A de novo variant in calponin2 causes intestinal pseudo-obstruction: Evidence from patient and mouse model.

Small intestinal bacterial overgrowth (SIBO) is a gastrointestinal disorder characterized by excessive bacterial colonization in the small intestine, leading to impaired digestion and nutrient malabsorption. Increasing evidence indicates that SIBO exerts systemic effects beyond the gut, contributing to metabolic, neurological, cardiovascular, dermatological, and autoimmune conditions. Current management strategies include nonsystemic antibiotics such as rifaximin, dietary interventions (low-FODMAP and biphasic diets), and nutraceuticals including berberine, oregano oil, peppermint oil, garlic derivatives, vitamins, and magnesium. Despite demonstrated clinical efficacy, challenges persist, including high recurrence rates, antimicrobial resistance, and long-term disruption of gut microbiota. Nutraceutical and dietary approaches offer promising patient-centered alternatives but require stronger clinical validation. This review critically examines the multifactorial pathophysiology of SIBO, emphasizing gut-brain axis dysregulation, microbial dysbiosis, oxidative stress, impaired intestinal motility, anatomical abnormalities, hypochlorhydria, bile acid malabsorption, and immune dysfunction. It synthesizes current diagnostic and therapeutic strategies, highlighting antibiotics, dietary approaches, and nutraceuticals, while distinguishing robust evidence from observational or preclinical findings. Finally, it identifies key research priorities, including improved diagnostics, global clinical trials, and microbiome- and genetics-based personalized treatments for sustained remission.

Levodopa remains the primary therapy for Parkinson's disease (PD); however, its benefits are largely confined to motor symptom relief, without altering disease progression. Growing evidence implicates the gut-brain axis in PD, linking gastrointestinal dysfunction and microbial shifts to neuronal cell death. Gut-brain metabolomics is critical for clarifying these interactions and guiding adjunct strategies to enhance intestinal motility and neuroprotection beyond levodopa. Therefore, this study aimed to characterize gut and brain metabolomic alterations induced by levodopa and to evaluate whether co-administration with 6-shogaol, previously identified as a gut-brain axis modulator, modifies these changes in relation to motor and gastrointestinal functions. Male C57BL/6 mice were assigned to normal, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid, levodopa, or 6-shogaol+levodopa groups. PD was induced by repeated MPTP/probenecid injections, and 6-shogaol was administered orally with levodopa. Motor performance, gut motility, dopamine levels in the brain, and metabolomic profiles were subsequently assessed. Levodopa improved motor deficits in the MPTP/probenecid model, while 6-shogaol co-administration preserved these benefits and additionally restored gastrointestinal motility, a non-motor feature unresponsive to levodopa alone. The combination further increased striatal dopamine and levodopa levels, suggesting enhanced dopaminergic availability. Metabolomic profiling revealed distinct brain-gut signatures, including alterations in energy, lipid, and amino acid pathways, with specific metabolites linked to motor function, dopamine regulation, and gut activity. These findings suggest that 6-shogaol complements levodopa by modulating brain-gut metabolomic networks to improve motor and non-motor features of PD.

Rhubarb Extract Ameliorates Slow-Transit Constipation in Rats by Modulating Gut Microbiota and Bile Acid Homeostasis.

Diarrhea is characterized by excessive intestinal secretion and motility, often linked to inflammatory activation. Although synthetic antidiarrheal drugs are effective, their prolonged use can cause side effects, underscoring the need for safe, natural alternatives.This study investigated the antidiarrheal and anti-inflammatory activities of Bacillus subtilis DKU_09-fermented soybean (FS) powder in a mouse model of castor oil-induced diarrhea.Male ICR mice were orally administered FS (100, 200, or 300 mg/kg) for 7 days before the induction of diarrhea with castor oil. Diarrheal onset, frequency, fecal water content, and gastrointestinal (GI) transit were recorded. Inflammatory mediators in the small intestine were analyzed using real-time polymerase chain reaction and Western blotting, while serum immunoglobulin A (IgA) and immunoglobulin G (IgG) were measured by enzyme-linked immunosorbent assay.Pretreatment with FS significantly delayed the onset of diarrhea (FS200: 132.0 ± 9.8 min vs. castor oil-treated control [DC]: 76.9 ± 5.6 min, P < .05) and reduced diarrheal frequency (FS200: 32.9 ± 5.4% vs. DC: 51.9 ± 6.1%, P < .05). FS normalized the accelerated GI transit and markedly suppressed intestinal inflammation. The expression of Il-1β, Cox-2, mPGES-1, and NF-κB (p65) mRNA was significantly decreased by FS, accompanied by inhibition of mitogen-activated protein kinase (MAPK) phosphorylation (ERK, JNK, and p38). Serum IgG and IgA levels were unaffected, indicating that the effects were localized to intestinal tissue.Soybeans fermented by B. subtilis DKU_09 exert potent antidiarrheal effects through suppression of the NF-κB/Cox-2/PGE2 and MAPK signaling pathways, thereby reducing intestinal inflammation and motility. These findings suggest that the FS used in the present study may serve as a safe and natural functional food for the management of acute diarrhea.

Slow-transit constipation (STC) is a disabling motility disorder with unclear smooth-muscle mechanisms. Through spatial proteomics of human colon and functional assays in primary human colonic smooth muscle cells (HCoSMCs), we identified Bridging Integrator 1 (BIN1) and Aldehyde Dehydrogenase 1B1 (ALDH1B1) as key regulators of intestinal motility. Both proteins were markedly reduced in smooth muscle from STC patients and localized to fibrotic areas. Lentiviral knockdown of BIN1 or ALDH1B1 impaired ATP-evoked Ca2 + responses and contraction, disrupted mitochondrial architecture, and increased reactive oxygen species. BIN1 deficiency activated mitochondrial apoptosis and extracellular matrix deposition, whereas ALDH1B1 loss induced mitophagy and NF-κB-driven inflammation. Transcriptomic and histological analyses confirmed convergence on profibrotic pathways. Together, these findings reveal a smooth-muscle-centric mechanism underlying STC pathogenesis and nominate BIN1 and ALDH1B1 as promising therapeutic entry points to restore intestinal motility.

Coordinated Interferon-γ/Tumor Necrosis Factor axis Drives Selective Loss of Activated Enteric Glia in Inflammatory Bowel Diseases.

Neonatal jaundice (NJ) is a common condition that may progress to serious complications such as kernicterus. Probiotics can also be used for treatment of jaundice by their effect on intestinal motility and microbial flora of the intestine. We aimed to evaluate the effect of probiotic supplementation as an adjuvant therapy in pathological neonatal unconjugated hyperbilirubinemia. A randomized, parallel-group comparative study was conducted on 44 neonates with confirmed pathological unconjugated hyperbilirubinemia admitted to the Neonatal Intensive Care Unit at Tanta University Hospital (Egypt) between May 2024 and April 2025. Participants were randomized (1:1) into two groups: phototherapy alone (control group n = 22) and phototherapy plus oral Bacillus clausii probiotic (probiotic group n = 22). Demographic data and bilirubin fractions were recorded. The primary outcome was the change in bilirubin levels; secondary outcomes included inflammatory biomarkers. Baseline characteristics were comparable between groups. Both groups exhibited significant declines in total serum bilirubin and indirect bilirubin, but only the probiotic group showed a significant reduction in direct bilirubin. By the end of treatment, the probiotic group showed a significantly greater reduction in lipopolysaccharide and tumor necrosis factor-α levels compared with the control group. Hospital stay was significantly shorter with probiotic therapy (3.8 ± 1.18 vs 6.3 ± 2.14 days; P < .001). Bacillus clausii supplementation alongside phototherapy significantly enhanced bilirubin reduction, decreased inflammatory markers, and shortened hospitalization, supporting its role as a beneficial adjunct therapy in neonatal hyperbilirubinemia.

Pediatric constipation, attributed to the functional immaturity of the gastrointestinal tract in children, is a common clinical disorder characterized by impaired gastrointestinal motility and infrequent bowel movements. Existing therapeutic strategies are frequently constrained by suboptimal efficacy owing to their single-target mechanisms and systemic toxicity. In contrast, Chinese medicinal formulas, with their multicomponent and multitarget intervention strategies, offer a highly suitable alternative for managing constipation. The traditional Chinese medicine formula “YiNianJin” (YNJ) is composed of cinnabar, rhubarb, stir-fried morning glory seeds, areca nut, and ginseng. It has demonstrated significant therapeutic efficacy in accelerating intestinal peristalsis through the synergistic regulation of aquaporin expression and the release of endocrine homeostatic transmitters. However, the clinical application of YNJ is significantly limited by conventional oral administration, which leads to Hg2+ accumulation and the low bioavailability of the active components. To address these challenges, we developed a sustained-release transdermal patch named YNJ patch (YNJP), which encapsulates cinnabar-loaded nanovesicles along with other active constituents in carboxymethyl cellulose sodium matrix. YNJP was shown to significantly enhance intestinal motility (as evidenced by a 24.02% increase in propulsion rate) by regulating the expression of mucin 2, aquaporin 3, and tight junction protein 1, while simultaneously promoting the release of endocrine homeostatic transmitters and Lactobacilli-mediated short-chain fatty acids. Therefore, YNJP is shown as a novel transdermal platform that alleviates pediatric constipation by modulating intestinal endocrine and metabolic homeostasis, enabling safe delivery of complex formulas with strong clinical potential for complex disorders.

Regulatory gene analysis in enteric neural crest cells stratified by GDNF activation status: An insight into Hirschsprung disease pathophysiology.

Capsaicinoids prevent intestinal fluid secretion and motility by inhibiting chloride channels.

This study aimed to investigate the mechanisms by which Citrus aurantium honey modulates gastrointestinal motility, inflammation, and barrier function using network pharmacology and Drosophila melanogaster models. Ultra-high-performance liquid chromatography coupled with Q Exactive high-field mass spectrometry (UHPLC-Q Exactive HF-MS) characterized the chemical profile. Network pharmacology predicted targets and enriched pathways, and molecular docking validated core component-target binding. In lipopolysaccharide (LPS)-induced Drosophila intestinal injury models, functional assays (fecal excretion, intestinal transit, barrier integrity) and mechanistic analyses (reactive oxygen species [ROS] levels, TORC1 pathway-related protein/gene expression) were performed. Network pharmacology revealed 17 key targets enriched in calcium signaling, cAMP/cGMP-PKG, and neuroactive ligand-receptor pathways. In Drosophila, honey dose-dependently (0.25% < 0.5% < 1%) enhanced intestinal motility (increased volume of stool and shorter transit time) and reduced inflammation (reduced ROS levels and improved barrier integrity, p < 0.01). Mechanistically, honey inhibited TORC1 overactivation by reducing 4E-BP phosphorylation and regulating Thor/Nprl2 expression. C. aurantium honey exerts gastrointestinal effects via a "multi-component, multi-target" mechanism. It modulates smooth muscle contraction through calcium/cAMP/cGMP pathways and alleviates inflammation by suppressing TORC1 signaling, highlighting its potential as a dietary intervention for dysmotility and inflammation.

Hyperactive Intestinal Motility and Postoperative Ileus: The Missing Link?

Aims: The effects of two Lactiplantibacillus plantarum strains and their probiotics on loperamide-induced constipation in mice were compared, and the possible mechanisms of the two strains in alleviating constipation were explored. Methods: KM mice were divided into the normal group, model group, positive control group, LTJ53 group, LP11824 group, HK-LTJ53 group and HK-LP11824 group. Loperamide was used to induce constipation in the mice. The study examined changes in defecation time, intestinal propulsion rate, gastric emptying rate, gastrointestinal peptides, colon histology, expression of intestinal barrier function genes, gut microbiota, and short-chain fatty acids (SCFAs). Results: Both live and postbiotic forms of L. plantarum significantly shortened defecation time, improved gastric emptying and intestinal motility, increased the levels of 5-hydroxytryptamine (5-HT), gastrin (GAS) and motilin (MTL), decreased the level of vasoactive intestinal peptide (VIP), restored colon morphology, upregulated the expression of Zonula Occludens-1 (ZO-1), mucin 2 (MUC2) and aryl hydrocarbon receptor (AhR), and downregulated the expression of aquaporin 4 (AQP4). They can also regulate the composition of the gut microbiota and alter the levels of SCFAs. Strain-specific effects were observed: LTJ53 was more effective in improving weight loss and gastric emptying, while LP11824 showed stronger efficacy in promoting small intestinal motility. Conclusions: L. plantarum and its postbiotics can relieve constipation through regulating the intestinal flora, enhancing gastrointestinal motility, adjusting the levels of neurotransmitters, and improving the intestinal barrier function. The specific effects of the two strains can support the selection of function-oriented precise intervention.

Hirschsprung disease (HSCR) is a congenital intestinal motility disorder characterized by the absence of enteric neurons in the distal bowel. Compared with bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq) enables gene expression profiling at the single-cell level, resolving cellular heterogeneity that is masked in population-averaged analyses. A standardized scRNA-seq workflow was established to characterize the transcriptional landscape of ganglionic and aganglionic segments from patients with HSCR. Colon tissues were collected, and hematoxylin and eosin staining was performed to identify ganglionic and aganglionic regions. Tissues were enzymatically and mechanically dissociated into single-cell suspensions, followed by filtration, viability assessment, and construction of single-cell transcriptome libraries. Libraries that passed quality control were sequenced, and raw data were processed for cell quantification and quality filtering to remove low-quality cells and technical artifacts. After normalization and dimensionality reduction, cells were clustered and annotated based on established marker genes. Downstream analyses compared cell-type composition between ganglionic and aganglionic tissues and identified differentially expressed genes within key immune cell subsets. The results reveal substantial differences in the immune microenvironment between ganglionic and aganglionic segments in HSCR.

We report the case of a 53-year-old woman with type 2 diabetes and bulimia nervosa who developed prolonged paralytic ileus after self-injecting tirzepatide 7.5 mg, 10 mg, and 15 mg on three consecutive days. Tirzepatide had been prescribed for diabetes treatment. However, the excessive self-administration resulted in paralytic ileus. No mechanical obstruction was found, and the condition resolved after three weeks of conservative therapy, including gastrointestinal decompression and prokinetic agents. Because tirzepatide has a long half-life, an overdose may cause the persistent suppression of intestinal motility. Misunderstanding about drug effects may lead to an overdose, thus requiring careful instruction and medication management.

To observe the synergistic analgesia and intestinal motility antagonism of electroacupuncture (EA) combined with morphine, and explore the mechanism of the "effect-enhancing and toxicity-reducing" of the combined therapy with acupuncture and medication. Sixty SPF-grade male C57BL/6J mice were randomly divided into a blank group, a model group, a sham-EA+normal saline (NS) group, a morphine+sham-EA group, an EA+NS group, and a morphine+EA group, with 10 mice in each group. Except in the blank group, the mice in the other groups were prepared to be inflammatory pain models induced by complete Freund's adjuvant. After successful modeling, the interventions were administered with EA, morphine, or morphine+EA, respectively. EA was delivered at "Zusanli" (ST36) bilaterally, with continuous wave, at a frequency of 2 Hz and a current of 2 mA, for 30 min, once daily and for 7 consecutive days. Intragastric administration with diluted morphine hydrochloride solution (24 mg/kg) was operated, twice daily and for 7 consecutive days. Sham-EA was obtained by no access to needle puncture and electric stimulation. The thermal pain threshold was measured using the hot plate method from day 0 to day 8. Intestinal motility was evaluated by time to first passage of melena, 2-hour fecal output and small intestinal transit rate. Immunofluorescence was used to detect the positive expression of μ-opioid receptor (MOR) and 5-hydroxytryptamine 1A receptor (5-HT1AR) in the hypothalamus, and that of MOR and purinergic receptor P2Y1 (P2Y1R) in the small intestine. ELISA was employed to measure the contents of β-endorphin (β-EP) and serotonin (5-HT) in the hypothalamus, and those of β-EP and adenosine triphosphate (ATP) in the small intestine. Compared with the blank group, the thermal pain threshold of mice decreased (P<0.05), the positive expression of MOR and 5-HT1AR and the content of 5-HT in the hypothalamus were reduced (P<0.05), the contents of β-EP in the hypothalamus and small intestine increased (P<0.05) in the model group. When compared with the model group, in the morphine+sham-EA group, the thermal pain threshold increased (P<0.05), the time to first passage of melena was prolonged (P<0.05), and the 2-hour fecal output and small intestinal transit rate decreased (P<0.05), and the positive expression of MOR in the hypothalamus and small intestine increased (P<0.05), while the positive expression of P2Y1R and the content of ATP in the small intestine decreased (P<0.05); in the EA+NS group, the thermal pain threshold was higher (P<0.05), the positive expression of MOR and 5-HT1AR in the hypothalamus and that of P2Y1R in the small intestine increased (P<0.05), and the contents of β-EP and 5-HT in the hypothalamus, and the content of ATP in the small intestine were elevated (P<0.05), the positive expression of MOR and the content of β-EP in the small intestine were reduced (P<0.05); in the morphine+EA group, the thermal pain threshold was higher (P<0.05), the time to first passage of melena was prolonged (P<0.05), the 2-hour fecal output and small intestinal transit rate were declined (P<0.05), and the positive expression of MOR and 5-HT1AR and the contents of β-EP and 5-HT in the hypothalamus increased (P<0.05), while the content of β-EP in the small intestine decreased (P<0.05). In comparison with the morphine+sham-EA group, the morphine+EA group showed the decrease in the time to first passage of melena (P<0.05), the increase in the 2-hour fecal output and small intestinal transit rate (P<0.05), and the increase in the positive expression of MOR and 5-HT1AR and the contents of β-EP and 5-HT in the hypothalamus (P<0.05), the decrease in the positive expression of MOR and the content of β-EP in the small intestine (P<0.05), and the increase in the positive expression of P2Y1R and the content of ATP in the small intestine (P<0.05). Compared with the EA+NS group, the morphine+EA group demonstrated the increase in the time to first passage of melena (P<0.05), the decrease in the 2-hour fecal output (P<0.05), and the increase in the positive expression of MOR in the hypothalamus and the small intestine and the content of β-EP in the hypothalamus (P<0.05), and the decrease in the positive expression of P2Y1R and the content of ATP in the small intestine (P<0.05). MOR and P2Y1R were co-located and the positive expression of them in the small intestine showed a significant negative correlation (r=-0.868, P<0.000 1). Electroacupuncture combined with morphine exerts synergistic analgesia by agonizing MOR and 5-HT1AR in the brain, and improves intestinal motility by inhibiting MOR and agonizing P2Y1R in the intestine, demonstrating the characteristic of "effect-enhancing and toxicity-reducing" in the combined therapy with acupuncture and medication.

Calcitonin gene-related peptide (CGRP), a neuropeptide with α and β isoforms, is a pivotal regulator connecting the neural, immune, and gastrointestinal systems. This comprehensive analysis delineates the evidence-based mechanistic roles of CGRP within the microbiome-gut-brain axis, focusing on its bidirectional modulation of enteric and central nervous system pathways. Both α- and β-CGRP are widely expressed in sensory and enteric neurons, where they govern vasodilation, intestinal motility, secretion, and mucosal homeostasis. CGRP-mediated signaling integrates gut microbiota-derived cues with central neurocircuitry, influencing visceral sensitivity, immune activation, and behavioral states such as anxiety and satiety. Furthermore, CGRP interacts with major neurotransmitter systems-including serotonin (5-HT), histamine, dopamine, and glutamatethereby linking peripheral microbial activity to central pain and emotional processing. We discuss isoform-specific and receptor-level mechanisms (e.g., CLR/RAMP1) as evidence permits and highlight gaps in translating preclinical findings to human physiology. Although CGRP has significant roles in other systems, such as in metabolism and pancreatic function, these are beyond the scope of this review, which focuses specifically on the neuro-immune-gastrointestinal interface. Collectively, CGRP emerges as a critical neuroendocrine mediator in coordinating communication across the microbiota-gut-brain axis. A deeper understanding of its spatiotemporal dynamics and isoformspecific functions will be crucial for the development of targeted therapeutic strategies for CGRPrelated disorders affecting both neurological and gastrointestinal systems.

How changes in salinity modify patterns of gastrointestinal motility in the intestine of freshwater barramundi.

Slow transit constipation (STC) is a prevalent functional gastrointestinal disorder that significantly affects people's quality of life. Aurantii Fructus Immaturus (Zhishi, ZS) and Atractylodis Macrocephalae Rhizoma (Baizhu, BZ) are a classic herbal pair in traditional Chinese medicine (TCM) for regulating spleen-stomach function, respectively recognized for their properties of "replenishing qi and fortifying the spleen" and "dispersing stagnation and promoting digestion". This study aimed to elucidate the mechanisms by which ZSBZ ameliorates STC through regulating mitophagy in ICCs and restructuring gut microbiota composition. A rat model of STC was established by oral gavage administration of loperamide hydrochloride (3 mg/kg·day). The therapeutic effects of ZSBZ were evaluated by assessing rat body weight, 6-h fecal number, fecal water content, and intestinal transit rate. Histopathological changes in the colon were observed using hematoxylin-eosin (HE) staining and Alcian blue-periodic acid Schiff (AB-PAS) staining. The ultrastructure of colon tissues was observed by transmission electron microscopy (TEM). Immunohistochemistry (IHC) was used to detect the expression of c-Kit, SCF, and autophagy-related markers (p62, Beclin1, and LC3II/I) in colon tissues. The expression levels of α-KGDHC and PDH were measured by ELISA. Combined with biochemical assays for SOD, MDA, respiratory chain complexes I and II, and ATP levels, a comprehensive assessment of cellular mitochondrial oxidative stress status and energy metabolism function was performed. Flow cytometry was used to quantify intracellular Ca2+ concentration and mitochondrial membrane potential (MMP) in cells isolated from colonic tissues. Mitophagy-related protein and mRNA expression were analyzed by Western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Apoptosis in rat colonic tissues was detected using TUNEL assay. Gut microbiota composition was analyzed by 16S rRNA gene sequencing, and its metabolic functional potential was predicted. Our results showed that ZSBZ significantly ameliorated defecation function and enhanced intestinal motility in a rat model of STC. Histopathological and ultrastructural analyses revealed that ZSBZ effectively restored colonic mucosal damage, increased goblet cell numbers, and attenuated mitochondrial swelling with cristae disruption in ICCs of STC rats. Meanwhile, ZSBZ improved mitochondrial dysfunction by reducing MDA levels and increasing SOD activity in colonic tissues. Furthermore, ZSBZ improved mitochondrial energy metabolism by increasing ATP content, restoring respiratory chain complex I and II activities, and elevating α-KGDHC and PDH activities, thereby reversing the decline in mitochondrial membrane potential and the increase in intracellular Ca2+ concentration in cells isolated from colonic tissues. Mechanistically, ZSBZ attenuated excessive mitophagy in colonic ICCs by downregulating autophagy-related genes and proteins, restoring p62 expression, and suppressing the elevated mRNA and protein expression of the mitophagy-related markers PINK1 and Parkin. In addition, 16S rRNA gene sequencing demonstrated that ZSBZ reshaped the gut microbiota in STC rats, characterized by a decreased abundance of Proteobacteria and an increased abundance of Bacteroidota. KEGG functional prediction further indicated that ZSBZ regulated mitochondrial metabolism-related pathways, possibly contributing to the amelioration of colonic dysmotility. ZSBZ significantly alleviated constipation symptoms in STC rats. The mechanism may involve inhibition of excessive mitophagy in ICCs and restructuring of gut microbiota composition. This study provides compelling theoretical support for ZSBZ as a therapeutic strategy against STC and offers novel insights into intestinal motility restoration in humans.