Effect of thumbtack needle on functional constipation: A pragmatic randomized controlled trial.

OBJECTIVE: Thumbtack Needling (TN) has been employed in the treatment of functional constipation (FC), although the existing evidence supporting its effectiveness is limited. This study is to evaluate the efficacy of TN in ameliorating FC. METHOD: A total of 482 eligible patients were recruited and randomly assigned to the TN group or the Mosapride Citrate (MC) group. The TN was buried once for three days, rest for one day after two consecutive burials, followed by a 4-week follow-up. The primary outcome measure was the score for Complete and spontaneous bowel movement score (CSBMs). Secondary outcome measures included the Bristol Stool Form Scale (BSFS), Cleveland Clinic Score (CCS), and the Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL). RESULTS: Out of the 482 patients randomized, 241 were allocated to each group. Of these, 216 patients (89.6 %) in both groups completed the intervention and follow-up. Compared with the baseline, the differences of CSBMs in TN group [1.76(95 % CI, 1.61 to 1.91)] and MC group [1.35(95 % CI, 1.20 to 1.50)] at week 4 meet the threshold for minimal clinically important difference (MCID). However, there were no clinical difference from baseline at week 2 and week 8 in both groups. Mean CSBMs at week 4 was 3.35 ± 0.99 in the TN group and 3 ± 1.03 in the MC group (adjusted difference between groups, 0.37 points [95 % CI, 0.18 to 0.55]; P < 0.001), although differences between the two groups did not meet the MCID threshold. CONCLUSION: Compared with mosapride citrate, thumbtack needling produced a greater improvement in CSBMs, although the difference from control was not clinically significant. GOV IDENTIFIER: ChiCTR2100043684.

Prunus persica (L.) Batsch blossom soluble dietary fiber synergia polyphenol improving loperamide-induced constipation in mice via regulating stem cell factor/C-kit, NF-κB signaling pathway and gut microbiota.

This study aimed to investigate the ameliorating effects of peach blossom soluble dietary fiber (PBSDF) and polyphenol (PBP) combinations on loperamide (Lop)-induced constipation in mice, together with the possible mechanism of action. The results demonstrated that the combined use of PBSDF and PBP could synergistically accelerate the gastrointestinal transit rate and gastric emptying rate, shorten first red fecal defecation time, accelerate the frequency of defecation, regulate the abnormal secretion of gastrointestinal neurotransmitters and pro-inflammatory cytokines, and down-regulate the expressions of AQP3 and AQP8. Western blotting and RT-qPCR analysis confirmed that PBSDF + PBP up-regulated the protein and mRNA expressions of SCF and C-kit in SCF/C-kit signaling pathway, and down-regulated pro-inflammatory mediator expressions in NF-κB signaling pathway. 16S rRNA sequencing showed that the diversity of gut microbiota and the relative abundance of specific strains, including Akkermansia, Bacteroides, Ruminococcus, Lachnospiraceae_NK4A136_group, and Turicibacter, rehabilitated after PBSDF + PBP intervention. These findings suggested that the combination of a certain dose of PBSDF and PBP had a synergistic effect on attenuating Lop-induced constipation, and the synergistic mechanism in improving constipation might associated with the regulating NF-κB and SCF/C-kit signaling pathway, and modulating the specific gut strains on constipation-related systemic types. The present study provided a novel strategy via dietary fiber and polyphenol interactions for the treatment of constipation.

A Decision Support Alert for Promoting Prophylactic Laxative Use with Clozapine.

We investigated the effectiveness of a decision support alert to improve prophylactic laxative use with clozapine in hospital. Prescribing data for first clozapine and laxative prescriptions were extracted and linked. Proportions of first clozapine prescriptions for which a laxative was co-prescribed within 24 hours was compared before and after alert implementation. The alert was associated with increased and earlier laxative co-prescribing.

GDNF's Role in Mitigating Intestinal Reactive Gliosis and Inflammation to Improve Constipation and Depressive Behavior in Rats with Parkinson's disease.

Constipation is a common symptom in patients with Parkinson's disease (PD) and is often associated with depression. Enteric glial cells (EGCs) are crucial for regulating intestinal inflammation and colon motility, and their activation can lead to the death of intestinal neurons. Glial cell line-derived neurotrophic factor (GDNF) has been recognized for its neuroprotective properties in various neurological disorders, including PD. This study explores the potential of GDNF in alleviating intestinal reactive gliosis and inflammation, thereby improving constipation and depressive behavior in a rat model of PD. A PD model was established via unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA). Five weeks post-injury, AAV5-GDNF (2 ~ 5 × 10^11) was intraperitoneally injected into experimental and control rats. Fecal moisture percentage (FMP) and colonic propulsion rate (CPPR) were used to evaluate colon motility. Colon-related inflammation and colonic epithelial morphology were assessed, and depressive behavior was analyzed one week before sampling. PD rats exhibited reduced colonic motility and GDNF expression, along with increased EGC reactivity and elevated levels of pro-inflammatory cytokines IL-1, IL-6, and TNF-α. Additionally, there was an up-regulation of CX43 and a decrease in PGP 9.5 expression. The intraperitoneal injection of AAV-GDNF significantly protected colonic neurons by inhibiting EGC activation and down-regulating CX43. This treatment also led to a notable reduction in depressive-like symptoms in PD rats with constipation. GDNF effectively reduces markers of reactive gliosis and inflammation, and promotes the survival of colonic neurons, and improves colonic motility in PD rats by regulating CX43 activity. Furthermore, GDNF treatment alleviates depressive behavior, suggesting that GDNF or its agonists could be promising therapeutic agents for managing gastrointestinal and neuropsychiatric symptoms associated with PD.

Tongbian formula alleviates slow transit constipation by increasing intestinal butyric acid to activate the 5-HT signaling.

Slow transit constipation (STC) is a long-lasting and prevalent intestinal condition, marked by hard, dry feces. The primary cause of STC may be attributed to an imbalance in the gut's microbial community and alterations in its metabolic byproducts. Tongbian formula (TB), a traditional Chinese medicinal formula, has been used to treat STC and shows a great effect on relieving constipation. The role of TB in regulating intestinal microbiota has not been fully elucidated. Herein, we investigated the potential effect of TB on gut microbiota and further explored the potential mechanism behind its effects. Our study demonstrated that TB significantly increased fecal water content and intestinal ink propulsion rate in loperamide (Lope)-induced STC rats. 5-HT signaling was suppressed in STC colon tissue, and the abundance of butyric acid (BA) in colonic contents was significantly down-regulated after Lope treatment. Notably, TB administration led to the restoration of microbial dysbiosis and the up-regulation of BA content, subsequently activating 5-HT signaling pathways. When BA was combined with a tryptophan hydroxylase-1 (TPH1) inhibitor, which is crucial for 5-HT synthesis, its therapeutic efficacy for treating STC was compromised. TB alleviates STC by reversing the intestinal microbiota imbalance and activating the 5-HT signaling in the colon through increasing BA levels. These findings suggest that TB is an ideal candidate for STC treatment.

Modified Zhizhu Pill improves the loperamide-induced slow transit constipation via gut microbiota and neurotransmitters in microbiota-gut-brain axis.

BACKGROUND: Slow-transmission constipation is a type of intractable constipation with unknown etiology and unclear pathogenesis. OBJECTIVE: The intention of this study was to evaluate the therapeutic effect and possible mechanism of Modified Zhizhu Pills on loperamide-induced slow transit constipation. METHODS: The effects of the Modified Zhizhu Pill were evaluated in a rat model of constipation induced by subcutaneous administration of loperamide. Fecal parameters (fecal count, fecal water content, and fecal hardness) were measured in constipated rats. The substance, target, and pathway basis of the Modified Zhizhu Pill on constipation was investigated using network pharmacology. The microflora in rats was determined. Serum neurotransmitters (acetylcholine and 5-hydroxytryptamine) were measured in rats and their relationship with the gut microbiota was assessed. RESULTS: Modified Zhizhu Pill increased the number of bowel movements and fecal water content, and decreased fecal hardness and transit time. Network pharmacological analysis showed that Modified Zhizhu Pill can target multiple constipation-related targets and pathways through multiple potential active ingredients. Modified Zhizhu Pill alleviated loperamide-induced microbiota dysbiosis. Modified Zhizhu Pill increased serum 5-hydroxytryptamine and acetylcholine. The increase in serum 5-hydroxytryptamine and acetylcholine was associated with rat gut microbiota. CONCLUSION: These results suggest that Modified Zhizhu Pill may increase intestinal motility and ultimately relieve constipation by improving microecological dysbiosis and neurotransmission.

The safety and effectiveness of naldemedine for opioid-induced constipation in patients with advanced cancer in real-world palliative care settings: a multicenter prospective observational study.

PURPOSE: In this study, we aimed to evaluate the safety and effectiveness of naldemedine for treating opioid-induced constipation (OIC) in patients with advanced cancer, who are receiving palliative care, and particularly explored its early effects. METHODS: Palliative care teams and inpatient palliative care units across 14 institutions in Japan were included in this multicenter, prospective, observational study. Patients who were newly prescribed a daily oral dose of 0.2 mg naldemedine were enrolled. The spontaneous bowel movement (SBM) within 24 h after the first dose of naldemedine was considered the primary outcome, whereas, the secondary outcomes included weekly changes in SBM frequency and adverse events. RESULTS: A total of 204 patients were enrolled and 184 completed the 7-day study. The average age of the participants (103 males, 101 females) was 63 ± 14 years. The primary cancer was detected in the lungs (23.5%), gastrointestinal tract (13.7%), and urological organs (9.3%). A considerable proportion of patients (34.8%) had ECOG performance status of 3-4. Most patients were undergoing active cancer treatment, however, 40.7% of the patients were receiving the best supportive care. Within 24 h of the first naldemedine dose, 146 patients (71.6%, 95% CI: 65.4-77.8%) experienced SBMs. The weekly SBM counts increased in 62.7% of the participants. The major adverse events included diarrhea and abdominal pain, detected in 17.6% and 5.4% of the patients, respectively. However, no serious adverse events were observed. CONCLUSION: Conclusively, naldemedine is effective and safe for OIC treatments in real-world palliative care settings. TRIAL REGISTRATION NUMBER: UMIN000031381, registered 20/02/2018.

Examining linaclotide for the treatment of chronic idiopathic constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is characterized by infrequent bowel movements and hard stools lasting for at least three months or longer. This disease affects 8-12% of the US population and 10-17% of the world population. Treatment and management involve identifying the primary cause, changing dietary habits, and adequate physical activity. Linaclotide is a guanylate cyclase-agonist acting locally in the luminal surface of the intestinal enterocyte leading to a signal transduction cascade, activation of the cystic fibrosis transmembrane conductance regulator (CFTR), thus increasing secretion of chloride and bicarbonate into the intestinal lumen with eventual increased intestinal fluid and faster transit time. AREAS COVERED: We reviewed multiple studies and did a thorough literature review on CIC including its pathophysiology. Through this literature review, we were able to discuss and give the context and rationale for drug regimens indicated for CIC. EXPERT OPINION: The era we live in right now is akin to nutrient-rich and fertilized soil as knowledge and resources are abundant. The opportunities and potential are endless. Constipation being more extensively studied, our understanding of medications and diseases broadens, leading to novel medications being discovered. Linaclotide is a pioneer in this aspect and can pave the way for future generations.

Multi-omics combined to explore the purging mechanism of Rhei Radix et Rhizoma and Magnoliae Officinalis Cortex.

Rhei Radix et Rhizoma and Magnoliae Officinalis Cortex have been used together to treat constipation in the clinical practices for more than 2000 years. Nonetheless, their compatibility mechanism is still unclear. In this study, the amelioration of Rhei Radix et Rhizoma combined with Magnoliae Officinalis Cortex on constipation was systematically and comprehensively evaluated. The results showed that their compatibility could markedly shorten gastrointestinal transport time, increase fecal water content and frequency of defecation, improve gastrointestinal hormone disorders and protect colon tissue of constipation rats compared with the single drug. Furthermore, according to 16S rRNA sequencing in conjunction with UPLC-Q-TOF/MS, the combination of two herbal medications could greatly raise the number of salutary bacteria (Lachnospiraceae, Romboutsia and Subdoligranulum) while decreasing the abundance of pathogenic bacteria (Erysipelatoclostridiaceae). And two herb drugs could markedly improve the disorder of fecal metabolic profiles. A total of 7 different metabolites associated with constipation were remarkably shifted by the compatibility of two herbs, which were mainly related to arachidonic acid metabolism, alpha-linolenic acid metabolism, unsaturated fatty acid biosynthesis and other metabolic ways. Thus, the regulation of intestinal microbiome and its metabolism could be a potential target for Rhei Radix et Rhizoma and Magnoliae Officinalis Cortex herb pair to treat constipation. Furthermore, the multi-omics approach utilized in this study, which integrated the microbiome and metabolome, had potential for investigating the mechanism of traditional Chinese medicines.

Management of functional constipation-associated halitosis: a retrospective study.

The features of functional constipation (FC)-associated halitosis were identified in the author's previous report. In this report, the author aimed to further investigate its treatment and efficacy. This retrospective study reviewed 100 FC patients, including 82 (82%) halitosis patients and 18 (18%) non-halitosis patients. They underwent the organoleptic test (OLT) to diagnose halitosis, and the organoleptic score (OLS) (0-5) was used to evaluated halitosis severity. The Cleveland Clinical Constipation Score (CCCS) (0-30) was used to evaluate FC severity. Patients were treated with the laxative polyethylene glycol electrolyte powder (PGEP) for four weeks. These tests were performed before and after treatment. The author found that, before treatment, the CCCS was 20.00 (18.00-23.00) for all patients, 21.00 (19.00-24.00) for halitosis patients, and 18.00 (17.00-18.25) for non-halitosis patients. A significant difference was observed between halitosis patients and non-halitosis patients (P< 0.001). The OLS for halitosis patients was 3.00 (3.00-4.00). A positive correlation (r= 0.814, 95% CI: 0.732-0.872,P< 0.001) was found between OLS and CCCS. A CCCS ⩾18 predicted over 50% probability of halitosis. After treatment, the CCCS significantly decreased to 11.50 (6.00-14.75) (P< 0.001), and OLS significantly decreased to 1.00 (0.00-2.00) (P< 0.001). A positive correlation (r= 0.770, 95% CI: 0.673-0.841,P< 0.001) persisted between OLS and CCCS. A pre-treatment CCCS ⩾21 predicted over 50% probability of post-treatment halitosis, while a post-treatment CCCS ⩾12 predicted over 50% probability of post-treatment halitosis. The author concludes that the severity of FC parallels the severity of FC-associated halitosis, and can predict the probability of halitosis. Laxative treatment with PGEP is effective in improving FC-associated halitosis.

Probiotics combination effectively improves constipation in pregnancy by modifying the gut microbiota composition.

Constipation during pregnancy can induce serious complications, including miscarriage and preterm labour, while the evidence of probiotics in improving constipation during pregnancy was little. In this study, 29 healthy pregnant women and 65 constipated pregnant women were enrolled to assess the effectiveness of probiotics on constipation during pregnancy. Our results showed that the probiotics were effective in improving the Constipation Severity Scale (CSS) and Bristol Stool Scale (BSS) scores, including increasing defecation frequency, decreasing defecation time, and improving fecal characteristics. 16S rRNA sequencing revealed that the probiotics effectively restored the diversity of intestinal microbiota. At the phylum level, Firmicutes (13.27% vs 57.20%) and Actinobacteria (3.77% vs 12.80%) were increased, while Bacteroidetes (77.82% vs 20.24%) was decreased. At the level of the genus, Faecalibacterium (2.03% vs 10.33%), Bifidobacterium (1.21% vs 8.56%), and Phascolarctobacterium (0.05% vs 2.88%), the beneficial bacteria were increased, while the Bacteroides (29.23% vs 12.28%) and Prevotella (24.32% vs 4.92%) were decreased. In conclusion, these results indicated that probiotics can effectively relieve the constipation symptoms by improving the diversity of intestinal microbiota, regulating the disturbance of microflorae, and restoring the balance of microflorae to exert a stronger moderating effect than diet and lifestyle modification. Our results provided clinical data and a theoretical basis for the exploitation of probiotics in treating constipation during pregnancy. Chinese Clinical Trial Registry: ChiCTR2100052069.

The relationship between small intestinal bacterial overgrowth and constipation in children - a comprehensive review.

Small intestinal bacterial overgrowth (SIBO) is characterized by an increase in the bacterial population of the small intestine due to an imbalance between the amount of bacteria and the intestinal barrier. Pediatric SIBO presents with a wide spectrum of symptoms, ranging from mild gastrointestinal complaints to malabsorption or malnutrition. Breath tests are commonly used as noninvasive diagnostic tools for SIBO, but a standardized methodology is currently unavailable. Intestinal flora produces methane which slows intestinal transit and increases the contractile activity of small intestine. Emerging literature suggests a correlation between overgrowth of methanogenic bacteria in the intestines and constipation. Treatment of SIBO involves administration of antibacterial therapy in addition to management of underlying conditions and optimal dietary adjustments. However, research on antibiotic treatment for pediatric patients with constipation and SIBO is limited and has yielded conflicting results. In the current review, we summarize the state-of-the-art of the field and discuss previous treatment attempts and currently used regimens for SIBO patients with constipation, with a focus on pediatric populations.

Effect of adding telerehabilitation home program to pharmaceutical treatment on the symptoms and the quality of life in children with functional constipation: a randomized controlled trial.

Painful defecation, the passage of hard stools, unpleasant or irregular bowel deviation/movements from regular rate, and/or the feeling of not enough elimination of stool are common symptoms of functional constipation. The goals in treating constipation are to produce soft, painless stools and to prevent the re-accumulation of feces. This study looked at how the telerehabilitation home program (TRP) affected the symptoms of FC and the children who were constipated in terms of their quality of life. A randomized controlled trial included 400 children aging 4-18 years with functional constipation distributed in two groups: control group consisted of 200 children receiving pharmaceutical treatment and the intervention group consisted of 200 children receiving the telerehabilitation home program in addition to pharmaceutical treatment. Both groups received the interventions for 6 months. The outcomes in terms of functional constipation symptoms and quality of life are measured and compared pre- and post-interventions. Adding the telerehabilitation home program to pharmaceutical treatment of functional constipation in children results in prominent improvement in the condition; there is a significant difference between the intervention and control group in all Rome criteria which assess symptoms of functional constipation except rush to the bath-room to poop which showed non-significant difference; there is also a significant difference between the intervention and control group in all domains of the SF-36 questionnaire which assess quality of life except the mental health domain which showed non-significant difference. CONCLUSION: Adding the telerehabilitation home program to pharmaceutical treatment of functional constipation in children results in prominent improvement in symptoms of functional constipation and quality of life. TRIAL REGISTRATION: Our study was registered retrospectively with Clinicaltrials.gov under the identifier NCT06207721 on 5 January 2024. WHAT IS KNOWN: • Painful defecation, passage of hard stools, unpleasant or irregular bowel movements, feeling of incomplete stool elimination are common symptoms of functional constipation. • Goals in treating constipation include producing soft, painless stools and preventing re-accumulation of feces. WHAT IS NEW: • Adding telerehabilitation home program to pharmaceutical treatment resulted in significant improvement in functional constipation symptoms and quality of life. • Significant differences between intervention group (200 children receiving telerehabilitation home program in addition to pharmaceutical treatment) and control group (200 children receiving pharmaceutical treatment) were observed in all Rome criteria except for rush to the bathroom to poop, and in all domains of SF36 questionnaire except for the mental health domain.

Effects and mechanisms of sciadonic acid on colonic transit function through regulating 5-HT4/cAMP/PKA/AQP4 signaling pathway in STC model mice.

Torreya grandis (T. grandis) oil has been reported to alleviate symptoms of slow transit constipation (STC). However, the impact of sciadonic acid (SA), a distinctive fatty acid found in T. grandis oil, on the pathological progression of STC remains unclear. This study aimed to evaluate the effect of SA on STC and uncover the underlying mechanisms. The STC model was established by feeding Balb/c mice with loperamide. After 2 weeks of intervention, SA significantly improved weight loss and intestinal motility decline induced by STC, along with enhancing plasma indices and reducing colon pathological damage. SA effectively reversed the STC-induced decrease in the 5-HT4/cAMP/PKA/AQP4 signaling pathway genes and expression. Furthermore, 16S rRNA analysis demonstrated that SA mitigated the imbalance of the intestinal microbiota induced by STC, by reducing the ratio of Firmicutes to Bacteroidetes (F/B) and increasing the abundance of beneficial bacteria such as Akkermansia. In conclusion, SA intervention alleviated colonic dysfunction in STC mice. The activation of the SA-mediated 5-HT4/cAMP/PKA/AQP4 signaling pathway may serve as a potential target for STC treatment. These findings suggest that SA holds promise as a treatment option for STC and could potentially be extended to other related gut diseases for further investigation.

A diet low in fermentable oligo-, di-, monosaccharides and polyols improves abdominal and overall symptoms in persons with all subtypes of irritable bowel syndrome.

BACKGROUND: A diet low in fermentable oligo-, di-, monosaccharides and polyols (LFD) improves symptoms in patients with irritable bowel syndrome (IBS). Previous studies have focused on patients with IBS and diarrhea (IBS-D). It is unclear whether LFD is effective for IBS with constipation (IBS-C) or IBS with mixed bowel habits (IBS-M). This open-label, real-world study evaluates the relative effectiveness of the LFD among IBS subtypes. METHODS: This study analyzes data from a service that provides low-FODMAP meals to individuals with IBS. Participants met with a registered dietitian and completed the IBS symptom severity survey (IBS-SSS) before and after undergoing a 2-4-week period of FODMAP restriction. The primary endpoint was the proportion of participants with ≥50-point decrease in IBS-SSS between the three IBS subtypes. KEY RESULTS: After FODMAP restriction, 90% of participants with IBS-D, 75% with IBS-C, and 84% with IBS-M met the primary endpoint (p = 0.045). Similar improvement was seen for a 100-point decrease, but the difference between IBS subtypes was not significant (p = 0.46). After FODMAP restriction, all groups had statistically significant improvement in total IBS-SSS as well as individual symptom categories. Improvement in IBS-SSS subcategories was similar among the groups except for the categories of bloating severity (IBS-M had greatest improvement) and bowel movement satisfaction (IBS-C had less improvement). CONCLUSION & INFERENCES: Though the proportion of responders was highest for IBS-D and lowest for IBS-C, the LFD led to robust improvement in overall symptoms in all IBS subtypes. Key individual symptoms also showed significant improvements in all IBS subtypes.

Hydrogen-rich water alleviates constipation by attenuating oxidative stress through the sirtuin1/nuclear factor-erythroid-2-related factor 2/heme oxygenase-1 signaling pathway.

BACKGROUND: Constipation, a highly prevalent functional gastrointestinal disorder, induces a significant burden on the quality of patients' life and is associated with substantial healthcare expenditures. Therefore, identifying efficient therapeutic modalities for constipation is of paramount importance. Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms. Consequently, we postulate that hydrogen therapy, an emerging and promising intervention, can serve as a safe and efficacious treatment for constipation. AIM: To determine whether hydrogen-rich water (HRW) alleviates constipation and its potential mechanism. METHODS: Constipation models were established by orally loperamide to Sprague-Dawley rats. Rats freely consumed HRW, and were recorded their 24 h total stool weight, fecal water content, and charcoal propulsion rate. Fecal samples were subjected to 16S rDNA gene sequencing. Serum non-targeted metabolomic analysis, malondialdehyde, and superoxide dismutase levels were determined. Colonic tissues were stained with hematoxylin and eosin, Alcian blue-periodic acid-Schiff, reactive oxygen species (ROS) immunofluorescence, and immunohistochemistry for cell growth factor receptor kit (c-kit), PGP 9.5, sirtuin1 (SIRT1), nuclear factor-erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1, Nrf2 and HO-1. A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor, EX527, into constipated rats. NCM460 cells were induced with H2O2 and treated with the metabolites to evaluate ROS and SIRT1 expression. RESULTS: HRW alleviated constipation symptoms by improving the total amount of stool over 24 h, fecal water content, charcoal propulsion rate, thickness of the intestinal mucus layer, c-kit expression, and the number of intestinal neurons. HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism. HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway. This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats. The serum metabolites, ß-leucine (ß-Leu) and traumatic acid, were also found to attenuate H2O2-induced oxidative stress in NCM460 cells by up-regulating SIRT1. CONCLUSION: HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway, modulating gut microbiota and serum metabolites. ß-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.

Current and future pharmacotherapies for the management of constipation-predominant irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder affecting 9-23% of the world's population, with a higher prevalence among women. IBS is a complex disorder influenced by psychosocial, physiological, and genetic factors, exacerbated by stress. AREAS COVERED: Research confirms that the most common subtype of IBS is IBS-C. Therefore, new therapies are being developed to speed up bowel movement and reduce constipation, with drugs such as linaclotide, plecanatide, lubiprostone, or tegaserod available to reduce IBS-C symptoms. In addition, patients' condition is improved by foods rich in fiber and low in FODMAP and the use of biotics. EXPERT OPINION: The topic is of great importance due to the growing number of patients suffering from IBS-C and its significant impact on quality of life. Current clinical trials of new therapeutic options are not too successful, and it seems that one of the plausible treatment options could be the multi-drug cocktail with some, or perhaps even all its ingredients emerging from drug re-purposing. Another important path that needs to be explored further in IBS-C patients is the adjustment of dietary habits and/or introduction of dietary or nutritional intervention.

Efficacy and Molecular Mechanism of Quercetin on Constipation Induced by Berberine via Regulating Gut Microbiota.

Berberine (BBR) is used to treat cancer, inflammatory conditions, and so on. But the side effects of BBR causing constipation should not be ignored. In clinical application, the combination of Amomum villosum Lour. (AVL) and BBR can relieve it. However, the effective ingredients and molecular mechanism of AVL in relieving constipation are not clear. A small intestine propulsion experiment was conducted in constipated mice to screen active ingredients of AVL. We further confirmed the molecular mechanism of action of the active ingredient on BBR-induced constipation. Quercetin (QR) was found to be the effective ingredient of AVL in terms of relieving constipation. QR can efficiently regulate the microbiota in mice suffering from constipation. Moreover, QR significantly raised the levels of substance P and motilin while lowering those of 5-hydroxytryptamine and vasoactive intestinal peptide; furthermore, it also increased the protein expression levels of calmodulin, myosin light-chain kinase, and myosin light chain. The use of QR in combination with BBR has an adverse effect-reducing efficacy. The study provides new ideas and possibilities for the treatment of constipation induced by BBR.

How do we define therapy-resistant constipation in children aged 4-18 years old? A systematic review with meta-narrative synthesis.

BACKGROUND: Therapy-resistant constipation often is a frustrating clinical entity recognised by the persistence of infrequent and painful bowel movements faecal incontinence and abdominal pain despite intensive treatment. It is important to clearly define therapy-resistant constipation before children are subjected to invasive diagnostic and therapeutic procedures. AIM: To conduct a systematic review determining how paediatric interventional studies define therapy-resistant constipation. METHOD: We searched CENTRAL, MEDLINE, Embase, WHO ICTR and ClinicalTrials.gov. Studies that included patients with therapy-resistant constipation were identified. Data were extracted on criteria used for defining therapy-resistant constipation and reported using a meta-narrative approach highlighting areas of convergence and divergence in the findings. RESULTS: A total of 1553 abstracts were screened in duplicate, and 47 studies were included in the review. There were at least seven definitions used in the paediatric literature to define medically resistant constipation. The term intractable was used in 24 articles and 21 used the term refractory to describe therapy-resistant constipation. Out of them, only 14 articles have attempted to provide an explicit definition including a predefined time and prior therapy. There were 10 studies without a clear definition for therapy-resistant constipation. The duration before being diagnosed as therapy-resistant constipation varied from 1 months to 2 years among studies. Seven studies employed the Rome criteria (Rome III or Rome IV) to characterising constipation while five adopted the Rome III and European and North American paediatric societies definition of paediatric gastroenterology, hepatology and nutrition guideline of management of constipation in children. CONCLUSION: The current literature has no explicit definition for therapy-resistant constipation in children. There is a need for a detailed consensus definition to ensure consistency of future research and to avoid unnecessary and maybe even harmful, invasive diagnostic and therapeutic interventions.

Laxative Weaning Protocol for Patients With Functional Constipation: A Pilot Study.

BACKGROUND: Children with functional constipation require prolonged laxative administration for proper emptying. Whether these laxatives can be weaned after better functioning is achieved is unknown. We aim to describe a standardized protocol for stimulant laxative weaning and its early outcomes. METHODS: Patients were candidates for weaning if they had been on a stable laxative dose for six months, defined as one bowel movement per day with no soiling, impaction, or enemas. Laxative dose was decreased by 10-25% with re-evaluation every two weeks. If patients remained well without constipation, dose was weaned further by 10-25%. If there were worsening of symptoms, lower dose was maintained for 3-6 months until re-evaluation. RESULTS: There were a total of sixteen patients evaluated. Median age was 12.7 years [IQR: 11.7-15.3] with laxative duration of 8.0 years [IQR: 5.4-10.7]. All patients were on senna; some were on fiber. Median starting senna dose was 71.3 mg [IQR: 54.3-75.0] and median fiber dose was 5.5 g [IQR: 4.0-6.0]. As of most recent follow up, nine patients (56.3%) had weaned off laxatives in 3.7 months [IQR: 1.3-11.6]. For those still on laxatives, median reduction in dose was 41.4 mg [30.0-75.0], and over half weaned their dose by >50%. Almost all (90.9%) of those on high doses were able to wean. CONCLUSION: A standardized laxative weaning process can be successful in patients with functional constipation, especially on high doses. Further prospective studies will be necessary to confirm the success of this protocol. LEVEL OF EVIDENCE: III.