Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome.

Limited treatment options have been shown to alter the natural course of constipation-predominant irritable bowel syndrome (IBS-C). Therefore, safer and more effective approaches are urgently needed. We investigated the effects of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of IBS-C. In the current study, C57BL/6 mice were randomly divided into normal control, IBS-C model control, sham-electrostimulation (sham-ES), taVNS, and drug treatment groups. The effects of taVNS on fecal pellet number, fecal water content, and gastrointestinal transit were evaluated in IBS-C model mice. We assessed the effect of taVNS on visceral hypersensitivity using the colorectal distention test. 16S rRNA sequencing was used to analyze the fecal microbiota of the experimental groups. First, we found that taVNS increased fecal pellet number, fecal water content, and gastrointestinal transit in IBS-C model mice compared with the sham-ES group. Second, taVNS significantly decreased the abdominal withdrawal reflex (AWR) score compared with the sham-ES group, thus relieving visceral hyperalgesia. Third, the gut microbiota outcomes showed that taVNS restored Lactobacillus abundance while increasing Bifidobacterium probiotic abundance at the genus level. Notably, taVNS increased the number of c-kit-positive interstitial cells of Cajal (ICC) in the myenteric plexus region in IBS-C mice compared with the sham-ES group. Therefore, our study indicated that taVNS effectively ameliorated IBS-C in the gut microbiota and ICC.

Chronic Electroacupuncture With High-Frequency at ST-36 Promotes Gastrointestinal Motility by Regulating Bone Morphogenetic Protein 2 Secretion of Muscularis Macrophages.

BACKGROUND: Electroacupuncture (EA) at Zusanli (ST36) is an alternative treatment for several gastrointestinal motility disorders; however, the exact mechanism is unconfirmed. We aimed to show the potential effects of EA on muscularis macrophages (MMφ), the bone morphogenetic protein (BMP)/BMP receptor (BMPR)-Smad signal pathway, and enteric neurons in diabetic mice. This may provide fresh insight into ways EA affects gastrointestinal motility. MATERIALS AND METHODS: C57BL/6J healthy adult male mice were randomly divided into five groups: regular control group, diabetes group, diabetes with sham EA group (acupuncture only), diabetes with low-frequency EA group (10 Hz), diabetes with high-frequency EA group (HEA) (100 Hz). The stimulation lasted eight weeks. Gastrointestinal motility was assessed. We identified M2-like MMφ in the layer of colonic muscle by flow cytometry. Western Blot, real-time polymerase chain reaction, and immunofluorescent staining were also used to determine the MMφ, molecules in the BMP2/BMPR-Smad pathway, and PGP9.5, neuronal nitric oxide synthase (nNOS) expression of enteric neurons in the colon of each group. RESULTS: 1) HEA improved the gastrointestinal motility (gastrointestinal transit time, defecation frequency) of diabetic mice. 2) HEA reversed the decreased proportion of M2-like MMφ and expression of the CD206 in the colon of diabetic mice. 3) HEA restored the downregulations of BMP2, BMPR1b, and Smad1 in the BMP2/BMPR-Smad pathway and increased downstream enteric neurons marked by PGP9.5, nNOS in the colon of diabetes mice. CONCLUSIONS: HEA might promote gut dynamics by upregulating M2-like MMφ in the colon of diabetic mice, which in turn leads to the accumulation of molecules in the BMP2/BMPR-Smad signaling pathway and downstream enteric neurons.

Effects of electroacupuncture combined with acupoint catgut embedding on gastrointestinal motility and gastrointestinal hormones in rats with functional dyspepsia.

Electroacupuncture (EA) or acupoint catgut embedding (ACE) plays a therapeutic role in functional dyspepsia (FD). Herein, we aimed to elucidate the influences of EA combined with ACE on gastrointestinal motility and gastrointestinal hormones in rats with FD. Sprague-Dawley rats were randomized into the control group, model group, EA group, ACE group, and EA + ACE group (n = 10). Except for the control group, the rats in all groups were modeled by combining neonatal iodoacetamide gastrogavage and modified tail-clamping stimulation. The rats were treated with different treatments according to their groups. The rats were observed for changes in general behavior, body weight, food intake, and paw mechanical pain threshold. Gastric emptying rate (GER) and intestinal propulsive ratio (IPR) were measured in each group, and serum gastrointestinal hormone (motilin [MTL], leptin, gastrin [GAS], vasoactive intestinal peptide [VIP], calcitonin gene-related peptide [CGRP], and somatostatin [SS]) levels, oxidative stress factors (superoxide dismutase [SOD] and malondialdehyde [MDA]) and 5-hydroxytryptamine (5-HT) levels were also measured. Decreased mean body weight, paw mechanical pain thresholds, food intake, and GER and IPR were found in rats of the model group in comparison to the control group. Serum MTL, GAS, SS, and SOD levels were reduced, and serum leptin, VIP, CGRP, MDA, and 5-HT levels were increased in rats of the model group in comparison to the control group. Elevated mean body weight, paw mechanical pain threshold, food intake, GER and IPR, and serum MTL, GAS, SS, and SOD levels, and reduced serum leptin, VIP, CGRP, MDA, and 5-HT levels were observed in rats of the EA, ACE, and EA + ACE groups relative to the model group. EA combined with ACE treatment was more effective than the EA or ACE treatment alone. EA combined with ACE treatment improves gastrointestinal motility and gastrointestinal hormone levels, promotes food intake, and reduces visceral hypersensitivity in FD rats.

The Impact of Nutritional Therapy on Gastrointestinal Motility in Older Adults.

Japan is becoming a superaged society, and nutrition therapy for the elderly population is very important. Elderly individuals often have multiple diseases and are prone to malnutrition. Furthermore, functional constipation, diarrhoea, faecal incontinence, etc., may occur despite no organic abnormality of digestive tract function. Due to these disabilities, the resulting malnutrition, and the slow recovery, it is often difficult for elderly individuals to reintegrate into society. Secondary or incorrect nutritional management increases complications, decreases physical function and worsens the prognosis. Previous statistical research suggests that in-hospital mortality is significantly higher among hospitalised patients aged ≥65 years who ingest less than half of their caloric needs. Therefore, appropriate nutritional management from an early stage is essential for elderly individuals. Moreover, functional excretion disorders, dementia, and sarcopenia (muscle-wasting disease) are attracting attention as pathological conditions unique to elderly individuals, and it is essential to undergo rehabilitation early with nutritional management. Being elderly does not preclude nutritional management, and it is necessary to reconsider appropriate nutritional therapy even in the terminal stage and in advanced physical and mental illnesses. This review explores the relationship between dietary intake and FGIDs, with a focus on elderly adults.

Noninvasive electrical neuromodulation for gastrointestinal motility disorders.

INTRODUCTION: Gastrointestinal motility disorders are highly prevalent without satisfactory treatment. noninvasive electrical neuromodulation is an emerging therapy for treating various gastrointestinal motility disorders. AREAS COVERED: In this review, several emerging noninvasive neuromodulation methods are introduced, including transcutaneous auricular vagal nerve stimulation, percutaneous auricular vagal nerve stimulation, transcutaneous cervical vagal nerve stimulation, transcutaneous electrical acustimulation, transabdominal interference stimulation, tibial nerve stimulation, and translumbosacral neuromodulation therapy. Their clinical applications in the most common gastrointestinal motility are discussed, including gastroesophageal reflux disease, functional dyspepsia, gastroparesis, functional constipation, irritable bowel syndrome, and fecal incontinence. PubMed database was searched from 1995 to June 2023 for relevant articles in English. EXPERT OPINION: Noninvasive neuromodulation is effective and safe in improving both gastrointestinal symptoms and dysmotility; it can be used when pharmacotherapy is ineffective. Future directions include refining the methodology, improving device development and understanding mechanisms of action.

Therapeutic role of Wuda granule in gastrointestinal motility disorder through promoting gastrointestinal motility and decreasing inflammatory level.

Introduction: Previous studies indicated that Wuda Granule (WDG) has been applied in the treatment of gastrointestinal motility disorder (GMD), but the effect and underlying mechanisms is yet to be elucidated. This study aimed to explore the mechanism and pharmacological effect of WDG for GMD via network analysis, verification of animal experiments and clinical experiments. Methods: The chemical components of WDG were identified from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP, http://lsp.nwu.edu.cn/index.php), and the Encyclopedia of Traditional Chinese Medicine (ETCM, http://www.tcmip.cn/ETCM/index.php/Home/Index/) according to oral bioavailability (OB) ≥ 20% and drug-likeness (DL) ≥ 0.10. The targets of WDG compounds were retrieved from the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) and targets related to GMD were retrieved from GeneCards database (https://www.genecards.org/). Network analysis were performed to screen the key active compounds of WDG and its hub targets. Then the pharmacological effect of WDG were verified via vivo experiments in rats and clinical experiments. Results: The results showed that 117 effective active compounds of WDG were screened and 494 targets of WDG compounds targeting GMD were selected. These targets were involved in the biological process of inflammatory regulation and the regulation of gastrointestinal motility. The mechanism was mainly involved in the regulation of PI3K-Akt signaling pathway and Rap1 signaling pathway. In addition, molecular docking analysis suggested that eight key active compounds of WDG may be mainly responsible for the effect of WDG on GMD by targeting HARS, AKT, and PIK3CA, respectively. Animal experiments and clinical trials both suggested that WDG could exert therapeutical effect on GMD via inhibiting inflammation and promoting gastrointestinal motility, it could also improve digestive function of patients with laparoscopic colorectal cancer after surgery. Conclusion: This study was the first to demonstrate that WDG improved GMD mainly via inhibiting inflammatory level and promoting gastrointestinal motility, providing new insights for the understanding of WDG for GMD, inspiration for future research and reference for clinical strategy in terms of the treatment of GMD.

Garcinia buchananii stem bark extract and its bioactive constituents manniflavanone, GB-2 and buchananiflavanone attenuate intestinal inhibitory neuromuscular transmission.

Garcinia buchananii stem bark extract (GBB), commonly used for treating diarrhea in Africa, triggers ectopic aboral contractions, causing inhibition of propulsive motility in the colon ex vivo. To determine whether or not these effects were associated with decreased inhibitory neuromuscular transmission, the responsible constituent compounds, and mechanisms of action, we studied the effects of GBB and specific fractions and flavanones isolated from GBB on intestinal motility using pellet propulsion assays in guinea pig distal colons. In addition, microelectrode recordings were used to measure the effects on the inhibitory junction potentials (IJPs) in the porcine ileum and descending colon smooth muscle. Psychoactive Drug Screening Program secondary receptor functional assays were used to determine whether or not GBB and its constituent compounds act via purinergic (P2Y) and muscarinic receptors. GBB inhibited propulsive motility, but (2R,3S,2″R,3″R)-manniflavanone (MNF), (2R,3S,2″R,3″R)-GB-2 (GB-2) and (2R,3S,2″S)-buchananiflavanone (BNF), the main ingredients of GBB, did not affect motility. We discovered that, in the porcine descending colon, IJPs contained purinergic, nitrergic, and nonpurinergic nonnitrergic components. Furthermore, ileal IJPs were purely purinergic. GBB blocked all components of IJPs, while MNF and GB-2 inhibited purinergic IJPs only. BNF inhibited the purinergic and nonpurinergic components of IJPs. MRS2365, a Y1 (P2Y) agonist, did not evoke sustained membrane hyperpolarization in the presence of GBB. However, GBB, MNF, GB-2 and BNF did not affect P2Y or muscarinic receptors. In conclusion, inhibitory neuromuscular transmission in the porcine descending colon involves all components of IJPs. GBB decreases inhibitory neuromuscular transmission, likely by the actions of MNF, GB-2 and BNF. These effects do not involve P2Y or muscarinic receptors.

Transcutaneous electrical stimulation for gastrointestinal motility disorders.

BACKGROUND/PURPOSE: Gastrointestinal (GI) dysmotility is categorized by muscle or nerve dysfunctions in any portion of the GI tract, which leads to abnormalities in GI motor and sensory function. Symptoms may vary depending on the organ affected and can be debilitating. Treatment usually involves diet and lifestyle changes. Pharmacotherapy is limited in effectiveness with various side effects. Transcutaneous electrical stimulation (TES), a noninvasive, needleless technique that provides electrical stimulation using cutaneous non-needle electrodes, has become increasingly popular. It has been shown to be beneficial in treating GI motility disorders. METHODS: This review paper navigates through the different TES techniques, including transcutaneous peripheral nerve (vagal/sacral/tibial nerves) electrical stimulation, transcutaneous electrical acustimulation (stimulation via acupuncture point), transcutaneous interferential current therapy, and transcutaneous electrical nerve stimulation. KEY RESULTS: As we delve deeper, we explore the promising effects of TES on dysphagia, gastroesophageal reflux disease, functional dyspepsia, gastroparesis, postoperative ileus, constipation, and irritable bowel syndrome. The literature at hand speaks volumes about the therapeutic prowess of this noninvasive technique. CONCLUSION & INFERENCES: The time is ripe to evaluate further the full therapeutic potential of TES, a noninvasive, nonpharmaceutical, nonsurgical, and home-based self-administrative technique in managing GI motility disorders.

Pharmacological effect of Heritiera fomes on Long Evans rats against Postprandial Hyperglycemia and adsorption in vitro.

Background: Natural restoratives from traditional medicinal plants are considered to be a convenient, potent, and risk-free substitute treatment for hyperglycaemia. Our objective was to explore the activity of the crude extract of Heritiera fomes on postprandial hyperglycaemia by assessing relative measurements in a laboratory animal model. Methods: The Streptozotocin induced diabetic rat (n = 88, twenty-two per group) was used for the glucose tolerance test as an initial support for the study. BaSO4 was administered orally as a marker to measure gut motility after one hour of methanolic extract (500 mg/kg body weight) administration where, only purified water (10 ml/kg) was used to treat the control group (n = 12) and a dose (500 mg/kg) of H. fomes extract was used for the test group (n = 12 in each group). After 60 min of incubation of the mixture of extract and glucose with 10% (v/v) yeast cell suspension, the absorbance was measured to determine the capacity of glucose absorption by yeast cells. Sixty Long Evans rats (n = 12 in each group) were used to assess disaccharidase enzyme activity as µmol/mg protein per hour by Lowry's protein estimation method. The carbohydrate absorption investigation was executed to evaluate the leftover sucrose content in the gastrointestinal system (n = 64). Results: After oral administration of MHFL (71.84%), MHFB (71.41%), and MHFR (72.55%), GI motility (%) increased significantly (p < 0.001) compared to the control group (59.06%). A significant increase in glucose uptake and adsorption capacity measured by different concentrations of glucose ensures the decrease of glucose bound rate and a significant drop in blood glucose concentration. The significant (p < 0.001) decrease in intestinal disaccharidase activity of MHFL (1.40), MHFB (1.36), and MHFR (1.20) in comparison to the control group (1.50) indicates that the presence of H. fomes may reduce glucose absorption in the small bowel. Significant (p < 0.001 & p < 0.05) accumulation of sucrose content in the six different parts of the GI tract suggests the absorption of sucrose was decreased. Conclusions: The findings of this study provide evidence on probable mechanisms for the anti-diabetic characteristics of H. fomes, and it is predicted that this plant will be studied further for the development of strong anti-hyperglycemic medicines.

Network Pharmacological Analysis and Experimental Validation of the Effect of Smilacis Glabrae Rhixoma on Gastrointestinal Motility Disorder.

Gastrointestinal motility disorder (GMD) is a disease that causes digestive problems due to inhibition of the movement of the gastrointestinal tract and is one of the diseases that reduce the quality of life of modern people. Smilacis Glabrae Rhixoma (SGR) is a traditional herbal medicine for many diseases and is sometimes prescribed to improve digestion. As a network pharmacological approach, we searched the TCMSP database for SGR, reviewed its constituents and target genes, and analyzed its relevance to gastrointestinal motility disorder. The effects of the SGR extract on the pacemaker activity in interstitial cells of Cajal (ICC) and gastric emptying were investigated. In addition, using the GMD mouse model through acetic acid (AA), we investigated the locomotor effect of SGR on the intestinal transit rate (ITR). As a result of network pharmacology analysis, 56 compounds out of 74 candidate compounds of SGR have targets, the number of targets is 390 targets, and there are 904 combinations. Seventeen compounds of SGR were related to GMD, and as a result of comparing the related genes with the GMD-related genes, 17 genes (active only) corresponded to both. When looking at the relationship network between GMD and SGR, it was confirmed that quercetin, resveratrol, SCN5A, TNF, and FOS were most closely related to GMD. In addition, the SGR extract regulated the pacemaker activity in ICC and recovered the delayed gastric emptying. As a result of feeding the SGR extract to AA-induced GMD mice, it was confirmed that the ITR decreased by AA was restored by the SGR extract. Through network pharmacology, it was confirmed that quercetin, resveratrol, SCN5A, TNF, and FOS were related to GMD in SGR, and these were closely related to intestinal motility. Based on these results, it is suggested that SGR in GMD restores digestion through the recovery of intestinal motility.

Transcriptome and Proteome Profiling of Primary Human Gastric Interstitial Cells of Cajal Predicts Pacemaker Networks.

Background/Aims: Interstitial cells of Cajal (ICC) are specialized gastrointestinal (GI) pacemaker cells required for normal GI motility. Dysfunctions in ICC have been reported in patients with GI motility disorders, such as gastroparesis, who exhibit debilitating symptoms and greatly reduced quality of life. While the proteins, calcium-activated chloride channel anoctamin-1 (ANO1) and the receptor tyrosine kinase (KIT), are known to be expressed by human ICC, relatively little is known about the broad molecular circuitry underpinning human ICC functions. The present study therefore investigates the transcriptome and proteome of ANO1-expressing, KITlow/CD45-/CD11B- ICC obtained from primary human gastric tissue. Methods: Excess human gastric tissue resections were obtained from sleeve gastrectomy patients. ICC were purified using fluorescence-activated cell sorting (FACSorting). Then, ICC were characterized by using immunofluorescence, real-time polymerase chain reaction, RNA-sequencing and mass spectrometry. Results: Compared to unsorted cells, real-time polymerase chain reaction showed the KITlow/CD45-/CD11B- ICC had: a 9-fold (P < 0.05) increase in ANO1 expression; unchanged KIT expression; and reduced expression for genes associated with hematopoietic cells (CD68, > 10-fold, P < 0.001) and smooth muscle cells (DES, > 4-fold, P < 0.05). RNA-sequencing and gene ontology analyses of the KITlow/CD45-/CD11B- cells revealed a transcriptional profile consistent with ICC function. Similarly, mass spectrometry analyses of the KITlow/CD45-/CD11B- cells presented a proteomic profile consistent with ICC activities. STRING-based protein interaction analyses using the RNA-sequencing and proteomic datasets predicted protein networks consistent with ICC-associated pacemaker activity and ion transport. Conclusion: These new and complementary datasets provide a valuable molecular framework for further understanding how ICC pacemaker activity regulates smooth muscle contraction in both normal GI tissue and GI motility disorders.

The Use of Peppermint Oil in Gastroenterology.

BACKGROUND: For decades, mint has been used worldwide for its relieving effects against gastrointestinal disturbances. Peppermint is a perennial herb common in Europe and North America. The active ingredient of peppermint oil is menthol and has various gastroenterological and non-gastroenterological uses, especially in the context of functional gastrointestinal disorders (FGIDs). METHODS: We conducted a literature search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials, and case series using the following keywords and acronyms and their associations: peppermint oil, gastro-intestinal motility, irritable bowel syndrome, functional dyspepsia, gastrointestinal sensitivity and gastrointestinal endoscopy. RESULTS: Peppermint oil and its constituents exert smooth muscle relaxant and anti-spasmodic effects on the lower esophageal sphincter, stomach, duodenum, and large bowel. Moreover, peppermint oil can modulate visceral and central nervous system sensitivity. Taken together, these effects suggest using peppermint oil both for improved endoscopic performance and for treating functional dyspepsia and irritable bowel syndrome. Importantly, peppermint oil has an attractive safety profile compared to classical pharmacological treatments, especially in FGIDs. CONCLUSION: Peppermint oil is a safe herbal medicine therapy for application in gastroenterology, with promising scientific perspectives and rapidly expanding use in clinical practice.

Electroacupuncture Alleviates Functional Constipation in Mice by Activating Enteric Glial Cell Autophagy via PI3K/AKT/mTOR Signaling.

OBJECTIVE: To investigate autophagy-related mechanisms of electroacupuncture (EA) action in improving gastrointestinal motility in mice with functional constipation (FC). METHODS: According to a random number table, the Kunming mice were divided into the normal control, FC and EA groups in Experiment I. The autophagy inhibitor 3-methyladenine (3-MA) was used to observe whether it antagonized the effects of EA in Experiment II. An FC model was established by diphenoxylate gavage. Then the mice were treated with EA stimulation at Tianshu (ST 25) and Shangjuxu (ST 37) acupoints. The first black stool defecation time, the number, weight, and water content of 8-h feces, and intestinal transit rate were used to assess intestinal transit. Colonic tissues underwent histopathological assessment, and the expressions of autophagy markers microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 were detected by immunohistochemical staining. The expressions of phosphoinositide 3-kinases (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signaling pathway members were investigated by Western blot and quantitative reverse transcription-polymerase chain reaction, respectively. The relationship between enteric glial cells (EGCs) and autophagy was observed by confocal immunofluorescence microscopy, localization analysis, and electron microscopy. RESULTS: EA treatment shortened the first black stool defecation time, increased the number, weight, and water content of 8-h feces, and improved the intestinal transit rate in FC mice (P<0.01). In terms of a putative autophagy mechanism, EA treatment promoted the expressions of LC3 and Beclin-1 proteins in the colonic tissue of FC mice (P<0.05), with glial fibrillary acidic protein (GFAP) and LC3 significantly colocalized. Furthermore, EA promoted colonic autophagy in FC mice by inhibiting PI3K/AKT/mTOR signaling (P<0.05 or P<0.01). The positive effect of EA on intestinal motility in FC mice was blocked by 3-MA. CONCLUSION: EA treatment can inhibit PI3K/AKT/mTOR signaling in the colonic tissues of FC mice, thereby promoting EGCs autophagy to improve intestinal motility.

Deciphering antidiarrheal effects of Meda pata (Litsea glutinosa (Lour.) C.B.Rob.) leaf extract in chemical-induced models of albino rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Diarrhea is one of the leading causes of preventable death in developing countries, mainly caused by bacterial infections and traditional therapies are very common in diarrheal incidences. Meda Pata (Litsea glutionsa) has a long history of use as traditional medicine for diarrhea, dysentery, and spasm in Bangladesh, India, and some other Asian countries. AIM OF THE STUDY: This research reports the antidiarrheal effects of Meda Pata (Litsea glutinosa leaf extract, LGLEx) in animal models. The work has been supported by in silico molecular docking study to verify the effects. MATERIALS AND METHODS: The antidiarrheal effect of LGLEx was investigated in castor oil-induced diarrhea, magnesium sulfate-induced diarrhea, and gastrointestinal motility test models. Antidiarrheal effects were supported by a molecular docking study through an interaction between LGLEx's GC-MS analyzed imidazole-containing compounds and muscarinic acetylcholine receptor (PDB: 4U14) and 5-HT3 receptor (PDB: 5AIN). RESULTS: LGLEx potentially reduced the diarrheal incidences in in vivo assays reducing gastrointestinal motility. The maximum diarrheal inhibition was obtained in the castor oil-induced model (62.63%) and and BaSO4-induced model (73.14%), which were statistically significant (P < 0.05) when compared to the reference drug loperamide. In the castor-oil and BaSO4-induced models, peristaltic movement was reduced by 25.96% and 32.17%, respectively. Biochemical markers particularly IgE, C-reactive proteins, and serum electrolytes were significantly (P < 0.0) restored in treated groups. A Molecular docking analysis revealed that two compounds (1-Ethyl-2-hydroxymethylimidazole and 1,6-Anhydro-beta-D-glucofuranose demonstrated the highest binding affinity with target receptors muscarinic acetylcholine receptor (PDB: 4U14) and 5-HT3 receptor (PDB: 5AIN) confirming their drug likeliness. The findings indicate a high potential antidiarrheal impact that warrants further investigation for its therapeutic application.

Efficacy of transcutaneous posterior tibial nerve stimulation in functional constipation.

Most children with functional constipation (FC) improve with conventional treatments. However, a proportion of children have poor treatment outcomes. Management of intractable FC may include botulinum toxin injections, transanal irrigation, antegrade enemas, colonic resections, and in some cases sacral nerve stimulation (SNS). SNS is surgically placed, not readily available and expensive. Posterior tibial nerve stimulation (PTNS) allows transmission of electronic impulses and retrograde stimulation to the sacral nerve plexus in a portable, simple and non-invasive fashion. To assess the efficacy and safety of transcutaneous PTNS for the treatment of FC in children. Single-center, prospective interventional study. Children 4-14 years with Rome IV diagnosis of FC received ten daily PTNS (30 min/day) sessions. Electrodes placed over skin of ankle. Strength of stimulus was below pain threshold. Outcomes were assessed during treatment and 7 days after. Twenty-three subjects enrolled. Two children excluded (acute gastroenteritis, COVID-19 contact). Twenty completed the study (4-14 years), (8.4 ± 3.2 years, 71.4% female). We found significant improvement in the consistency of bowel movements (BM) (p = 0.005), fecal incontinence (FI) (p = 0.005), abdominal pain presence (p = < 0.001) and intensity (p = 0.005), and a significant for improvement in blood in stools (p = 0.037). There was 86.3% improvement in abdominal pain. 96.7% reported treatment satisfaction. Only one child required rescue therapy. CONCLUSION: We found significant improvement in stool consistency, FI, abdominal pain, and hematochezia. This suggests that transcutaneous PTNS could be a promising noninvasive treatment for FC in children. Large studies are needed. WHAT IS KNOWN: • Functional constipation is one of the most common disorders in children. • Current management of functional constipation consists of an integrative approach that includes medications, diet and behavioral strategies. WHAT IS NEW: • Posterior tibial nerve stimulation is a novel noninvasive and easy to use therapy that can improve stool consistency, fecal incontinence and blood in stools.

CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats.

BACKGROUND: Strong opioid analgesics such as morphine alleviate moderate to severe acute nociceptive pain (e.g. post-surgical or post-trauma pain) as well as chronic cancer pain. However, they evoke many adverse effects and so there is an unmet need for opioid analgesics with improved tolerability. Recently, a prominent hypothesis has been that opioid-related adverse effects are mediated by ß-arrestin2 recruitment at the µ-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and δ-opioid (DOP) receptor antagonist profiles are promising for reducing side effects c.f. morphine. Herein, we report on the in vivo pharmacology of a novel opioid peptide (CYX-5) that is a G-protein biassed MOP receptor agonist, DOP receptor antagonist and kappa opioid (KOP) receptor agonist. METHODS: Male Sprague-Dawley received intracerebroventricular bolus doses of CYX-5 (3, 10, 20 nmol), morphine (100 nmol) or vehicle, and antinociception (tail flick) was assessed relative to constipation (charcoal meal and castor oil-induced diarrhoea tests) and respiratory depression (whole body plethysmography). RESULTS: CYX-5 evoked naloxone-sensitive, moderate antinociception, at the highest dose tested. Although CYX-5 did not inhibit gastrointestinal motility, it reduced stool output markedly in the castor oil-induced diarrhoea test. In contrast to morphine that evoked respiratory depression, CYX-5 increased tidal volume, thereby stimulating respiration. CONCLUSION: Despite its lack of recruitment of ß-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than ß-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands.

Effect of Acupressure Applied After Cesarean Section Under Spinal Anesthesia Postpone the Duration of Taking Analgesics and on The Gastrointestinal System: A Randomized Controlled Trial.

OBJECTIVES: Cesarean deliveries are one of the primary conditions associated with postoperative decreased motility of the gastrointestinal system and are characterized by acute pain and distention. The aim of the present study was to investigate the application of acupressure and the administration of analgesics for women who underwent cesarean section under spinal anesthesia could be delayed and how spontaneous gastrointestinal system motility could be achieved in the postoperative period. DESIGN: Randomized controlled trial SETTING: Private Medipol Nisa Hospital, Istanbul, Turkey INTERVENTION: This trial was conducted with 112 primipara pregnant women who delivered via cesarean section under spinal anesthesia and were randomly assigned into the acupressure (n=52) and control (n=60) groups. The participants in the acupressure group (n=52) were treated for 20 minutes. The participants in the control group (n=60) were treated per the hospital protocol (analgesics for pain, flatulation and defecation, no pharmacological or non-pharmacological application was performed). RESULTS: The time that elapsed for the administration of analgesics was significantly later in the acupressure group than in the control group (p <.001). The first occurrence of flatulation and defecation were significantly earlier in the acupressure group (19 and 23 hours, respectively) than in the control group (34 and 27 hours, respectively) (p <.001). CONCLUSION: Acupressure is an easy, non-invasive method that postpones the administration of analgesics in the postoperative period and prevents flatulence and constipation caused by the decreased motility of GIS.

Psychiatric comorbidities among adult patients with disorders of gut-brain interaction: Prevalence and relationships to treatment outcomes.

BACKGROUND: Little is known about the impact of psychiatric comorbidity on pharmacologic treatment outcomes, including neuromodulators (medications targeting the gut-brain axis), among adult patients with disorders of gut-brain interaction (DGBI). Accordingly, we aimed to examine associations between psychiatric comorbidity and DGBI pharmacologic treatment outcomes. METHODS: In a retrospective study of consecutively referred new patients (N = 410; ages 18-90; 73% female) to a tertiary neurogastroenterology clinic in 2016 with follow-up through 2018, relationships between psychiatric illness (any psychiatric illness, anxiety disorders, depressive disorders) and pharmacologic treatment selection (any medication, neuromodulating medication) and treatment outcomes, respectively, were examined using multivariable logistic regression, adjusting for demographics, gastrointestinal (GI) diagnoses, and pre-existing neuromodulator use. KEY RESULTS: Anxiety disorders (35%) were the most common psychiatric comorbidity, followed by depressive disorders (29%). Patients with anxiety disorders were more likely to be prescribed a neuromodulator by their gastroenterologist (OR = 1.72 [95% CI 1.10-2.75]) yet less likely to respond to neuromodulators (OR = 0.43 [0.21-0.90]) or any GI medication (OR = 0.24 [0.12-0.50]) in fully adjusted analyses. In contrast, depressive disorders were not associated with neuromodulator prescription or response. CONCLUSIONS AND INFERENCES: Anxiety disorders are common among patients with DGBI and significantly reduce the likelihood of GI pharmacologic treatment response to any medication prescribed, including neuromodulators.

Noninvasive Transcutaneous Auricular Vagal Nerve Stimulation Improves Gastric Slow Waves Impaired by Cold Stress in Healthy Subjects.

BACKGROUND/AIMS: Stress is known to inhibit gastric motility. The aim of this study was to investigate the effects and autonomic mechanisms of transcutaneous auricular vagal nerve stimulation (taVNS) on cold stress (CS)-induced impairment in gastric motility that are relevant to the brain-gut interactions in healthy volunteers. MATERIALS AND METHODS: Healthy volunteers (eight women; age 28.2 ± 1.8 years) were studied in four randomized sessions (control, CS, CS + taVNS, and CS + sham-electrical stimulation [sham-ES]). Each session was composed of 30 minutes in the fasting state and 30 minutes after a standard test meal. CS was induced during minutes 10 to 30 after the meal, whereas taVNS or sham-ES was performed during minutes 0 to 30 after the meal. The electrogastrogram and electrocardiogram were recorded for assessing gastric slow waves and autonomic functions, respectively. RESULTS: First, CS decreased the percentage of normal gastric slow waves (59.7% ± 9.8% vs 85.4% ± 4.5%, p < 0.001 vs control); this impairment was dramatically improved by taVNS (75.5% ± 6.3% vs 58.4% ± 12.5%, p < 0.001 vs sham-ES). Second, CS increased the symptom score (22.0 ± 12.1 vs 39.3 ± 11.5, p = 0.001 vs control); taVNS, but not sham-ES, reduced the symptom score (26.0 ± 12.2 vs 38.3 ± 21.6, p = 0.026 vs sham-ES). Third, CS decreased vagal activity assessed from the spectral analysis of heart rate variability (0.21 ± 0.10 vs 0.26 ± 0.11, p < 0.05 vs control) and increased the sympathovagal ratio (4.89 ± 1.94 vs 3.74 ± 1.32, p = 0.048 vs control); taVNS normalized CS-induced suppression in vagal activity (0.27 ± 0.13 vs 0.22 ± 0.10, p = 0.049 vs sham-ES; p > 0.05 vs control) and CS-induced increase in the sympathovagal ratio (3.28 ± 1.61 vs 4.28 ± 2.10, p = 0.042 vs sham-ES; p > 0.05 vs control). CONCLUSION: The noninvasive taVNS improves the CS-induced impairment in gastric pace-making activity, possibly by reversing the detrimental effect of CS on autonomic functions. taVNS may have a therapeutic potential for stress-induced gastric dysmotility.

Laparoscopic Electromyography and Electrostimulation of the Gastrointestinal Tract Before Placement of Theranostic Devices.

NEED: Electrical stimulation (ES) is a promising therapy for multisegmental gastrointestinal (GI) motility disorders such as gastroparesis with slow-transit constipation or chronic intestinal pseudo-obstruction. Wireless communicating GI devices for smart sensing and ES-based motility modulation will soon be available. Before placement, a potential benefit for each GI segment must be intraoperatively assessed. TECHNICAL SOLUTION: A minimally invasive multisegmental electromyography (EMG) analysis with ES of the GI tract is required. PROOF OF CONCEPT: Two porcine experiments were performed with a laparoscopic setup. Multiple hook-needle electrodes were subserosally applied in the stomach, duodenum, jejunum, ileum, and colon. EMG signals were acquired for computer-assisted motility analysis. Gastric ES, duodenal ES, jejunal ES, ileal ES, and colonic ES were applied. NEXT STEPS: Further technological and rapid regulatory solutions are desired to initialize a clinical trial of the next generation devices in the near future. CONCLUSION: We demonstrate a laparoscopic strategy with EMG analysis and ES of multiple GI segments. Thus, GI function may be evaluated before theranostic devices are placed. Extended GI resection or organ transplantation may be delayed or even avoided in affected patients.