly journals Multi-target Treatment for Irritable Bowel Syndrome with STW 5: Pharmacological Modes of Action

2020 ◽  
Vol 29 (2) ◽  
pp. 227-233
Author(s):  
Hans-Dieter Allescher ◽  
Rebecca Burgell ◽  
Peter Malfertheiner ◽  
Fermin Mearin
Keyword(s):  
Irritable Bowel Syndrome ◽  
Treatment Options ◽  
Smooth Muscles ◽  
Gastrointestinal Disorder ◽  
In Vivo Studies ◽  
Afferent Nerves ◽  
Target Treatment ◽  
Irritable Bowel

Irritable bowel syndrome (IBS) is a heterogeneous and complex functional gastrointestinal disorder with aglobal prevalence of approximately 11% and high geographic variation. IBS encompasses various symptomclusters considered to reflect complex patho-etiological mechanisms, and effective treatment options arelimited, with most medications targeting individual mechanisms and symptoms. Therefore, multi-targetedtreatment is required. IBS is currently viewed as a disorder of disturbed gut–brain interactions withabnormalities at different sites along the gut–brain axis, including altered gastrointestinal motility, visceralhypersensitivity, increased intestinal permeability, and altered gut microbiota. All of these abnormalitiesrepresent individual targets for STW 5, a herbal preparation with nine different extracts indicated for thetreatment of functional dyspepsia and IBS. As a multi-targeted medicinal drug, STW 5 possesses multiplepharmacodynamic effects. Several in vitro and in vivo studies have demonstrated STW 5 efficacy on numerousIBS patho-mechanisms targeting gastrointestinal smooth muscles, visceral afferent nerves, inflammation, gutpermeability, and the gut microbiome.

scholarly journals (-)-Epicatechin Prevents High Fat Diet-Induced Bile-Associated Intestinal Permeabilization Both In Vivo and In Vitro

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 487-487
Author(s):  
Ziwei Wang ◽  
Corina Litterio ◽  
Michael Müller ◽  
David Vauzour ◽  
Patricia Oteiza
Keyword(s):  
Nadph Oxidase ◽  
High Fat Diet ◽  
Cell Monolayer ◽  
Intestinal Barrier ◽  
Mek Inhibitor ◽  
High Fat ◽  
Protein Levels ◽  
Fecal Bile Acids

Abstract Objectives This work investigated the capacity of (-)-epicatechin (EC) to prevent high fat diet (HFD)-induced intestinal permeabilization and the underlying mechanisms both in rodents and in Caco-2 cells. Methods Male C57BL/6J mice (7 mice/group) (20–25 g) were fed for 15 w control or HFD, supplemented without or with 20 mg EC/kg body weight. Tissues and feces were collected and stored at −80 °C for further analysis. Caco-2 cells were differentiated into intestinal epithelial cells, which were incubated in the absence or the presence of deoxycholic acid (DCA), with or without EC, NADPH oxidase (NOX) inhibitors (apocynin and VAS-2870) and MEK inhibitor (U0126). After the corresponding incubations, monolayer permeability and the activation of signaling pathways and events involved in tight junction (TJ) opening/disruption were evaluated. Results Consumption of a HFD caused intestinal permeabilization which was associated with decreased expression of ileal TJ proteins in mice. Supplementation with EC mitigated all these adverse effects. However, EC did not prevent neither the increase nor the altered profile of fecal bile acids caused by HFD consumption. DCA content was particularly elevated. In vitro, EC inhibited DCA-induced Caco-2 cell monolayer permeabilization. EC also prevented DCA-mediated increase in oxidant production and the parallel increase in NOX4 expression, which were both prevented by EC. Inhibition of the ERK1/2 pathway with U0126 prevented DCA-induced monolayer permeabilization, stressing the key involvement of NADPH oxidase and ERK1/2 in this process. DCA-mediated ERK1/2 activation was also inhibited by EC, apocynin and VAS-2870. DCA increased myosin light chain (MLC) phosphorylation levels, which was related to ERK1/2-mediated MLC phosphatase inactivation. DCA also decreased TJ protein levels, in part via Matrix Metallopeptidase-2 (MMP2) activation. Both events were prevented by EC, apocynin, VAS-2870 and U0126. Conclusions EC protects the intestinal barrier from HFD-induced TJ alterations, and associated intestinal permeability both in vivo and in vitro. This is in part to mediated by EC's capacity to inhibit bile-induced NADPH oxidase, ERK1/2, and MMP2 activation, resulting in the preservation of TJ structure. Funding Sources This work was supported by HE Jastro awards to ZW, and grant NIFA-USDA (CA-D-NTR-7244-H) to P.O.

scholarly journals All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1202
Author(s):  
Bojjibabu Chidipi ◽  
Syed Islamuddin Shah ◽  
Michelle Reiser ◽  
Manasa Kanithi ◽  
Amanda Garces ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mitochondrial Fission ◽  
Normal Function ◽  
Mitochondrial Network ◽  
Protein Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Area And Perimeter

In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.

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