INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising therapy for irritable bowel syndrome (IBS). The aims of this clinical trial were to evaluate the influence of taVNS on autonomic functions, rectal sensation, and acetylcholine (Ach) levels and to explore potential mechanisms involving gut microbiota and metabolic profiles. METHODS: This study was a single-center, single-blind, randomized controlled trial executed at the First Affiliated Hospital of USTC, Anhui, China. Individual patients' constipation-predominant IBS (IBS-C)-related symptoms and mental health were assessed and scored using questionnaires at baseline and at week 4. Levels of serum Ach and nitric oxide, anorectal manometry, and heart rate variability were assessed both before and after the therapy. Fecal samples from each group were assessed to compare the gut microbiota, short-chain fatty acids, and gut microbiota-derived tryptophan metabolites. RESULTS: Between September 2023 and May 2024, 40 patients (n = 20 in both taVNS and sham-taVNS groups) completed the 4-week study by performing an intention-to-treat analysis. No differences in all parameters between taVNS and sham-taVNS groups at the baseline were found. The taVNS significantly improved the visual analog scale score (P < 0.001), IBS Severity Scoring System score (P < 0.001), weekly frequency of spontaneous bowel movements (P < 0.001), weekly frequency of complete spontaneous bowel movements (P = 0.004), Bristol Stool Form Scale score (P < 0.001), Hamilton Anxiety Scale score (P < 0.001), Hamilton Depression Scale score (P < 0.001), and IBS Quality of Life score (P < 0.001). Furthermore, taVNS improved rectal sensation in patients with IBS-C, including improvements in the threshold volume for initial sensation (P = 0.033), urge to defecate (P = 0.022), and rectoanal inhibitory reflex (P = 0.002). Moreover, taVNS elevated serum levels of Ach (P = 0.005) and reduced nitric oxide (P = 0.016) while also enhancing vagal activity (P < 0.001) as determined by spectral analysis of heart rate variability. Three patients in the taVNS group and 2 in the control group had adverse consequences, which were manageable. In addition, taVNS led to a significant rise in the level of the genus Bifidobacterium (P = 0.038) and increased levels of acetic (P = 0.003), butyric (P = 0.011), and propionic (P = 0.005) acids. It also decreased tryptophan metabolism content, including 3-hydroxyanthranilic acid (P = 0.007), anthranilic acid (P = 0.026), and L-tryptophan (P = 0.002). DISCUSSION: The study manifested that noninvasive taVNS effectively improved constipation and abdominal pain symptoms in patients with IBS-C. The alleviation of IBS-C symptoms may be attributed to the integrative effects of taVNS on rectal functions, mediated through vagal, cholinergic, and multiomics mechanisms.

Chronic pancreatitis is associated with pancreatic cancer (PC), although the relationship between acute pancreatitis (AP) and the risk of PC remains unclear due to inconsistent and contradictory results. To conduct a meta-analysis of retrospective and prospective studies to explore the association between AP and PC risk. We first searched original articles on the association of AP with PC using PubMed, Web of Science, Cochrane, and EMBASE databases. Then we calculated the combined overall effect estimates (EEs) between AP and PC risk at a 95% confidence interval (CI) deploying a random-effects model, and assessed heterogeneity using the I² test. The combined relative risk with 95%CI was performed to examine the relationship between AP and PC. Publication bias and subgroup analyses were also conducted. Furthermore, we performed sensitivity analysis to explain this heterogeneity. Eleven studies were eligible for inclusion standards in this meta-analysis, resulting in pooled EEs of 2.07 (95%CI: 1.36-2.78) for AP and PC risk. Additionally, five prospective cohort studies reported 103961 patients in the AP group, relative to 1442158 subjects in the control group, with a pooled relative risk of 7.81 (95%CI: 5.00-12.19). We also performed subgroup analyses using different follow-up times and type of research methods (case-control or cohort). Results from analyses of different follow-up times revealed the following pooled effect values: 1-year lag period (EEs = 23.47, 95%CI: 3.26-43.68), 2-year lag period (EEs = 9.82, 95%CI: 3.01-16.64), 5-year lag period (EEs = 2.47, 95%CI: 1.93-3.02), 10-year lag period (EEs = 1.69, 95%CI: 1.26-2.11), and > 10-year lag period (EEs = 1.17, 95%CI: 0.78-1.57). With regards to the methods, the case-control studies recorded EEs = 3.03 (95%CI: -1.02 to 7.08), whereas cohort studies had EEs = 2.09 (95%CI: 1.22-2.97) pooled effect values. Overall, our findings indicated an association between AP and PC risk. Based on subgroup analyses, AP is unlikely to be a causal factor for PC.

Background: Functional dyspepsia (FD) is a functional digestive disease with limited management selection. Previous studies revealed that acupuncture therapy is effective for FD. However, because sham controls were not implemented in most clinical trials following acupuncture therapy, it is difficult to differentiate overall treatment responses from placebo. This study aims to quantify placebo responses in clinical trials in which FD patients received sham manual acupuncture (MA) and sham electroacupuncture (EA). Materials and Methods: Randomized controlled trials of MA and EA for FD patients were searched in PubMed, Web of Science, Cochrane Library, and Embase databases, as well as 4 Chinese language databases from inception to January 2021. RevMan 5.20 software was used for pooled analysis of symptom scores and quality of life. The symptom scores were combined using standard mean difference (SMD) or weighted mean difference (WMD) with a 95% confidence interval (CI). The quality of included studies was tested using modified Jadad scale and Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) checklist. Egger’s test, Begg’s test, and sensitivity analyses were conducted using Stata 11.0 statistical software. The protocol of this study is registered in PROSPERO as CRD42021233858. Results: After screening, the current systematic review included 13 randomized controlled trials, of which 8 studies were used in the meta-analysis. Regarding subjective outcomes, the combined effect of sham MA on FD symptoms was [SMD=−0.42, 95% CI (−0.72, −0.12); P=0.005], whereas sham EA treatment was [SMD=−0.54, 95% CI (−0.81, −0.27); P<0.001]. The combined effect on FD quality of life of post-sham MA group was [SMD=−0.32, 95% CI (−0.52, −0.12); P=0.002]. With regard to objective outcomes, the combined effect of sham EA on dominant frequency was [WMD=−0.11, 95% CI (−0.30, −0.08); P=0.24], while the combined effect of sham EA on dominant power was [WMD=−3.35, 95% CI (−8.04, 1.35); P=0.16]. Conclusions: Sham MA and sham EA remarkably improve symptoms and quality of life scores of FD without influencing objective outcomes, highlighting the significance of sham controls in acupuncture therapy clinical trials.

Background. Accurate dyssynergic defecation (DD) diagnosis depends on anorectal physiological tests that are not widely available. Aim. The purpose of this study is to evaluate the diagnostic yield of digital rectal examination (DRE) compared with anorectal physiological tests in diagnosing DD in patients with constipation. Methods. A total of 218 chronic constipation patients who fulfilled the Rome IV diagnostic criteria for functional constipation (FC) and underwent a standardized DRE and high‐resolution anorectal manometry (HRAM) test were enrolled in this study. The diagnostic accuracy of DRE compared with HRAM was evaluated, and the agreement between DRE and HRAM was calculated. Furthermore, a comprehensive literature search on PubMed, Web of Science, Cochrane Library, and Embase database was conducted to further elucidate the pooled diagnostic accuracy of DRE in DD patients. Results. A total of 101 patients (46.33%) had a DD pattern using HRAM, while 117 patients (53.67%) were diagnosed without DD. The sensitivity of DRE in diagnosing dyssynergia was 71.3%, and the specificity was 76.1%. There was a moderate agreement between DRE and HRAM for diagnosing DD (κ‐coefficient = 0.474, P < 0.001). Meanwhile, six studies (including our study) comprising 964 constipated patients were included in our meta‐analysis. The outcomes demonstrated that the AUC was 0.85 (95% CI 0.82–0.88) with 77% summary sensitivity (95% CI 65–86) and 80% summary specificity (95% CI 71–86) to diagnose DD. Conclusions. DRE could be a valuable tool for screening DD. Our study revealed acceptable sensitivity and specificity of DRE in detecting dyssynergia compared with the physiological tests. Meanwhile, our study highlights that DRE remains an important tool in clinical practice.

Background. Stimulant laxatives are still considered the most common treatment for functional outlet obstruction constipation (FOOC). However, the effectiveness of laxatives is unsatisfactory, and the long‐term use of laxatives may cause certain adverse events. With this in mind, it is, however, paramount that novel complementary treatment(s) and/or other forms of alternative medicine are adequately investigated. Aims. The study aims to explore the effects and potential mechanism(s) of transcutaneous electrical acustimulation (TEA) combined with adaptive biofeedback training (ABT) on FOOC. Methods. A total of forty‐five patients with FOOC were recruited and were randomly assigned to receive either Macrogol 4000 Powder (MAC, 10 g bid) (group A, n = 15) only, ABT + MAC + Sham‐TEA (group B, n = 15), or TEA + ABT + MAC (group C, n = 15) in a six‐week study. Individual patients′ constipation‐symptoms (PAC‐SYM) and constipation‐quality of life (PAC‐QOL) were both assessed and scored. Serum acetylcholine (Ach) and nitric oxide (NO) were measured from drawn blood samples while individual patients′ heart rate variability (HRV) was calculated at baseline and after each corresponding therapy. Anorectal manometry and balloon expulsion test were both performed before and after treatment. Results. Firstly, participants in group C had significantly lower scores of PAC‐SYM, PAC‐QOL, and a decreased anal defecating pressure (ADP) as compared to participants in group B (all p < 0.050). These results, however, suggest the TEAs effect. Secondly, the low‐frequency band (LF)/(LF + HF) ratio in groups B and C were decreased as compared to group A (p = 0.037, p = 0.010, respectively) regarding HRV. On the other hand, the high‐frequency band (HF)/(LF + HF) ratio in groups B and C showed an opposite outcome. Finally, the serum Ach in groups B and C was significantly higher as compared to group A (p = 0.023, p = 0.012, respectively). Of significant importance, the serum NO in groups B and C were notably low as compared to group A (p = 0.001, p < 0.001, respectively). Conclusions. TEA, combined with ABT, effectively improves constipation symptoms as well as QOL in FOOC patients. It is, however, achieved by decreasing ADP, which mechanisms are mediated via the autonomic and enteric mechanisms.