Muscularis macrophages controlled by NLRP3 maintain the homeostasis of excitatory neurons.

Peristaltic movements in gut are essential to propel ingested materials through the gastrointestinal tract. Intestinal resident macrophages play an important role in this physiological function through protecting enteric neurons. However, it is incompletely clear how individuals maintain the homeostasis of gut motility. Here we found that NLRP3 is a critical factor in controlling loss of muscularis resident macrophages (MMs), and demonstrate that MMs are involved in the homeostasis of excitatory neurons such as choline acetyltransferase (ChAT)+ and vesicular glutamate transporter 2 (VGLUT2)+ but not inhibitory neuronal nitric oxide synthase (nNOS)+ neurons. NLRP3 knockout (KO) mice had enhanced gut motility and increased neurons, especially excitatory ChAT+ and VGLUT2+ neurons. Single cell analyses showed that there had increased resident macrophages, especially MMs in NLRP3 KO mice. The MM proportion in the resident macrophages was markedly higher than those in wild-type (WT) or caspase 1/11 KO mice. Deletion of the MMs and transplantation of the NLRP3 KO bone marrow cells showed that survival of the gut excitatory ChAT+ and VGLUT2+ neurons was dependent on the MMs. Gut microbiota metabolites ß-hydroxybutyrate (BHB) could promote gut motility through protecting MMs from pyroptosis. Thus, our data suggest that MMs regulated by NLRP3 maintain the homeostasis of excitatory neurons.

Evaluation of the impact of overlapping upper gastrointestinal symptoms on the clinical characteristics of patients with functional constipation, along with risk factor analysis.

OBJECTIVES: Functional constipation (FC), a common functional gastrointestinal disorder, is usually overlapping with upper gastrointestinal symptoms (UGS). We aimed to explore the clinical characteristics of patients with FC overlapping UGS along with the related risk factors. METHODS: The differences in the severity of constipation symptoms, psychological state, quality of life (QoL), anorectal motility and perception function, autonomic function, and the effect of biofeedback therapy (BFT) among patients with FC in different groups were analyzed, along with the risk factors of overlapping UGS. RESULTS: Compared with patients with FC alone, those with FC overlapping UGS had higher scores in the Patient Assessment of Constipation Symptoms and Self-Rating Anxiety Scale and lower scores in the Short Form-36 health survey (P < 0.05). Patients with FC overlapping UGS also had lower rectal propulsion, more negative autonomic nervous function, and worse BFT efficacy (P < 0.05). Overlapping UGS, especially overlapping functional dyspepsia, considerably affected the severity of FC. Logistic regression model showed that age, body mass index (BMI), anxiety, exercise, and sleep quality were independent factors influencing overlapping UGS in patients with FC. CONCLUSIONS: Overlapping UGS reduces the physical and mental health and the QoL of patients with FC. It also increases the difficulty in the treatment of FC. Patient's age, BMI, anxiety, physical exercise, and sleep quality might be predictors for FC overlapping UGS.

BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system.

Epigenetic regulatory mechanisms are underappreciated, yet are critical for enteric nervous system (ENS) development and maintenance. We discovered that fetal loss of the epigenetic regulator Bap1 in the ENS lineage caused severe postnatal bowel dysfunction and early death in Tyrosinase-Cre Bap1fl/fl mice. Bap1-depleted ENS appeared normal in neonates; however, by P15, Bap1-deficient enteric neurons were largely absent from the small and large intestine of Tyrosinase-Cre Bap1fl/fl mice. Bowel motility became markedly abnormal with disproportionate loss of cholinergic neurons. Single-cell RNA sequencing at P5 showed that fetal Bap1 loss in Tyrosinase-Cre Bap1fl/fl mice markedly altered the composition and relative proportions of enteric neuron subtypes. In contrast, postnatal deletion of Bap1 did not cause enteric neuron loss or impaired bowel motility. These findings suggest that BAP1 is critical for postnatal enteric neuron differentiation and for early enteric neuron survival, a finding that may be relevant to the recently described human BAP1-associated neurodevelopmental disorder.

Bowel function and inflammation: Is motility the other side of the coin?

Digestion and intestinal absorption allow the body to sustain itself and are the emblematic functions of the bowel. On the flip side, functions also arise from its role as an interface with the environment. Indeed, the gut houses microorganisms, collectively known as the gut microbiota, which interact with the host, and is the site of complex immune activities. Its role in human pathology is complex and scientific evidence is progressively elucidating the functions of the gut, especially regarding the pathogenesis of chronic intestinal diseases and inflammatory conditions affecting various organs and systems. This editorial aims to highlight and relate the factors involved in the pathogenesis of intestinal and systemic inflammation.

Purinergic inhibitory regulation of esophageal smooth muscle is mediated by P2Y receptors and ATP-dependent potassium channels in rats.

Purines such as ATP are regulatory transmitters in motility of the gastrointestinal tract. The aims of this study were to propose functional roles of purinergic regulation of esophageal motility. An isolated segment of the rat esophagus was placed in an organ bath, and mechanical responses were recorded using a force transducer. Exogenous application of ATP (10-100 µM) evoked relaxation of the esophageal smooth muscle in a longitudinal direction under the condition of carbachol (1 µM) -induced precontraction. Pretreatment with a non-selective P2 receptor antagonist, suramin (500 µM), and a P2Y receptor antagonist, cibacron blue F3GA (200 µM), inhibited the ATP (100 µM) -induced relaxation, but a P2X receptor antagonist, pyridoxal phosphate-6-azophenyl-2,4-disulfonic acid (50 µM), did not affect it. A blocker of ATP-dependent potassium channels (KATP channels), glibenclamide (200 µM), inhibited the ATP-induced relaxation and application of an opener of KATP channels, nicorandil (50 µM), produced relaxation. The findings suggest that ATP is involved in inhibitory regulation of the longitudinal smooth muscle in the muscularis mucosae of the rat esophagus via activation of P2Y receptors and then opening of KATP channels.

Mechanism of Mulberry Leaves and Black Sesame in Alleviating Slow Transit Constipation Revealed by Multi-Omics Analysis.

Traditional Chinese medicine (TCM) possesses the potential of providing good curative effects with no side effects for the effective management of slow transit constipation (STC), an intestinal disease characterized by colonic dyskinesia. Mulberry leaves (Morus alba L.) and black sesame (Sesamum indicum L.), referred to as SH, are processed and conditioned as per standardized protocols. SH has applications as food and medicine. Accordingly, we investigated the therapeutic potential of SH in alleviating STC. The analysis of SH composition identified a total of 504 compounds. The intervention with SH significantly improved intestinal motility, reduced the time for the first black stool, increased antioxidant activity, and enhanced water content, thereby effectively alleviating colon damage caused by STC. Transcriptome analysis revealed the SH in the treatment of STC related to SOD1, MUC2, and AQP1. The analysis of 16S rRNA gene sequences indicated notable differences in the abundance of 10 bacteria between the SH and model. Metabolomic analysis further revealed that SH supplementation increased the levels of nine metabolites associated with STC. Integrative analysis revealed that SH modulated amino acid metabolism, balanced intestinal flora, and targeted key genes (i.e., SOD1, MUC2, AQP1) to exert its effects. SH also inhibited the AQP1 expression and promoted SOD1 and MUC2 expression.

[Snoring noise removal method for bowel sound signal during sleep].

Monitoring of bowel sounds is an important method to assess bowel motility during sleep, but it is seriously affected by snoring noise. In this paper, the complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) method was applied to remove snoring noise from bowel sounds during sleep. Specifically, the noisy bowel sounds were first band-pass filtered, then decomposed by the CEEMDAN method, and finally the appropriate components were selected to reconstruct the pure bowel sounds. The results of semi-simulated and real data showed that the CEEMDAN method was better than empirical mode decomposition and wavelet denoising method. The CEEMDAN method is used to remove snoring noise from bowel sounds during sleep, which lays an important foundation for using bowel sounds to assess the intestinal motility during sleep.

Inhibition of calcium-sensing receptor by its antagonist promotes gastrointestinal motility in a Parkinson's disease mouse model.

BACKGROUND: The Calcium-sensing receptor (CaSR) participates in the regulation of gastrointestinal (GI) motility under normal conditions and might be involved in the regulation of GI dysmotility in patients with Parkinson's disease (PD). METHODS: CaSR antagonist-NPS-2143 was applied in in vivo and ex vivo experiments to study the effect and underlying mechanisms of CaSR inhibition on GI dysmotility in the MPTP-induced PD mouse model. FINDINGS: Oral intake of NPS-2143 promoted GI motility in PD mice as shown by the increased gastric emptying rate and shortened whole gut transit time together with improved weight and water content in the feces of PD mice, and the lack of influence on normal mice. Meanwhile, the number of cholinergic neurons, the proportion of serotonergic neurons, as well as the levels of acetylcholine and serotonin increased, but the numbers of nitrergic and tyrosine hydroxylase immunoreactive neurons, and the levels of nitric oxide synthase and dopamine decreased in the myenteric plexus in the gastric antrum and colon of PD mice in response to NPS-2143 treatment. Furthermore, the numbers of c-fos positive neurons in the nucleus tractus solitarius (NTS) and cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) increased in NPS-2143 treated PD mice, suggesting the involvement of both the enteric (ENS) and central (CNS) nervous systems. However, ex vivo results showed that NPS-2143 directly inhibited the contractility of antral and colonic strips in PD mice via a non-ENS mediated mechanism. Further studies revealed that NPS-2143 directly inhibited the voltage gated Ca2+ channels, which might, at least in part, explain its direct inhibitory effects on the GI muscle strips. INTERPRETATION: CaSR inhibition by its antagonist ameliorated GI dysmotility in PD mice via coordinated neuronal regulation by both ENS and CNS in vivo, although the direct effects of CaSR inhibition on GI muscle strips were suppressive.

Gut motility and hormone changes after bariatric procedures.

PURPOSE OF REVIEW: Metabolic and bariatric surgery (MBS) and endoscopic bariatric therapies (EBT) are being increasingly utilized for the management of obesity. They work through multiple mechanisms, including restriction, malabsorption, and changes in the gastrointestinal hormonal and motility. RECENT FINDINGS: Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) cause decrease in leptin, increase in GLP-1 and PYY, and variable changes in ghrelin (generally thought to decrease). RYGB and LSG lead to rapid gastric emptying, increase in small bowel motility, and possible decrease in colonic motility. Endoscopic sleeve gastroplasty (ESG) causes decrease in leptin and increase in GLP-1, ghrelin, and PYY; and delayed gastric motility. SUMMARY: Understanding mechanisms of action for MBS and EBT is critical for optimal care of patients and will help in further refinement of these interventions.

The critical role of muscularis macrophages in modulating the enteric nervous system function and gastrointestinal motility.

Macrophages are the originators of inflammatory compounds, phagocytic purifiers in their local environment, and wound healing protectors in oxidative environments. They are molded by the tissue milieu they inhabit, with gastrointestinal (GI) muscularis macrophages (MMs) being a prime example. MMs are located in the muscular layer of the GI tract and contribute to muscle repair and maintenance of GI motility. MMs are often in close proximity to the enteric nervous system, specifically near the enteric neurons and interstitial cells of Cajal (ICCs). Consequently, the anti-inflammatory function of MMs corresponds to the development and maintenance of neural networks in the GI tract. The capacity of MMs to shift from anti-inflammatory to proinflammatory states may contribute to the inflammatory aspects of various GI diseases and disorders such as diabetic gastroparesis or postoperative ileus, functional disorders such as irritable bowel syndrome, and organic diseases such as inflammatory bowel disease. We reviewed the current knowledge of MMs and their influence on neighboring cells due to their important role in the GI tract.

Feasibility and repeatability of ultrasound-guided surface electroenterography to measure colonic slow wave motility in healthy adults.

Surface electroenterography is a potential non-invasive alternative to current diagnostics of colonic motility disorders. However, electrode positioning in electroenterography is often based on general anatomy and may lack generalizability. Furthermore, the repeatability of electroenterography measurements is unknown. This study aimed to evaluate ultrasound-guided electrode positioning for electroenterography measurements and to determine the repeatability of those measurements. In ten healthy adults, two electroenterography procedures were performed, consisting of fasting, ultrasound-guided electrode localization and two 20-minute electroenterography recordings separated by a meal. The dominant frequency, the mean power density (magnitude of colonic motility) and the power percent difference (relative pre- to postprandial increase in magnitude) were determined. Repeatability was determined by Lin's concordance correlation coefficient. The results demonstrated that the dominant frequency did not differ between pre- and postprandial recordings and was 3 cpm, characteristic of colonic motility. The mean power density increased between the pre- and postprandial measurements, with an average difference of over 200%. The repeatability of both the dominant frequency and power density was poor to moderate, whereas the correlation coefficient of the power percent difference was poor. Concluding, ultrasound-guided surface electroenterography seems able to measure the gastrocolic reflex, but the dissatisfactory repeatability necessitates optimization of the measurement protocol.

Radiopaque marker colonic transit study in the pediatric population BSPGHAN Motility Working Group consensus statement.

Functional constipation (FC) is a common condition in childhood in the United Kingdom and worldwide. Various radiological approaches have been established for diagnostic purposes. The radiopaque marker study (ROMS) is universally accepted and used to assess colonic transit time (CTT) in children with FC. Despite being widely used, there is a lack of standardization with various technical protocols, reproducibility of different populations, the purpose for using investigation, variance in the number of markers used, the amount of study days and calculations, the need to empty the colon before performing the test, and whether to perform on medication or off, or the use of specific diets. As part of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) motility working group (MWG), we decided to explore further into the evidence, in order to provide guidance regarding the use of ROMS in dealing with FC in the pediatric population.

Got the Munchies for an Egg Sandwich? The Effects of Cannabis on Bowel Motility and Beyond.

The use of medicinal cannabis has a long history dating back thousands of years. Recent discoveries have shed light on its mechanism of action with the identification of cannabinoid receptors and endocannabinoids, which make up the body's endocannabinoid system. Cannabinoid receptors, particularly the cannabinoid 1 and 2 receptors, play a crucial role in modulating the gut-brain axis and serve as potential therapeutic targets for gastrointestinal motility and inflammatory disorders. With increasing legalization of cannabis and a rising number of users, understanding the effects of cannabis on gut motility is essential for nuclear medicine providers. Although tetrahydrocannabinol, the principal psychoactive constituent of cannabis, may decrease gut motility in experimental settings, it appears to paradoxically improve symptoms in gastroparesis. Treatment effects are difficult to measure given the large number of variables that could significantly alter outcomes, such as cannabinoid type, potency, and route of intake. Another consideration is the highly personalized gut microbiome, which directly interacts with the endocannabinoid system. Further research is required to delineate these multifaceted, complex cannabinoid interactions. The goal of this article is to explore the knowns and unknowns of the impact of cannabis on the alimentary system.

Optimization of pacing parameters to entrain slow wave activity in the pig jejunum.

Pacing has been proposed as a therapy to restore function in motility disorders associated with electrical dysrhythmias. The spatial response of bioelectrical activity in the small intestine to pacing is poorly understood due to a lack of high-resolution investigations. This study systematically varied pacing parameters to determine the optimal settings for the spatial entrainment of slow wave activity in the jejunum. An electrode array was developed to allow simultaneous pacing and high-resolution mapping of the small intestine. Pacing parameters including pulse-width (50, 100 ms), pulse-amplitude (2, 4, 8 mA) and pacing electrode orientation (antegrade, retrograde, circumferential) were systematically varied and applied to the jejunum (n = 15 pigs). Pulse-amplitudes of 4 mA (p = 0.012) and 8 mA (p = 0.002) were more effective than 2 mA in achieving spatial entrainment while pulse-widths of 50 ms and 100 ms had comparable effects (p = 0.125). A pulse-width of 100 ms and a pulse-amplitude of 4 mA were determined to be most effective for slow wave entrainment when paced in the antegrade or circumferential direction with a success rate of greater than 75%. These settings can be applied in chronic studies to evaluate the long-term efficacy of pacing, a critical aspect in determining its therapeutic potential.

Prokinetics-safety and efficacy: The European Society of Neurogastroenterology and Motility/The American Neurogastroenterology and Motility Society expert review.

BACKGROUND: Prokinetics are a class of pharmacological drugs designed to improve gastrointestinal (GI) motility, either regionally or across the whole gut. Each drug has its merits and drawbacks, and based on current evidence as high-quality studies are limited, we have no clear recommendation on one class or other. However, there remains a large unmet need for both regionally selective and/or globally acting prokinetic drugs that work primarily intraluminally and are safe and without systemic side effects. PURPOSE: Here, we describe the strengths and weaknesses of six classes of prokinetic drugs, including their pharmacokinetic properties, efficacy, safety and tolerability and potential indications.

Mind shift I: Fructus Aurantii - Rhizoma Chuanxiong synergistically anchors stress-induced depression-like behaviours and gastrointestinal dysmotility cluster by regulating psycho-immune-neuroendocrine network.

BACKGROUND: Researchers have not studied the integrity, orderly correlation, and dynamic openness of complex organisms and explored the laws of systems from a global perspective. In the context of reductionism, antidepressant development formerly focused on advanced technology and molecular details, clear targets and mechanisms, but the clinical results were often unsatisfactory. PURPOSE: MDD represents an aggregate of different and highly diverse disease subtypes. The co-occurrence of stress-induced nonrandom multimorbidity is widespread, whereas only a fraction of the potential clusters are well known, such as the MDD-FGID cluster. Mapping these clusters, and determining which are nonrandom, is vital for discovering new mechanisms, developing treatments, and reconfiguring services to better meet patient needs. STUDY DESIGN: Acute stress 15-minute forced swimming (AFS) or CUMS protocols can induce the nonrandom MDD-FGID cluster. Multiple biological processes of rats with depression-like behaviours and gastrointestinal dysmobility will be captured under conditions of stress, and the Fructus Aurantii-Rhizoma Chuanxiong (ZQCX) decoction will be utilized to dock the MDD-FGID cluster. METHODS/RESULTS: Here, Rhizoma Chuanxiong, one of the seven components of Chaihu-shugan-San, elicited the best antidepressant effect on CUMS rats, followed by Fructus Aurantii. ZQCX reversed AFS-induced depression-like behaviours and gastrointestinal dysmobility by regulating the glutamatergic system, AMPAR/BDNF/mTOR/synapsin I pathway, ghrelin signalling and gastrointestinal nitric oxide synthase. Based on the bioethnopharmacological analysis strategy, the determined meranzin hydrate (MH) and senkyunolide I (SI) by UPLC-PDA, simultaneously absorbed by the jejunum and hippocampus of rats, have been considered major absorbed bioactive compounds acting on behalf of ZQCX. Cotreatment with MH and SI at an equivalent dose in ZQCX synergistically replicated over 50.33 % efficacy of the parent formula in terms of antidepressant and prokinetic actions by modulating neuroinflammation and ghrelin signalling. CONCLUSION: Brain-centric mind shifts require the integration of multiple central and peripheral systems and the elucidation of the underlying neurobiological mechanisms that ultimately contribute to novel therapeutic options. Ghrelin signalling and the immune system may partially underlie multimorbidity vulnerability, and ZQCX anchors stress-induced MDD-FGID clusters by docking them. Combining the results of micro details with the laws of the macro world may be more effective in finding treatments for MDD.

Huanglian-banxia promotes gastric motility of diabetic rats by modulating brain-gut neurotransmitters through MAPK signaling pathway.

BACKGROUND: Gastric motility disorder is an increasingly common problem among people with diabetes. Neurotransmitters have been recognized as critical regulators in the process of gastric motility. Previous study has shown that herb pair huanglian-banxia (HL-BX) can improve gastric motility, but the underlying mechanism is still unclear. The aim of this study was to further investigate the role of HL-BX in modulating brain-gut neurotransmission to promote gastric motility in diabetic rats, and to explore its possible mechanism. METHODS: The diabetic rats were divided into five groups. Gastric emptying rate, intestinal propulsion rate, body weight, and average food intake were determined. Substance P (SP), 5- hydroxytryptamine (5-HT), and glucagon-like peptide -1 (GLP-1) in the serum were measured by enzyme-linked immunosorbent assay. Dopamine (DA) and norepinephrine (NE) in the brain were analyzed by high-pressure liquid chromatography with a fluorescence detector. Protein expression of the tissues in the stomach and brain was determined by Western blot. KEY RESULTS: HL-BX reduced average food intake significantly, increased body weight, and improved gastric emptying rate and intestinal propulsion rate. HL-BX administration caused a significant increase in SP, GLP-1, and 5-HT, but a significant decrease in DA and NE. Interestingly, HL-BX regulated simultaneously the different expressions of MAPK and its downstream p70S6K/S6 signaling pathway in the stomach and brain. Moreover, berberine exhibited a similar effect to HL-BX. CONCLUSIONS: These results indicated that HL-BX promoted gastric motility by regulating brain-gut neurotransmitters through the MAPK signaling pathway. HL-BX and MAPK provide a potential therapeutic option for the treatment of gastroparesis.

Understanding the gastrointestinal tract in obesity: From gut motility patterns to enzyme secretion.

BACKGROUND AND PURPOSE: The pathophysiology of obesity has been the product of extensive research, revealing multiple interconnected mechanisms contributing to body weight regulation. The regulation of energy balance involves an intricate network, including the gut-neuroendocrine interplay. As a consequence, research on the gut-brain-microbiota axis in obesity has grown extensively. The physiology of the gastrointestinal tract, far from being underexplored, has significant implications for the development of specific complications in people living with obesity across the fields of gastroenterology, nutrition, and pharmacology. Clinical research indicates higher fasting bile acids serum levels, and blunted postprandial increases in bilious secretions in people living with obesity. Findings are less straightforward for the impact of obesity on gastric emptying with various studies reporting accelerated, normal, or delayed gastric emptying rates. Conversely, the effect of obesity on gastrointestinal pH, gastrointestinal transit, and gastric and pancreatic enzyme secretion is largely unknown. In this review, we explore the current evidence on the gastrointestinal physiology of obesity.

Diagnostic yield of left-sided colonic manometry in identifying colonic dysmotility in pediatric patients.

BACKGROUND: Colonic manometry (CM) is a diagnostic procedure utilized in the evaluation of intractable constipation and involves endoscopic insertion of a manometry catheter with the tip placed in the cecum. Difficulty in advancing the colonic manometry catheter to the right colon and/or distal displacement of the catheter after appropriate placement can result in partial evaluation of the colon. Our study aimed to assess the value of limited left CM in identifying motility disorders. METHODS: We evaluated CM studies conducted at a tertiary pediatric center (2019-2022). Abnormal CM studies with catheter tips located in the cecum or ascending colon were included. KEY RESULTS: Of 161 CM studied, 68 with abnormal CM studies met inclusion criteria (29 [42.7%] females, median age 10.3 years). Pan-colonic dysmotility was noted in 29 (42.7%) studies and segmental dysmotility in 39 (57.4%) studies. Dysmotility of the descending and/or sigmoid colon was the most common segmental dysmotility (30, 76.9%). Isolated dysmotility of the ascending colon was noted only in patients with a cecostomy (6/13, 46.2%). The diagnostic sensitivity for dysmotility by left CM was 91.2%, which increased to 100% when excluding patients with cecostomy. CONCLUSIONS AND INFERENCES: Left CM is a valuable and sensitive diagnostic tool for identifying abnormal colonic motility in most pediatric patients with constipation without cecostomy. Our study results provide reassurance when the manometry catheter becomes dislodged from the cecum and moves distally. Those with cecostomy have a high prevalence of dysmotility in the ascending colon and need a complete CM to identify it.