Calcineurin inhibition enhances Caenorhabditis elegans lifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling.

Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan of Caenorhabditis elegans through multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) in C. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. The TFEB ortholog, HLH-30, is required for lifespan extension mediated by calcineurin inhibition. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is necessary for the increased lifespan. Our studies uncover a role for calcineurin in the C. elegans DMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.

Many research efforts currently focus on identifying the dietary, pharmacological or genetic interventions that could help to prolong life. In the process, these investigations often uncover complex or even unexpected relationships between a range of physiological processes. The link between longevity and the immune system, for example, is yet to be fully understood. To explore these dynamics, Das et al. focused on calcineurin, an enzyme present in organisms across the tree of life. In humans, calcineurin is known to regulate a set of proteins essential for the immune response; these proteins are absent in the microscopic worm Caenorhabditis elegans, in which inhibiting calcineurin extends lifespan. Investigating how calcineurin inhibition impacts the immune system of C. elegans therefore presents a unique opportunity to better understand the complex links between immunity and longevity. Experiments conducted on worms genetically modified to lack calcineurin showed that these animals lived longer than their 'normal' counterparts, but that they were also more susceptible to infection when exposed to a harmful species of bacteria. Further experiments showed that the enzyme was crucial for regulating defecation in C. elegans. Without calcineurin, the worms became bloated and constipated; they could not properly eliminate bacteria, which could then proliferate in the digestive system and cause issues. However, intestinal bloating also activated signalling pathways normally triggered by calorie restriction ­ an intervention well-known for extending the lifespan of various species. Taken together, the findings by Das et al. help explain why calcineurin inhibition in C. elegans leads to opposite effects on longevity and resistance to infection. They also align with a recent body of work showing the profound effect of gut bloating on food-seeking behaviors, immunity and lifespan. Further investigations into these mechanisms may one day uncover new ways to improve human health.

Eight-Week Supplementation With Bifidobacterium lactis HN019 and Functional Constipation: A Randomized Clinical Trial.

Importance: Probiotic supplementation may improve bowel movements. However, large, properly designed studies are lacking. Objective: To evaluate the potential benefit of Bifidobacterium animalis subsp lactis HN019 on constipation, expressed as complete spontaneous bowel movements (CSBMs). Design, Setting, and Participants: This randomized triple-blind placebo-controlled clinical trial with 2 weeks of run-in and 8 weeks of intervention was conducted from December 25, 2020, to February 28, 2022, at 5 hospitals in Shanghai, China. Participants included healthy volunteers with functional constipation according to Rome III criteria, 18 to 70 years of age, and a body mass index (calculated as the weight in kilograms divided by the height in meters squared) of less than 30.0. Eligibility after the run-in phase required the randomized participants to have 3 or fewer CSBMs/wk. Data were analyzed from September 29, 2022, to March 23, 2023, and reported as intention to treat. Intervention: Participants were randomized to receive probiotic (B lactis HN019, 7.0 × 109 colony forming units (CFU)/d in maltodextrin at the start of the study and 4.69 × 109 CFU/d at the end of the study or maltodextrin placebo once a day for 8 weeks. Main Outcomes and Measures: Primary outcome was change in CSBMs. Secondary outcomes included use of rescue medication, stool consistency, degree of straining for each bowel movement, abdominal pain, and bloating. Further, dietary habits and physical activity were recorded. Fecal samples were analyzed for moisture content, short-chain fatty acids, branched-chain fatty acids, microbiota composition, and calprotectin. Results: Of the 283 individuals assessed for eligibility, 229 were randomized to either the placebo (n = 117) or the HN019 (n = 112) group. One participant in the placebo group discontinued due to COVID-19 restrictions. The 229 participants (194 [84.7% female) had a median age of 45 (38-52) years, mean (SD) BMI of 22.8 (2.5), and a mean (SD) of 0.77 (1.0) CSBM/wk. There was no difference in the change of weekly CSBMs from baseline to the end of study between the HN019 (least-square mean change, 0.80 [95% CI, 0.54-1.05]) and placebo (least-square mean change, 0.66 [95% CI, 0.41-0.90]) groups. Conclusions and Relevance: Although probiotics have been reported to improve bowel function, this large, well-conducted randomized clinical trial did not confirm such results. Daily consumption of B lactis HN019 at the tested dose of 4.69 × 109 CFU did not outperform placebo to increase CSBMs. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000029215.

Laxative Properties of Microencapsulated Oleic Acid Delivered to the Distal Small Intestine in Patients with Constipation after Bariatric Surgery or Treatment with Glucagon-Like- Peptide 1 Analogues.

BACKGROUND: Constipation is prevalent after bariatric surgery and glucagon-like-peptide 1 (GLP-1) analogues. Increasing fat content in the distal small intestine and colon can enhance colonic peristalsis, potentially alleviating symptoms of constipation. AIM: We investigated whether oleic acid can ameliorate constipation in patients undergoing bariatric surgery or receiving GLP-1 analogues. METHODOLOGY: Fourteen adults with chronic constipation according to Rome IV criteria following bariatric surgery or GLP-1 analogues were on stable treatment for constipation for more than 4 weeks. This randomized double-blind crossover trial compared microcapsules containing 21.25 g of oleic acid delivered in the distal small intestine or the stomach. The primary outcome was changed in the number of bowel motions over 24 h. Exploratory endpoints included alterations in straining, diarrhoea, faecal leakage over 24 h and hunger, fullness, nausea and calorie intake for the 3 h after ingesting the microcapsules. FINDINGS: Receiving oleic acid into the distal small intestine increased number of bowel movements per day (2.5 vs 1.1, p = 0.009) and caused softer stool consistency (p = 0.03). 9/14 of the control group passed motions and 13/14 of the intervention group passed motions in 24 h (p = 0.059). No significant differences were observed in straining (p = 0.65), rapid bowel movements (p = 0.08), accidental leakage (p = 0.32), hunger, fullness, nausea or food intake between the groups (all p > 0.05). There were no disparities in safety profile between groups. CONCLUSION: Microcapsules containing oleic acid delivered to the distal small intestine appear to be a safe and effective relief from chronic constipation in patients undergoing bariatric surgery and/or receiving GLP-1 analogues.

Effect of sugammadex with neostigmine on postoperative bowel function and on recovery of neuromuscular functions: A randomized controlled trial.

BACKGROUND: Early recovery of neuromuscular and bowel function after abdominal surgery are important clinical indicators of postoperative recovery. This study aimed to investigate the effects of sugammadex, and neostigmine added to sugammadex, on postoperative bowel function and recovery from neuromuscular blocking agents. METHODS: Ninety gynecological surgery patients, aged 18 to 65 years, with American Society of Anesthesiologists of 1 to 2 were randomly assigned to 3 groups: sugammadex 2 mg/kg (Group S), sugammadex 1 m/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S1N), and sugammadex 1.5 mg/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S2N), for reversal at the end of surgery during moderate block (train-of-four [TOF] count 1-2). Propofol, remifentanil, rocuronium, and sevoflurane were used for general anesthesia, and neuromuscular function was assessed using kinemyography. The primary outcomes assessed the effects of sugammadex alone and in combination with neostigmine on the time to first flatus. The secondary outcomes included time to first defecation and recovery time; defined as the administration of reversal agent to TOF ratio 90%. RESULTS: Data from 90 female patients who underwent abdominal gynecological surgery were analyzed. No significant differences were found between the groups in term of the time to first flatus, defecation, or postoperative nausea and vomiting after surgery. However, significant differences were observed in the time to reach a TOF ratio 90% (P < .001) and extubation time (P = .003). CONCLUSION: The addition of neostigmine to sugammadex did not affect bowel function recovery. However, combining 20 µg/kg neostigmine with 1.5 mg/kg sugammadex or 2 mg/kg sugammadex alone antagonized moderate-depth nondepolarizing neuromuscular blockade with similar efficacy.

Efficacy of Lacticaseibacillus paracasei fermented milk on a model of constipation induced by loperamide hydrochloride in BALB/c mice.

Currently, most studies focus on the functions of probiotic-fermented milk, whereas there are relatively few studies on the function of postbiotic-fermented milk in relieving constipation. In this study, we aimed to assess the modulation of constipation symptoms and its mechanism of action by different concentrations of Lacticaseibacillus paracasei-fermented milk as a postbiotic in a loperamide hydrochloride-induced constipation model in BALB/c mice. By comparing the relevant indexes, colon histological analysis, gene expression level, and intestinal flora structure in the constipation model of mice, we found that high and ultra-high doses of fermented milk can effectively relieve constipation. Fermented milk effectively reduced defecation time, increased the rate of small intestinal propulsion in constipated mice, and alleviated colonic inflammation, safeguarding the normal function of the intestinal tract. In addition, it can regulate the intestinal flora, downregulate the abundance of Proteobacteria, upregulate the abundance of species of Firmicutes and Actinobacteriota, and improve the overall abundance level of intestinal flora in mice.

Evaluation of the efficacy of polyethylene glycol in combination with different doses of linaclotide in a fractionated bowel preparation for colonoscopy: a prospective randomized controlled study.

BACKGROUND AND AIM: The ideal bowel cleansing program still needs to be explored. The aim was to compare the bowel cleansing effect and patient tolerance of low-dose polyethylene glycol (PEG) combined with different doses of linaclotide in fractionated bowel preparation. METHODS: The subjects were randomly assigned to the 3LPEG group, 2LPEG + 2L group, or 2LPEG + L group. The primary outcome was to use the Ottawa Bowel Preparation Scale (OBPS) to evaluate the efficacy of bowel cleansing, and the secondary outcomes were the detection rate of adenomas and polyps, adverse reactions, tolerance, and defecation dynamics; subsets of patients with chronic constipation and irritable bowel syndrome were also analyzed. RESULTS: A total of 753 patients were randomly assigned. In ITT analysis, the success of preparation of the 2LPEG + 2L group was better than that of the 2LPEG + L group or the 3LPEG group (92.0% vs. 82.3% vs. 82.1%; P = 0.002). Compared with the 3LPEG group, the 2LPEG + L group showed similar but non-inferior results (82.3% vs. 82.1%, P > 0.05). The 2LPEG + 2L group was similar to the 2LPEG + L group in terms of adverse reaction, tolerance, willingness to reuse, and sleep quality, but both were superior to the 3LPEG group. In a subgroup analysis of chronic constipation, the 2LPEG + 2L group had the best cleansing effect on the right colon and mid colon, while in the subgroup analysis of irritable bowel syndrome, the tolerance was better in the 2LPEG + 2L group and the 2LPEG + L group than the 3LPEG group. CONCLUSIONS: 2LPEG + 2L is a feasible bowel preparation regimen.

The influence of tramadol on bowel function: A randomised, placebo-controlled trial.

Tramadol is a weak opioid used to treat moderate pain. Stronger opioids inhibit gastrointestinal function, but little is known about the gastrointestinal effects of tramadol. Our aim was to investigate if tramadol causes opioid-induced bowel dysfunction (OIBD). Twenty healthy male participants (mean age 24 [range 20-31] years) were included. Tramadol (extended-release formulation, 200 mg/day) or placebo was administered for 10 days in two study periods separated by 3 weeks. Gastrointestinal transit times and segmental volume, motility and water content were investigated with the 3D-transit system and magnetic resonance imaging. Bowel movements and gastrointestinal symptoms were recorded daily. Tramadol prolonged colonic transit time (34 h vs. 25 h, p < 0.001) and increased small bowel motility (p < 0.01) and water content (p = 0.002) compared to placebo. Across all days of treatment, tramadol reduced the number of mean daily bowel movements (p = 0.001) and increased mean stool consistency (p = 0.006). Gastrointestinal symptom scores increased with tramadol (indigestion: +358%, p = 0.01; constipation: +475%, p = 0.01). Additionally, more participants fulfilled the diagnostic criteria for constipation after tramadol treatment compared to placebo (40% vs. 0%, p < 0.001). This study showed that tramadol treatment is associated with OIBD, and management of constipation and other bowel symptoms should, therefore, be prioritised when treating pain patients with tramadol.

Effects of neuromuscular block reversal with neostigmine/glycopyrrolate versus sugammadex on bowel motility recovery after laparoscopic colorectal surgery: A randomized controlled trial.

STUDY OBJECTIVE: To compare the effects of neostigmine/glycopyrrolate (a traditional agent) and sugammadex on bowel motility recovery and the occurrence of digestive system complications after colorectal surgery. DESIGN: Prospective, randomized controlled trial. SETTING: A single tertiary center. PATIENTS: 111 patients undergoing laparoscopic colorectal surgery. INTERVENTIONS: Patients were randomized into two groups based on the block reversal agent: 1) a mixture of 50 µg.kg-1 of neostigmine and 10 µg.kg-1 of glycopyrrolate (neostigmine group) and 2) 2 mg.kg-1 of sugammadex (sugammadex group). MEASUREMENTS: The primary outcome was the time from the surgery's completion to the first flatus. The time to the first postoperative defecation, incidences of postoperative nausea or vomiting, ileus, and dry mouth, as well as postoperative length of stay, were also assessed. MAIN RESULTS: The time to the first flatus was significantly shorter in the sugammadex group than in the neostigmine group (59 [42-79] h vs 69 [53-90] h, P = 0.027). The time to the first defecation and the incidences of postoperative nausea or vomiting and ileus did not differ between the groups, nor did the postoperative length of stay. However, the incidence of postoperative dry mouth was significantly lower in the sugammadex group than in the neostigmine group (7 patients [13%] vs 39 patients [71%], P < 0.001). CONCLUSIONS: The time to the first flatus was shorter using 2 mg.kg-1 sugammadex to reverse the neuromuscular block for laparoscopic colorectal surgery compared to reversal with conventional neostigmine/glycopyrrolate.

Clinical trial: Effects of treatment with a vibrating capsule in patients with severe chronic constipation.

BACKGROUND: There is little information on the effectiveness of therapies for severe chronic constipation. In a phase 3 trial, we previously demonstrated that a vibrating capsule was significantly more efficacious than a placebo in chronic constipation. AIM: To examine the effects of a vibrating capsule and placebo on symptoms and health-related quality of life (HRQoL) in patients with severe chronic constipation. METHODS: We performed a post hoc analysis of phase 3, multicentre, randomised, double-blind, and placebo-controlled 8-week clinical trial of a vibrating capsule to specifically assess outcomes among subjects who reported 0 complete spontaneous bowel movements (CSBMs) during the 2-week baseline period. We assessed effects of treatment on bowel symptoms, patient satisfaction, and HRQoL. CSBM responders were defined as subjects with increases of ≥1 or ≥2 or ≥3 weekly CSBMs (CSBM1 or CSBM2, CSBM3, respectively) over baseline for ≥6 out of 8 weeks of treatment. RESULTS: The severe chronic constipation subgroup comprised 175 (56%) of the 312 subjects. Significantly more subjects with severe chronic constipation who received the vibrating capsule than those who received the placebo were CSBM1 (44.9% vs. 20.9%, p = 0.007), CSBM2 (29.2% vs. 11.6%, p = 0.004), and CSBM3 (19.10% vs 6.98%, p = 0.017) responders. Straining effort, stool consistency, patient satisfaction, and HRQoL significantly improved in the severe chronic constipation subgroup. A mild vibrating sensation was reported in 10%. CONCLUSION: The vibrating capsule significantly improved constipation-related symptoms and HRQoL in patients with severe constipation, affirming its efficacy and safety across the spectrum of chronic constipation.

Physiologic and behavioral effects of long-acting subcutaneous and transdermal buprenorphine in rats.

OBJECTIVE: To investigate thermoregulation, thermal antinociception, food/kaolin intake, fecal output, and behavior following long-acting buprenorphine preparations in rats. ANIMALS: 8 adult male rats (Rattus norvegicus) were administered long-acting SC buprenorphine (SB; 0.65 mg/kg), transdermal buprenorphine (TB; 10 mg/kg), and controls in a randomized, cross-over design. METHODS: Body temperature, self-injury, sedation, food/kaolin intake, fecal output, and thermal withdrawal latencies were measured 1, 4, 8, 12, 24, 48, and 72 hours posttreatment. Data analysis was performed with mixed linear models. RESULTS: Self-injury was present between 1 and 12 hours and 4 and 12 hours following TB and SB, respectively; sedation was associated with TB at 12 to 24 hours. Withdrawal latencies were longer in both TB and SB groups than in the control group. Food intake decreased with time in all groups but was significantly lower 24 to 48 hours after TB and 24 to 72 hours after SB versus controls. Kaolin intake decreased from baseline 48 to 72 hours in the control group. Fecal output decreased from baseline 24 to 72 hours in all groups but was significantly lower than controls 24 hours following TB and 24 to 48 hours in SB. Body temperature increased from baseline at 1 hour, 1 to 12 hours, and 1 to 24 hours in the control, TB, and SB groups, respectively, and was significantly higher than the control group 1 to 72 hours following TB and 4 to 24 hours after SB. Transdermal buprenorphine and SB in normal rats produced antinociception, self-injurious behavior, hyperthermia, and decreased food/fecal output. CLINICAL RELEVANCE: Although these buprenorphine preparations may produce antinociception, untoward effects such as hyperthermia, self-injurious behavior, and reduced food intake/fecal output may be seen.

Safety and efficacy of linaclotide in children aged 2-5 years with functional constipation: Phase 2, randomized study.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC). This study evaluated the dose-response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2-5 years of age with FC. METHODS: In this phase 2, randomized, double-blind, placebo-controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 µg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 µg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded. RESULTS: Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 µg group versus placebo. A dose-response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment-emergent AEs, one of which was treatment-related (mild diarrhea). All AEs were mild or moderate and none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 µg versus placebo.

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 effect of Cuminum cyminum on the return of bowel motility after abdominal surgery: a triple-blind randomized clinical trial.

BACKGROUND AND OBJECTIVES: Considering the significant prevalence of ileus after abdominal surgery and the beneficial effects of Cuminum cyminum in digestive problems, this study aimed to examine whether Cuminum cyminum has any effect on the return of bowel motility after abdominal surgery. MATERIALS AND METHODS: In this triple-blind clinical trial study, 74 patients undergoing abdominal surgery were assigned to the intervention and control groups using minimization methods. The patients in the intervention group consumed 250 mg capsules containing Cuminum cyminum extract 4 h after the surgery and another dose of the drug 1 h afterward. The patients in the control group consumed a 250 mg capsule containing starch as a placebo at hours similar to those in the intervention group. The instruments used to collect the data were a demographic questionnaire and a researcher-made checklist to assess bowel habits. The data were analyzed using SPSS-22 software. RESULTS: The average time of gas passing in the intervention and control groups was 9.03 ± 3.41 and 11.72 ± 4.21 h, respectively. The defecation times in the intervention and control groups were 16.97 ± 5.02 and 26 ± 9.87 h, showing a significant difference between the two groups as indicated by the independent samples T-test (P > 0.001). Furthermore, abdominal pain, abdominal bloating, nausea, and vomiting were significantly less frequent in the intervention group compared to the control group as confirmed by Fisher's exact test (P > 0.001). CONCLUSION: According to the results, the consumption of Cuminum cyminum after abdominal surgery helps to reduce the time of gas passing, defecation, and the return of bowel motility. However, additional studies need to address the effectiveness of Cuminum cyminum by changing the time and duration of its use.

Opium tincture has anti-propulsive effects in patients with chronic diarrhea: a randomized, placebo-controlled, and cross-over trial.

OBJECTIVE: Chronic diarrhea affects approximately 5% of the population. Opioids inhibit gastrointestinal motility, and opium tincture has shown anti-propulsive effects in healthy, but no controlled studies of its clinical efficacy exist. We aimed to investigate the anti-propulsive and central nervous system (CNS) effects of opium tincture in patients with chronic diarrhea. MATERIALS AND METHODS: The study was a randomized, double-blinded, placebo-controlled, cross-over trial in subjects with chronic diarrhea refractory to standard treatment. Participants received opium tincture or placebo during two intervention periods, each lasting seven days. Bowel movements were recorded daily, and gastrointestinal transit time was investigated with the wireless motility capsule system. Gastrointestinal symptoms, health-related quality of life, and CNS effects (pupil size, reaction time, memory, and general cognition) were also investigated, along with signs of addiction. RESULTS: Eleven subjects (mean age: 45 ± 17 years, 46% males) with a median of 4.7 daily bowel movements were included. The number of daily bowel movements was reduced during opium tincture treatment to 2.3 (p = 0.045), but not placebo (3.0, p = 0.09). Opium tincture prolonged the colonic transit time compared to placebo (17 h vs. 12 h, p < 0.001). In both treatment arms, there were no changes in self-reported gastrointestinal symptoms, health-related quality of life, or CNS effects, and no indication of addiction was present. CONCLUSION: Opium tincture induced anti-propulsive effects in patients with chronic diarrhea refractory to standard treatment. This indicates that opium tincture is a relevant treatment strategy for selected patients with chronic diarrhea. Moreover, no evidence of opioid-induced sedation or addiction was found.Trial Registration Number: NCT05690321 (registered 2023-01-10).

Perioperative liberal drinking management promotes postoperative gastrointestinal function recovery after gynecological laparoscopic surgery: A randomized controlled trial.

STUDY OBJECTIVE: This study aims to evaluate the effect of perioperative liberal drinking management, including preoperative carbohydrate loading (PCL) given 2 h before surgery and early oral feeding (EOF) at 6 h postoperatively, in enhancing postoperative gastrointestinal function and improving outcomes in gynecologic patients. The hypotheses are that the perioperative liberal drinking management accelerates the recovery of gastrointestinal function, enhances dietary tolerance throughout hospitalization, and ultimately reduces the length of hospitalization. DESIGN: A prospective randomized controlled trial. SETTING: Operating room and gynecological ward in Wuhan Union Hospital. PATIENTS: We enrolled 210 patients undergoing elective gynecological laparoscopic surgery, and 157 patients were included in the final analysis. INTERVENTIONS: Patients were randomly allocated in a 1:1:1 ratio into three groups, including the control, PCL, and PCL-EOF groups. The anesthetists and follow-up staff were blinded to group assignment. MEASUREMENTS: The primary outcome was the postoperative Intake, Feeling nauseated, Emesis, Examination, and Duration of symptoms (I-FEED) score (range 0 to 14, higher scores worse). Secondary outcomes included the incidence of I-FEED scores >2, and other additional indicators to monitor postoperative gastrointestinal function, including time to first flatus, time to first defecation, time to feces Bristol grade 3-4, and time to tolerate diet. Additionally, we collected other ERAS recovery indicators, including the incidence of PONV, complications, postoperative pain score, satisfaction score, and the quality of postoperative functional recovery at discharge. MAIN RESULTS: The PCL-EOF exhibited significantly enhanced gastrointestinal function recovery compared to control group and PCL group (p < 0.05), with the lower I-FEED score (PCL: 0[0,1] vs. PCL-EOF: 0[0,0] vs. control: 1[0,2]) and the reduced incidence of I-FEED >2 (PCL:8% vs. PCL-EOF: 2% vs. control:21%). Compared to the control, the intervention of PCL-EOF protected patients from the incidence of I-FEED score > 2 [HR:0.09, 95%CI (0.01-0.72), p = 0.023], and was beneficial in promoting the patient's postoperative first flatus [PCL-EOF: HR:3.33, 95%CI (2.14-5.19),p < 0.001], first defecation [PCL-EOF: HR:2.76, 95%CI (1.83-4.16), p < 0.001], Bristol feces grade 3-4 [PCL-EOF: HR:3.65, 95%CI (2.36-5.63), p < 0.001], first fluid diet[PCL-EOF: HR:2.76, 95%CI (1.83-4.16), p < 0.001], and first normal diet[PCL-EOF: HR:6.63, 95%CI (4.18-10.50), p < 0.001]. Also, the length of postoperative hospital stay (PCL-EOF: 5d vs. PCL: 6d and control: 6d, p < 0.001), the total cost (PCL-EOF: 25052 ± 3650y vs. PCL: 27914 ± 4684y and control: 26799 ± 4775y, p = 0.005), and postoperative VAS pain score values [POD0 (PCL-EOF: 2 vs. control: 4 vs. PCL: 4, p < 0.001), POD1 (PCL-EOF: 1 vs. control: 3 vs. PCL: 2, p < 0.001), POD2 (PCL-EOF: 1 vs. control:2 vs. PCL: 1, p < 0.001), POD3 (PCL-EOF: 0 vs. control: 1 vs. PCL: 1, p < 0.001)] were significantly reduced in PCL-EOF group. CONCLUSIONS: Our primary endpoint, I-FEED score demonstrated significant reduction with perioperative liberal drinking, serving as a protective intervention against I-FEED>2. Gastrointestinal recovery metrics, such as time to first flatus and defecation, also showed substantial improvements. Furthermore, the intervention enhanced postoperative dietary tolerance and expedited early recovery. TRIAL REGISTRATION: ChiCTR2300071047(https://www.chictr.org.cn/).

Treatments for intractable constipation in childhood.

BACKGROUND: Constipation that is prolonged and does not resolve with conventional therapeutic measures is called intractable constipation. The treatment of intractable constipation is challenging, involving pharmacological or non-pharmacological therapies, as well as surgical approaches. Unresolved constipation can negatively impact quality of life, with additional implications for health systems. Consequently, there is an urgent need to identify treatments that are efficacious and safe. OBJECTIVES: To evaluate the efficacy and safety of treatments used for intractable constipation in children. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers up to 23 June 2023. We also searched reference lists of included studies for relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any pharmacological, non-pharmacological, or surgical treatment to placebo or another active comparator, in participants aged between 0 and 18 years with functional constipation who had not responded to conventional medical therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were symptom resolution, frequency of defecation, treatment success, and adverse events; secondary outcomes were stool consistency, painful defecation, quality of life, faecal incontinence frequency, abdominal pain, hospital admission for disimpaction, and school absence. We used GRADE to assess the certainty of evidence for each primary outcome. MAIN RESULTS: This review included 10 RCTs with 1278 children who had intractable constipation. We assessed one study as at low risk of bias across all domains. There were serious concerns about risk of bias in six studies. One study compared the injection of 160 units botulinum toxin A (n = 44) to unspecified oral stool softeners (n = 44). We are very uncertain whether botulinum toxin A injection improves treatment success (risk ratio (RR) 37.00, 95% confidence interval (CI) 5.31 to 257.94; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Frequency of defecation was reported only for the botulinum toxin A injection group (mean interval of 2.6 days). The study reported no data for the other primary outcomes. One study compared erythromycin estolate (n = 6) to placebo (n = 8). The only primary outcome reported was adverse events, which were 0 in both groups. The evidence is of very low certainty due to concerns with risk of bias and serious imprecision. One study compared 12 or 24 µg oral lubiprostone (n = 404) twice a day to placebo (n = 202) over 12 weeks. There may be little to no difference in treatment success (RR 1.29, 95% CI 0.87 to 1.92; low certainty evidence). We also found that lubiprostone probably results in little to no difference in adverse events (RR 1.05, 95% CI 0.91 to 1.21; moderate certainty evidence). The study reported no data for the other primary outcomes. One study compared three-weekly rectal sodium dioctyl sulfosuccinate and sorbitol enemas (n = 51) to 0.5 g/kg/day polyethylene glycol laxatives (n = 51) over a 52-week period. We are very uncertain whether rectal sodium dioctyl sulfosuccinate and sorbitol enemas improve treatment success (RR 1.33, 95% CI 0.83 to 2.14; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Results of defecation frequency per week was reported only as modelled means using a linear mixed model. The study reported no data for the other primary outcomes. One study compared biofeedback therapy (n = 12) to no intervention (n = 12). We are very uncertain whether biofeedback therapy improves symptom resolution (RR 2.50, 95% CI 1.08 to 5.79; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). The study reported no data for the other primary outcomes. One study compared 20 minutes of intrarectal electromotive botulinum toxin A using 2800 Hz frequency and botulinum toxin A dose 10 international units/kg (n = 30) to 10 international units/kg botulinum toxin A injection (n = 30). We are very uncertain whether intrarectal electromotive botulinum toxin A improves symptom resolution (RR 0.96, 95% CI 0.76 to 1.22; very low certainty evidence) or if it increases the frequency of defecation (mean difference (MD) 0.00, 95% CI -1.87 to 1.87; very low certainty evidence). We are also very uncertain whether intrarectal electromotive botulinum toxin A has an improved safety profile (RR 0.20, 95% CI 0.01 to 4.00; very low certainty evidence). The evidence for these results is of very low certainty due to serious concerns with risk of bias and imprecision. The study did not report data on treatment success. One study compared the injection of 60 units botulinum toxin A (n = 21) to myectomy of the internal anal sphincter (n = 21). We are very uncertain whether botulinum toxin A injection improves treatment success (RR 1.00, 95% CI 0.75 to 1.34; very low certainty evidence). No adverse events were recorded. The study reported no data for the other primary outcomes. One study compared 0.04 mg/kg oral prucalopride (n = 107) once daily to placebo (n = 108) over eight weeks. Oral prucalopride probably results in little or no difference in defecation frequency (MD 0.50, 95% CI -0.06 to 1.06; moderate certainty evidence); treatment success (RR 0.96, 95% CI 0.53 to 1.72; moderate certainty evidence); and adverse events (RR 1.15, 95% CI 0.94 to 1.39; moderate certainty evidence). The study did not report data on symptom resolution. One study compared transcutaneous electrical stimulation to sham stimulation, and another study compared dietitian-prescribed Mediterranean diet with written instructions versus written instructions. These studies did not report any of our predefined primary outcomes. AUTHORS' CONCLUSIONS: We identified low to moderate certainty evidence that oral lubiprostone may result in little to no difference in treatment success and adverse events compared to placebo. Based on moderate certainty evidence, there is probably little or no difference between oral prucalopride and placebo in defecation frequency, treatment success, or adverse events. For all other comparisons, the certainty of the evidence for our predefined primary outcomes is very low due to serious concerns with study limitations and imprecision. Consequently, no robust conclusions could be drawn.

Caffeine intake enhances bowel recovery after colorectal surgery: a meta-analysis of randomized and non-randomized studies.

Postoperative ileus (POI) after colorectal surgery is a major problem that affects both patient recovery and hospital costs highlighting the importance of preventive strategies. Therefore, we aimed to perform a systematic analysis of the effects of postoperative caffeine consumption on bowel recovery and surgical morbidity after colorectal surgery. A comprehensive literature search was conducted through September 2023 for randomized and non-randomized trials comparing the effect of caffeinated versus non-caffeinated drinks on POI by evaluating bowel movement resumption, time to first flatus and solid food intake, and length of hospital stay (LOS). Secondary outcome analysis included postoperative morbidity in both groups. After data extraction and inclusion in a meta-analysis, odds ratios (ORs) for dichotomous variables and standardized mean differences (SMDs) for continuous outcomes with 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed in cases of substantial heterogeneity. Six randomized and two non-randomized trials with a total of 610 patients were included in the meta-analysis. Caffeine intake significantly reduced time to first bowel movement [SMD -0.39, (95% CI -0.66 to -0.12), p = 0.005] and time to first solid food intake [SMD -0.41, (95% CI -0.79 to -0.04), p = 0.03] in elective laparoscopic colorectal surgery, while time to first flatus, LOS, and the secondary outcomes did not differ significantly. Postoperative caffeine consumption may be a reasonable strategy to prevent POI after elective colorectal surgery. However, larger randomized controlled trials (RCTs) with homogeneous study protocols, especially regarding the dosage form of caffeine and coffee, are needed.

A Comparison of the Effect of Kegel Exercises and Conventional Therapy versus Conventional Therapy Alone in the Treatment of Functional Constipation in Children: A Randomized Clinical Trial.

Background: There have been few studies on the effect of Kegel exercises on the treatment of functional constipation in children. Hence, the present study investigated the add-on role of Kegel exercises in children with functional constipation. Methods: This clinical trial was conducted on children with functional constipation, according to Rome IV, who were referred to the pediatric department of Imam Reza Clinic (Shiraz, Iran) in 2022. The sample consisted of 64 children who were randomly assigned to either the intervention or the control groups. In the control group, a pediatrician administered conventional therapy, including diet training, defecation training, and polyethylene glycol (PEG) syrup (0.7 g/Kg daily). In the treatment group, in addition to conventional therapy, a pediatrician taught Kegel exercises to the child both verbally and in writing in the presence of their parents. To investigate the effectiveness of the intervention, frequency of defecation, defecation time, assistance used for defecation, incomplete emptying, unsuccessful defecation, abdominal pain, and painful defecation were selected as the outcomes. Independent sample t test was used for continuous variables. Categorical variables were reported as frequency and percentages. To examine the difference in categorical outcome variables, Wilcoxon (pre and post), Chi square, and Fisher exact tests were used. Data were analyzed using SPSS software version 21. P<0.05 were considered statistically significant. Results: Twenty-seven (88.4%) patients in the Kegel exercise group reported a defecation time of less than 5 min, while only 12 (37.5%) patients in the control group reached this time, and this difference was statistically significant (P=0.001). Moreover, patients in the treatment group showed significant improvements in terms of incomplete emptying of stool, unsuccessful defecation, abdominal pain, and painless defecation (P=0.001, P=0.001, P=0.001, P=0.037, respectively). After intervention, the use of laxatives, digits, or enemas to assist defecation was not significantly different between the groups (P=0.659). Conclusion: Kegel exercise was an effective adjunctive treatment for pediatric functional constipation.Trial Registration Number: IRCT20230424057984N1.

Efficacy and safety of galacto-oligosaccharide in the treatment of functional constipation: randomized clinical trial.

The efficacy and safety of galacto-oligosaccharides (GOS) in treating functional constipation were evaluated in a four-week randomized, double-blind clinical trial on 63 patients who met Rome IV criteria (34 GOS, 29 placebo group). The number of bowel movements per day and changes in the shape of bowel movements in the treatment group significantly improved compared to those in the control group after four weeks. The Patient Assessment Constipation Quality of Life questionnaire showed that satisfaction with constipation significantly increased in the treatment group. The levels of Bifidobacterium sp. and Lactobacillus sp. significantly increased after four weeks of GOS treatment compared to those measured at baseline. No significant adverse drug reactions were identified in any indicator except for pulse rate. Thus, the prebiotic GOS can be safely used in foods and pharmaceuticals to alleviate symptoms of functional constipation by improving the intestinal flora.

A Novel Herbal Composition Alleviates Functional Constipation, Reduces Gastrointestinal Transit Time, and Improves Bowel Function in Adults: A Double-Blind, Randomized Clinical Study.

BACKGROUND AND OBJECTIVE: A recent proof-of-concept pilot clinical study has demonstrated that consumption of CL18100F4, a proprietary herbal blend of Withania somnifera root and Abelmoschus esculentus fruit extracts, significantly relieved the participants from functional constipation and improved their quality of life. The objective of the present randomized, double-blind, placebo-controlled study was to reevaluate the efficacy and tolerability of CL18100F4 in a larger number of subjects. METHODS: Male and female subjects (n = 135; age: 25-60 years), selected through Rome-IV criteria for functional constipation, were randomized into placebo and 300 or 500 mg of CL18100F4 groups and supplemented daily over 60 consecutive days. The primary efficacy outcome measure was Patient Assessment of Constipation-Symptoms (PAC-SYM), evaluated at baseline and on days 7, 30, and 60 of supplementation. The secondary efficacy parameters included Patient Assessment of Constipation-Quality of Life (PAC-QOL), Gastrointestinal Symptom Rating Scale (GSRS) scores, Gastrointestinal Transit Time (GIT), and Complete Spontaneous Bowel Movement (CSBM). Serum levels of Interleukin (IL)-6, IL-10, cortisol, gastrin, serotonin, Diamine oxidase (DAO), and Zonulin were measured. RESULTS: CL18100F4 supplementation significantly (p < 0.001) reduced the PAC-SYM, PAC-QOL, GSRS scores, and GIT and improved CSBM scores. CL18100F4 significantly improved (p < 0.001) sleep quality and decreased depression and anxiety symptoms in the participants. Notably, relief in constipation symptoms and improved gastrointestinal (GI) function were reported starting from day 7. Furthermore, CL18100F4 supplementation significantly (p < 0.001) increased the serum levels of IL-10, DAO, serotonin, gastrin, reduced IL-6, cortisol, and Zonulin. No major adverse events were observed. Participants' vital signs, hematology, clinical biochemistry, and urinalysis parameters were within the normal ranges. CONCLUSION: The present investigation demonstrates that CL18100F4 is tolerable and efficacious in relieving functional constipation, alleviating GI dysfunction, and improving associated non-GI factors in male and female adults.