Expression and clinical significance of 5‑HT and 5‑HT3R in the intestinal mucosa of patient with diarrhea‑type irritable bowel syndrome

Fu, Rui; Chen, Mingxian; Chen, Yu; Mao, Guoqun; Liu, Saiyue

doi:10.3892/etm.2019.7297

Cited by 20 publications

(23 citation statements)

References 34 publications

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“…Consistent with the previous studies , peripheral administration of the precursor of 5-HT, 5-HTP, increased the sensitivity of CSTI-300 Could Treat Patients with Gastrointestinal Ailments rats to the colonic distension such that the abdominal contraction was evident at lower balloon pressures. This was likely because of the conversion of 5-HTP to 5-HT, which would increase the signaling tone upon the 5-HT 3 receptor; this also mimics the biochemical pathology reported in patients with IBS-d (Bearcroft et al, 1998;Dunlop et al, 2005;Enck et al, 2016;Fu et al, 2019;Gunn et al, 2019). This increased sensitivity to colon distension after 5-HTP administration was reversed by the clinically proven 5-HT 3 receptor antagonist, alosetron; this finding supported the validation of the model.…”

Section: Discussionsupporting

confidence: 68%

“…It has been known for over 2 decades that 5-HT 3 receptor antagonists, such as alosetron, deliver strong clinical efficacy to patients with IBS-d (e.g., Crowell, 2004), presumably by blocking elevated 5-HT function in these patients (Bearcroft et al, 1998;Dunlop et al, 2005;Enck et al, 2016;Fu et al, 2019;Gunn et al, 2019) that may arise from lower expression of the 5-HT transporter (Faure et al, 2010) to decrease gut motility and visceral sensation (e.g., Michel et al, 2005;Kapeller et al, 2011). Furthermore, increased expression of gut 5-HT 3 receptor by patients with IBS-d (Gunn et al, 2019) and associated 5-HT 3 receptor subunit polymorphisms (Kapeller et al, 2008(Kapeller et al, , 2009Kilpatrick et al, 2011;Gunn et al, 2019) support therapeutic targeting of this receptor.…”

Section: Introductionmentioning

confidence: 99%

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CSTI-300 (SMP-100); a Novel 5-HT₃Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

Roberts

Grafton

Powell

et al. 2020

J Pharmacol Exp Ther

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The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT 3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT 3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT 3 receptor (K i approximately 2.0 nM) and acted as a partial agonist (approximately 30%-50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the K i value for the 5-HT 3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t 1/2 range of 1.6-4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced "on-target" side-effect profile relative to 5-HT 3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT There is a lack of effective current treatment for diarrheapredominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT 3 receptor is thought to be implicated in the pathophysiology. Because 5-HT 3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT 3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

CSTI-300 (SMP-100); a Novel 5-HT₃Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

Roberts

Grafton

Powell

et al. 2020

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Diarrhea-predominant irritable bowel syndrome (IBS-D) is a chronic intestinal disease, [ 22 ] which seriously affects the study and life of the patients. However, little is known about the pathogenesis of IBS-D.…”

Section: Discussionmentioning

confidence: 99%

Study on the clinical mechanism of Tong-Xie-An-Chang Decoction in the treatment of diarrheal irritable bowel syndrome based on single-cell sequencing technology

Tan

Zhao

et al. 2020

Medicine

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Background: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a kind of functional gastrointestinal disorder with obscure pathogenesis, and exploration about differential gene expression and cell heterogeneity of T lymphocytes in peripheral blood in IBS-D patients still remains unknown. Clinicians tend to use symptomatic treatment, but the efficacy is unstable and symptoms are prone to relapse. Traditional Chinese Medicine (TCM) is used frequently in IBS-D with stable and lower adverse effects. Tong-Xie-An-Chang Decoction (TXACD) has been proven to be effective in the treatment of IBS-D. However, the underlying therapeutic mechanism remains unclear. This trial aims to evaluate the clinical efficacy and safety of TXACD in IBS-D and elucidate the gene-level mechanism of IBS-D and therapeutic targets of TXACD based on single-cell sequencing technology. Methods/design: This is a randomized controlled, double-blind, double-simulation clinical trial in which 72 eligible participants with IBS-D and TCM syndrome of liver depression and spleen deficiency will be randomly allocated in the ratio of 1:1 to two groups: the experimental group and the control group. The experimental group receives Tong-Xie-An-Chang Decoction (TXACD) and Pinaverium bromide tablets placebo; the control group receives pinaverium bromide tablets and TXACD placebo. Each group will be treated for 4 weeks. The primary outcome: the rate of IBS-Symptom Severity Score (IBS-SSS). The secondary outcomes: TCM syndrome score, adequate relief and IBS-Quality of Life Questionnaire (IBS-QOL). Mechanistic outcome is the single-cell sequencing profiling of the T lymphocytes in peripheral blood from IBS-D participants before and after the treatment and healthy individuals. Discussion: This trial will prove the efficacy and safety of TXACD with high-quality evidence and provide a comprehensive perspective on the molecular mechanism of IBS-D by single-cell sequencing profiling, which makes us pinpoint specific biomarkers of IBS-D and therapeutic targets of TXACD.

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“…In addition, Lacy et al [ 3 ] show the disturbances in the brain-gut function were one of the most important mechanisms in IBS. A retrospective analysis has shown 5-HT and 5-hydroxytryptamine receptor 3 (5-HT3R) were both prominently expressed in the intestinal mucosa tissue of IBS-D patients when compared with healthy subjects [ 128 ]. At the same time, 5-HT3R antagonists contributed to suppress urgency, alleviate symptoms, and prolong the intestine transit in IBS-D, while 5-HT3R agonists could promote intestinal motility, and accelerated transit in IBS-C patients [ 129 ].…”

Section: Bile Acid-activated Receptors and Signalsmentioning

confidence: 99%

Gut Microbiota-Bile Acid Crosstalk in Diarrhea-Irritable Bowel Syndrome

Zhan

Zheng

et al. 2020

BioMed Research International

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The occurrence of diarrhea-predominant irritable bowel syndrome (IBS-D) is the result of multiple factors, and its pathogenesis has not yet been clarified. Emerging evidence indicates abnormal changes in gut microbiota and bile acid (BA) metabolism have a close relationship with IBS-D. Gut microbiota is involved in the secondary BA production via deconjugation, 7α-dehydroxylation, oxidation, epimerization, desulfation, and esterification reactions respectively. Changes in the composition and quantity of gut microbiota have an important impact on the metabolism of BAs, which can lead to the occurrence of gastrointestinal diseases. BAs, synthesized in the hepatocytes, play an important role in maintaining the homeostasis of gut microbiota and the balance of glucose and lipid metabolism. In consideration of the complex biological functional connections among gut microbiota, BAs, and IBS-D, it is urgent to review the latest research progress in this field. In this review, we summarized the alterations of gut microbiota in IBS-D and discussed the mechanistic connections between gut microbiota and BA metabolism in IBS-D, which may be involved in activating two important bile acid receptors, G-protein coupled bile acid receptor 1 (TGR5) and farnesoid X receptor (FXR). We also highlight the strategies of prevention and treatment of IBS-D via regulating gut microbiota-bile acid axis, including probiotics, fecal microbiota transplantation (FMT), cholestyramine, and the cutting-edge technology about bacteria genetic engineering.

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Expression and clinical significance of 5‑HT and 5‑HT3R in the intestinal mucosa of patient with diarrhea‑type irritable bowel syndrome

Cited by 20 publications

References 34 publications

CSTI-300 (SMP-100); a Novel 5-HT₃Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

CSTI-300 (SMP-100); a Novel 5-HT₃Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

Study on the clinical mechanism of Tong-Xie-An-Chang Decoction in the treatment of diarrheal irritable bowel syndrome based on single-cell sequencing technology

Gut Microbiota-Bile Acid Crosstalk in Diarrhea-Irritable Bowel Syndrome

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Expression and clinical significance of 5‑HT and 5‑HT3R in the intestinal mucosa of patient with diarrhea‑type irritable bowel syndrome

Cited by 20 publications

References 34 publications

CSTI-300 (SMP-100); a Novel 5-HT3Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

CSTI-300 (SMP-100); a Novel 5-HT3Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

Study on the clinical mechanism of Tong-Xie-An-Chang Decoction in the treatment of diarrheal irritable bowel syndrome based on single-cell sequencing technology

Gut Microbiota-Bile Acid Crosstalk in Diarrhea-Irritable Bowel Syndrome

Contact Info

Product

Resources

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CSTI-300 (SMP-100); a Novel 5-HT₃Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome

CSTI-300 (SMP-100); a Novel 5-HT₃Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome