VIP Levels Research Articles

Bifidobacterium animalis subsp. lactis TG11 ameliorates loperamide-induced constipation in mice by modulating gut microbiota

IntroductionConstipation is a common gastrointestinal disorder that can affect quality of life. Probiotics have garnered substantial attention for their potential to alleviate constipation. This study investigates the preventive effects of Bifidobacterium animalis subsp. lactis TG11 on loperamide-induced constipation in mice.MethodsMice were randomly assigned to normal control (NC), constipation model (CM), and low, medium, and high-dose TG11 treatment groups (LG, MG, HG). From days 1–14, LG, MG, and HG groups received 106, 107, and 108 CFU/mouse of TG11, respectively, while NC and CM groups received saline. On day 14, all groups except NC were administered loperamide (4 mg/kg) orally to induce constipation. Fecal samples were collected for short-chain fatty acid and gut microbiota analyses. Following a 16-hour fasting period, various parameters were assessed on day 15, including intestinal motility, fecal water content, defecation status, gut peptide levels in blood, and mRNA expression levels of SCF and c-kit in colonic tissue.ResultsTG11 significantly enhanced intestinal motility and maintained fecal water content. It normalized blood levels of MTL, SP, SS, ET-1, Gas, and VIP in constipated mice, promoted short-chain fatty acid production, and improved microbial metabolism. TG11 markedly upregulated mRNA expression of SCF and c-kit in colonic tissue. Metagenomic sequencing revealed that TG11 modulated gut microbiota composition, increasing the abundance of beneficial bacteria, particularly Muribaculum_sp. and uncultured_Duncaniella.DiscussionBifidobacterium animalis subsp. lactis TG11 demonstrates efficacy in ameliorating constipation, potentially through modulation of the gut microbiota composition.

Study on the effects of Massa Medicata Fermentata with different formulations on the intestinal microbiota and enzyme activities in mice with spleen deficiency constipation.

This study aims to explore the therapeutic mechanism of Massa Medicata Fermentata (MMF) with different formulations on spleen deficiency constipation in mice by analyzing gastrointestinal hormones, D-xylose, intestinal microbiota, and intestinal enzyme activities. A spleen deficiency constipation model was established using an oral administration of Sennae Folium decoction combined with controlled diet and water intake. After successful model establishment, the mice with spleen deficiency constipation were treated with MMF S1, S2, S3. Following the intervention, serum samples from each group of mice were collected to measure VIP, 5-HT, and D-xylose. Additionally, small intestine contents were analyzed for intestinal enzyme activity and subjected to 16S rRNA high-throughput sequencing. Mice with spleen deficiency constipation showed significant decreases in body weight and fecal water content. In contrast, the body weight of the CS2 and CS3 groups returned to normal levels, and fecal water content in the CS2 and CS3 groups also returned to normal. The MMF S2 and S3 significantly increased protease and sucrase enzymes levels compared with CM group. Serum D-xylose levels were significantly reduced in the CM and CS2 group. VIP levels increased significantly in the CM group but decreased in the CS2 and CS3 groups. Additionally, 5-HT levels in the CM and CS1 groups decreased significantly, with the CS2 group returning to normal and the CS3 group showing significant increases. 16S rRNA sequencing analysis revealed that all three MMF formulations effectively restored the intestinal microbiota composition in mice. LEfSe analysis identified characteristic microbiota linked to different intervention groups. The CS3 group significantly upregulated the chloroalkane and chloroalkene degradation and vibrio cholerae pathogenic cycle pathways compared to the CM group. Candidatus_Arthromitus in the CS3 group and Psychrobacter in the CS2 group were positive and negative correlations with 5-HT and VIP, respectively. The three formulations of MMF significantly alleviated spleen deficiency constipation symptoms by modulating intestinal enzyme activities, D-xylose, VIP, and 5-HT levels, and restoring intestinal microbiota balance. Psychrobacter and Candidatus_Arthromitus were identified as potential biomarkers for the treatment of spleen deficiency constipation. Different formulations of MMF have different mechanisms of regulating constipation through intestinal microbiota.

The polysaccharide from purple sweet potato (Ipomoea batatas (L.) Lam) alleviates lipopolysaccharide-induced acute lung injury in mice via the VIP/cAMP/PKA/AQPs signaling pathway

BackgroundThe polysaccharide (PSP) from purple sweet potato has great potential for regulating apoptosis, but its regulatory role in acute lung injury (ALI) is unknown. MethodsThe objective of this study was to investigate the protective effect of PSP on lipopolysaccharide (LPS)-induced ALI in mice and lung epithelial A549 cells and its mechanism. Moreover, subacute toxicity evaluation of PSP was carried out on ICR mice. ResultsThe results showed that compared with the ALI group, PSP significantly reduced the total protein content, wet-to-dry (W/D) ratio, the number of neutrophils, lymphocytes, and monocytes. Moreover, PSP was able to reduce cell apoptosis, the levels of macrophage inflammatory protein-2 (MIP-2), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and myeloperoxidase (MPO) and increase the level of superoxide (SOD). In addition, PSP could up-regulate the levels of VIP, cAMP, p-PKA/PKA and AQP1 in mice and A549 cells. And PSP exhibited no apparent adverse effects on the mice. ConclusionsPSP had a protective effect on LPS-induced ALI in mice and lung epithelial A549 cells, which may be related to the inflammatory response and via VIP/cAMP/PKA/AQPs signaling pathway. Thus, PSP may be a promising pharmacologic agent for ALI therapy.

Frequency and impact of post-traumatic stress disorder and traumatic life events in patients with migraine

IntroductionPost-traumatic stress disorder (PTSD) has been proposed as a risk factor for chronification of migraine. The aim of this study was to investigate the frequency of PTSD and traumatic life events (TE) in patients with episodic (EM) and chronic migraine (CM) and their impact on clinical parameters, other comorbidities, and migraine biomarkers. Material and methodsPatients with EM and CM according to the International Classification of Headache Disorders (third edition; beta version) were recruited at a headache unit and a primary care centre. We used questionnaires validated for research on PTSD, TEs, cranial autonomic symptoms, comorbidities (depression, anxiety, and fatigue), disability, migraine impact, and quality of life. Baseline serum levels of CGRP, VIP, and PACAP were determined by ELISA. ResultsThe study included 116 patients: 35 with EM and 81 with CM. Nineteen presented refractory migraine. PTSD was detected in 23 patients (19.8%): 20 with CM and 3 with EM (chi-square: P = .046; Fisher T: P = .073). No significant differences were identified between the EM and CM groups for frequency of any TE nor the number of TEs per patient. A total of 5/19 patients with refractory migraine had experienced sexual violence (vs 2/97 with non-refractory migraine; P = .002). PTSD was associated with more autonomic symptoms; higher scores on anxiety, depression, and fatigue scales; and poorer quality of life; it did not change neuropeptide levels. ConclusionsOur results suggest that PTSD is frequent in patients with migraine, and especially CM, in our setting; history of sexual violence is particularly frequent in patients with refractory migraine. PTSD has a negative impact on migraine, with higher numbers of comorbidities and poorer quality of life; therefore, further research is needed in this patient group.

External damp environment aggravates diarrhea in spleen deficiency and dampness syndrome in mice: involvement of small intestinal contents microbiota, energy metabolism, gastrointestinal and fluid functions.

Recent studies have increasingly demonstrated that a multiplatform water environment combined with lard gavage is an effective method for establishing a mouse model of diarrhea. However, the interactions between intestinal microorganisms and diarrhea, as well as the relationships among energy metabolism, fluid balance, and gastrointestinal function in this model, remain poorly understood. Building on previous research, this study aimed to optimiz and replicate a multiplatform water environment combined with a lard gavage model. Male Kunming mice, free of specific pathogens, were randomly divided into four groups: a normal control group (ZC), a standing group (ZL), a standing combined with lard group (ZLZ), and a standing combined with internal and external wet conditions group (ZLZS). The mice in the ZL, ZLZ, and ZLZS groups were subjected to 4 hours of daily standing in a custom-designed multiplatform water environment. Starting on day 8, mice in the ZLZ and ZLZS groups were gavaged with lard (0.4 mL per session, twice daily) for 7 consecutive days, while those in the ZLZS group were additionally exposed to a wet litter environment (50 g/100 mL). The ZC and ZL groups received equal volumes of sterile water via gavage. The microbiota in the small intestine, as well as serum levels of cAMP, cGMP, VIP, Gas, and D-xylose, were analyzed. Compared with the ZLZ group, the ZLZS group showed significantly lower serum levels of cAMP/cGMP (p<0.01) and Gas (p<0.01). D-xylose levels were lower in the ZL, ZLZ, and ZLZS groups compared to the ZC group, while VIP levels were significantly higher in the ZL and ZLZS groups (p<0.01). Moverover, Corynebacterium, Empedobacter, and Pseudochrobactrum were identified as characteristic bacterial genera in the ZLZS group. The mechanism by which the small intestinal microbiota induces diarrhea was linked to the biosynthesis of secondary bile acids. A multiplatform water environment combined with lard gavage can effectively induce diarrhea, and the addition of an external wet environment exacerbates this condition by affecting small intestinal contents microbiota and other functions.

Intranasal administration of recombinant human BDNF as a potential therapy for some primary headaches

BackgroundIn addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors.MethodsIn a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague–Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration.ResultsBoth doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP.ConclusionsThe findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine.

Odor Fingerprinting of Chitosan and Source Identification of Commercial Chitosan: HS-GC-IMS, Multivariate Statistical Analysis, and Tracing Path Study.

Chitosan samples were prepared from the shells of marine animals (crab and shrimp) and the cell walls of fungi (agaricus bisporus and aspergillus niger). Fourier-transform infrared spectroscopy (FT-IR) was used to detect their molecular structures, while headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) was employed to analyze their odor composition. A total of 220 volatile organic compounds (VOCs), including esters, ketones, aldehydes, etc., were identified as the odor fingerprinting components of chitosan for the first time. A principal component analysis (PCA) revealed that chitosan could be effectively identified and classified based on its characteristic VOCs. The sum of the first three principal components explained 87% of the total variance in original information. An orthogonal partial least squares discrimination analysis (OPLS-DA) model was established for tracing and source identification purposes, demonstrating excellent performance with fitting indices R2X = 0.866, R2Y = 0.996, Q2 = 0.989 for independent variable fitting and model prediction accuracy, respectively. By utilizing OPLS-DA modeling along with a heatmap-based tracing path study, it was found that 29 VOCs significantly contributed to marine chitosan at a significance level of VIP > 1.00 (p < 0.05), whereas another set of 20 VOCs specifically associated with fungi chitosan exhibited notable contributions to its odor profile. These findings present a novel method for identifying commercial chitosan sources, which can be applied to ensure biological safety in practical applications.

Clinical effect of acupuncture for gastroesophageal reflux disease based on the "heart-stomach connection" theory and its effects on serum gastrointestinal hormones

To observe the effect of acupuncture on gastroesophageal reflux disease (GERD) based on the "heart-stomach connection" theory, and to explore its possible mechanisms. Seventy patients with GERD were randomly divided into an acupuncture group (35 cases, 2 cases dropped out) and a medication group (35 cases, 1 case dropped out). The patients in the acupuncture group received acupuncture at bilateral Shenmen (HT 7), Neiguan (PC 6), Burong (ST 19), Tianshu (ST 25), Zusanli (ST 36), Gongsun (SP 4), and Zhongwan (CV 12), with needles retained for 30 min, every other day, three times a week. The patients in the medication group were treated with oral omeprazole capsules, once daily, 20 mg each time. Both groups were treated for 8 weeks. Before and after treatment, the GERD questionnaire (GERDQ), GERD-quality of life scale (GERD-QOL), Hamilton depression scale-24 (HAMD-24), Zung self-rating depression scale (SDS), and Zung self-rating anxiety scale (SAS) scores were observed. Serum levels of gastrointestinal hormones (gastrin [GAS], motilin [MTL], and vasoactive intestinal peptide [VIP]) were measured, and the clinical efficacy of both groups was evaluated. Correlation between pre-treatment GERDQ score and GERD-QOL score, HAMD-24 score, SDS score, and SAS score was analyzed. After treatment, the scores of GERDQ, HAMD-24, SDS, and SAS were decreased (P<0.001) and the scores of GERD-QOL were increased (P<0.001), serum levels of GAS and MTL were increased (P<0.001) in both groups, while the serum level of VIP in the acupuncture group was decreased (P<0.001) compared with those before treatment. The acupuncture group had higher GERD-QOL score and lower SAS score than the medication group (P<0.05), with lower serum VIP level (P<0.05). The total effective rate was 75.8% (25/33) in the acupuncture group, and 76.5% (26/34) in the medication group, with no significant difference between the two groups (P>0.05). GERDQ score was negatively correlated with GERD-QOL scores (r =-0.762, P<0.01) and positively correlated with HAMD-24 score, SDS score, and SAS score (r =0.709, 0.649, 0.689, P<0.01) before treatment. Based on the "heart-stomach connection" theory, acupuncture could effectively improve clinical symptoms, quality of life, and negative emotions in patients with GERD. Its mechanism may be related to the regulation of gastrointestinal hormone levels, thereby promoting the contraction of the lower esophageal sphincter.

The preparation of synbiotic AHY relieving loperamide-induced constipation and its modulation mechanism in vivo

Constipation is a common intestinal disorder linked to an imbalance in the gut microbiota, which can be alleviated by synbiotics as a blend of probiotics and prebiotics. In this study, three strains of Lactiplantibacillus plantarum AHQ-14, HM22 and Y12, which have shown to have constipation-relieving ability, and four prebiotics including stachyose, galactooligosaccharides, isomaltooligosaccharide and fructooligosaccharides, were selected to design a synbiotic named AHY. Its intervention in vivo experiment using loperamide-induced constipated mice was performed. Relevant biochemical indexes, histological morphology, metabolites, constipation-related gene expression and intestinal flora of loperamide-induced constipated mice were investigated to elucidate the potential mechanism for AHY relieving constipation. The results showed that AHY increased the abundance of the flora associated to short-chain fatty acids (SCFAs) and water pathway protein, such as Muribaculaceae and Prevotellaceae, thereby the content of propionic acid and isovaleric acid were increased by 56.8% and 20%, respectively, and the expression of water pathway protein genes was significantly down-regulated. It was also found that AHY significantly increased the serum levels of excitatory gastrointestinal regulatory peptides GAS and MTL, and decreased the levels of inhibitory gastrointestinal regulatory peptide VIP and oxidative stress indicators MDA and NO in constipated mice. Furthermore, it significantly increased the fecal water content and gastrointestinal motility, and restored the colonic damage, thus alleviating the symptoms of constipation. These findings suggest AHY has the potential used as a promising functional synbiotic for constipation relief.

Mismatch novelty exploration training shifts VPAC1 receptor-mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats.

Novelty influences hippocampal-dependent memory through metaplasticity. Mismatch novelty detection activates the human hippocampal CA1 area and enhances rat hippocampal-dependent learning and exploration. Remarkably, mismatch novelty training (NT) also enhances rodent hippocampal synaptic plasticity while inhibition of VIP interneurons promotes rodent exploration. Since VIP, acting on VPAC1 receptors (Rs), restrains hippocampal LTP and depotentiation by modulating disinhibition, we now investigated the impact of NT on VPAC1 modulation of hippocampal synaptic plasticity in male Wistar rats. NT enhanced both CA1 hippocampal LTP and depotentiation unlike exploring an empty holeboard (HT) or a fixed configuration of objects (FT). Blocking VIP VPAC1Rs with PG 97269 (100 nM) enhanced both LTP and depotentiation in naïve animals, but this effect was less effective in NT rats. Altered endogenous VIP modulation of LTP was absent in animals exposed to the empty environment (HT). HT and FT animals showed mildly enhanced synaptic VPAC1R levels, but neither VIP nor VPAC1R levels were altered in NT animals. Conversely, NT enhanced the GluA1/GluA2 AMPAR ratio and gephyrin synaptic content but not PSD-95 excitatory synaptic marker. In conclusion, NT influences hippocampal synaptic plasticity by reshaping brain circuits modulating disinhibition and its control by VIP-expressing hippocampal interneurons while upregulation of VIP VPAC1Rs is associated with the maintenance of VIP control of LTP in FT and HT animals. This suggests VIP receptor ligands may be relevant to co-adjuvate cognitive recovery therapies in aging or epilepsy, where LTP/LTD imbalance occurs.

The effect of luxury brand erotic capital on luxury brand consumption value and purchase intention - focus on VIP customers

ABSTRACT In today’s society, individuals invest considerable effort into enhancing their physical appearance for socioeconomic success. Despite significantly expanding the boundaries of luxury brands, there has been limited academic exploration into the analysis of luxury brand value from an erotic capital perspective. This study explores the effect of erotic capital on the consumption value and purchase intention of luxury brands. We surveyed 148 VIP customers of major luxury brands and ascertained key elements of erotic capital, notably finding that factors such as pleasure, beauty, and arousal positively influence consumer behavior. Additionally, we confirmed the moderating effects of age and VIP level. Our findings suggest that luxury brands should incorporate the concept of erotic capital into their designs and marketing strategies while maintaining their brand identity to effectively navigate rapidly changing market environments and expand their customer base.

Comparing massa medicata fermentata before and after charred in terms of digestive promoting effect via metabolomics and microbiome analysis

Ethnopharmacological relevanceMassa Medicata Fermentata, a fermented Chinese medicine, is produced by the fermentation of six traditional Chinese medicines. Liu Shenqu (LSQ) and charred Liu Shenqu (CLSQ) have been used for strengthening the spleen and enhancing digestion for over a thousand years, and CLSQ is commonly used in clinical practice. However, it is unclear whether there is a difference in the spleen strengthening and digestion effects between LSQ and CLSQ, as well as their mechanisms of action. Aim of studyThis study aims to compare the effects of LSQ and CLSQ on the digestive function of functional dyspepsia (FD) rats and reveal their mechanisms of action. Materials and methodsSPF grade SD rats were randomly divided into 6 groups: control group, model group, Liu Shenqu decoction low-dosage (LSQ LD) group, Liu Shenqu decoction high-dosage (LSQ HD) group, charred Liu Shenqu decoction low-dosage (CLSQ LD) group, and charred Liu Shenqu decoction high-dosage (CLSQ HD) group. Rats were injected intraperitoneally with reserpine to create an FD model and then treated by intragastric administration. During this period, record the weight and food intake of the animals. After 18 days of treatment, specimens of the gastric antrum, spleen, and duodenum of rats were taken for pathological staining and immunohistochemical detection of Ghrelin protein expression. Enzyme linked immunosorbent assay (ELISA) was used to determine the concentration of relevant gastrointestinal hormones in serum. The 16 S rDNA sequencing method was used to evaluate the effect of cecal contents on the structure of the gut microbiota in experimental rats. Plasma metabolomics analysis was performed using ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-QTOF-MS) to further reveal their mechanism of action. ResultsLSQ and CLSQ improved the pathological tissue histological structure of FD rats and increased the levels of MTL and GAS hormones in serum and the levels of ghrelin in the gastric antrum, spleen, and duodenum, while reducing VIP, CCK, and SP hormone levels. The above results showed that the therapeutic efficacy of CLSQ is better than that of LSQ. Futhermore, the mechanism of action of LSQ and CLSQ were revealed. The 16 S rDNA sequencing results showed that both LSQ and CLSQ can improve the composition and diversity of the gut microbiota. And metabolomic analysis demonstrated that 20 metabolites changed after LSQ treatment, and 16 metabolites underwent continuous changes after CLSQ treatment. Further analysis revealed that LSQ mainly intervened in the metabolic pathways of glycerol phospholipid metabolism and arginine and proline metabolism, but CLSQ mainly intervened in the metabolic pathways of ether lipid metabolism, sphingolipid metabolism, and glycerophospholipid metabolism. ConclusionsBoth LSQ and CLSQ can improve functional dyspepsia in FD rats, but CLSQ has a stronger improvement effect on FD. Although their mechanisms of action are all related to regulating gastrointestinal hormone secretion, significantly improving intestinal microbiota disorders, and improving multiple metabolic pathways, but the specific gut microbiota and metabolic pathways they regulate are different.

Insights into Q-markers of honey-fried licorice in treating spleen deficiency based on substance and energy metabolism regulation

BackgroundHoney-fried Licorice (HFL) is a dosage form of Glycyrrhizae Radix et Rhizome processed with honey, which has been recorded to exhibit better efficacy in tonifying the spleen compared to the raw product. In contrast, different processing methods of Glycyrrhizae Radix et Rhizome exhibit different efficacies and applications, but their current quality control index components remain consistent. PurposeBased on the discovery and research strategy of traditional Chinese medicine decoction piece quality marker (Q-marker), this study aimed to conduct a multidimensional integration of constituents absorbed into the body and metabolomics based on the tonifying spleen and stomach effects of HFL to effectively identify the Q-marker of HFL. MethodsIn this study, a spleen deficiency rat model was established using the "exhausted swimming + poor diet" method to investigate the pharmacodynamics of tonifying the spleen and stomach by HFL. The constituents absorbed into blood was conducted using UPLC-Q-TOF/MS, correlation analysis between metabolomics and constituents absorbed into blood recognized the Q-Marker of HFL. ResultsThe pharmacodynamic data demonstrated that HFL exhibited a significant regulatory effect on the disordered levels of PP, trypsin, chymase, PL, α-Glu, MTL, GAS, VIP, IL-2, IFN-γ, and IgA in the spleen deficiency model. Furthermore, HFL was found to improve the pathological changes in the spleen and intestine in the spleen deficiency model, highlighting its significant "tonifying spleen and stomach" effect. In the serum containing HFL, a total of 17 constituents were identified as being absorbed into the blood. Among these, 11 were prototypical components, while 6 were metabolites. Metabolomics data revealed that 9 differentially expressed metabolic markers were observed. Furthermore, the analysis of endogenous metabolic markers indicated that 10 components exhibited significant correlations with these biomarkers. ConclusionThe effect of "tonifying spleen and stomach" of HFL is closely related to the regulation of the material and energy metabolism pathway. The Q-Marker of HFL is glycyrrhizic acid and 18β-glycyrrhetinic acid as the main control standards and liquiritin, isoliquiritin, liquiritin, isoliquiritin, isolicorice flavonol, licorice chalcone C and Formononetin were used as auxiliary standards.

Vasoactive Intestinal Peptide Receptor, CRTH2, Antagonist Treatment Improves Eosinophil and Mast Cell-Mediated Esophageal Remodeling and Motility Dysfunction in Eosinophilic Esophagitis.

Ultrasonography has shown that eosinophils accumulate in each segment of the esophageal mucosa in human EoE, ultimately promoting esophageal motility dysfunction; however, no mechanistic evidence explains how or why this accumulation occurs. Quantitative PCR, ELISA, flow cytometry, immunostaining, and immunofluorescence analyses were performed using antibodies specific to the related antigens and receptors. In deep esophageal biopsies of EoE patients, eosinophils and mast cells accumulate adjacent to nerve cell-derived VIP in each esophageal segment. qRT-PCR analysis revealed five- to sixfold increases in expression levels of VIP, CRTH2, and VAPC2 receptors and proteins in human blood- and tissue-accumulated eosinophils and mast cells. We also observed a significant correlation between mRNA CRTH2 levels and eosinophil- and nerve cell-derived VIPs in human EoE (p < 0.05). We provide evidence that eosinophil and mast cell deficiency following CRTH2 antagonist treatment improves motility dysfunction in a chronic DOX-inducible CC10-IL-13 murine model of experimental EoE. CRTH2 antagonist treatment is a novel therapeutic strategy for inflammatory cell-induced esophageal motility dysfunction in IL-13-induced chronic experimental EoE.

Bifidobacterium longum S3 alleviates loperamide-induced constipation by modulating intestinal acetic acid and stearic acid levels in mice.

Constipation is a major gastrointestinal (GI) symptom worldwide, with diverse causes of formation, and requires effective and safe therapeutic measures. In the present study, we used loperamide hydrochloride to establish a constipation model and assessed the effect of Bifidobacterium on constipation and its possible mechanism of relief. The results showed that B. longum S3 exerted a constipation-relieving effect primarily by improving the gut microbiota, enriching genera including Lactobacillus, Alistipes, and Ruminococcaceae UCG-007, and decreasing the bacteria Lachnospiraceae NK4B4 group. These changes may thereby increase acetic acid and stearic acid (C18:0) levels, which significantly increase the expression levels of ZO-1 and MUC-2, repair intestinal barrier damage and reduce inflammation (IL-6). Furthermore, it also inhibited oxidative stress levels (SOD and CAT), decreased the expression of water channel proteins (AQP4 and AQP8), significantly elevated the Gas, 5-HT, PGE2, and Ach levels, and reduced nNOS and VIP levels to improve the intestinal luminal transit time and fecal water content. Collectively, these changes resulted in the alleviation of constipation.

Broccoli-Derived Exosome-like Nanoparticles Alleviate Loperamide-Induced Constipation, in Correlation with Regulation on Gut Microbiota and Tryptophan Metabolism.

Constipation, a common gastrointestinal dysfunction, damages patients' life quality and predisposes them to other serious diseases. Current strategies against constipation often cause drug dependency and side effects. Here, we demonstrated that broccoli-derived exosome-like nanoparticles (BENs), a natural product with high gastrointestinal stability, ameliorated LOP-induced constipation in mice. Specifically, orally administered BENs (17.5 mg/kg/d) effectively shortened defecation time, sped up intestinal propulsion rate, and increased feces amount in constipated mice. BENs also raised excitatory neurotransmitters SP and MTL and reduced inhibitory neurotransmitters VIP and ET-1. Mechanistically, BENs were taken up by gut microbes, restored LOP-disordered gut microbiota, and altered microbial metabolism of SCFAs and tryptophan, as evidenced by the results of fluorescence microscopy, 16S rRNA gene sequencing, and nontargeted metabolomics. Thereinto, BEN-enriched SCFA-producing microorganisms are closely associated with the feces amount and SP and VIP levels and BEN-elevated indole-3-pyruvic acid and 3-indoleacetic acid are highly linked to ET-1, SP, and MTL levels. Conclusively, BENs, mitigating constipation by regulating gut microbiota and microbial tryptophan metabolism, showed high potential to be developed as alternative regimens for constipation.

Mitochondrial metabolism related markers GDF-15, FGF-21, and HIF-1α are elevated in pediatric migraine attacks.

The purpose of this study was to investigate the serum levels of mitochondrial metabolism/reactive oxygen species (ROS)-related peptides (hypoxia inducible factor-1α [HIF-1α], fibroblast growth factor-21 [FGF-21], growth differentiation factor-15 [GDF-15]) and key migraine-related neuropeptides (calcitonin gene-related peptide [CGRP], pituitary adenylate cyclase-activating peptide-38 [PACAP-38], substance P [SP], and vasoactive intestinal peptide [VIP]) during migraine attacks and to evaluate their diagnostic value in pediatric migraine. There is increasing evidence for the important role of impairment in oxidative mitochondrial metabolism in the pathophysiology of migraine. Potential biomarkers that may reflect the relationship between migraine and mitochondrial dysfunction are unclear. A total of 68 female pediatric migraine patients without aura and 20 female healthy controls aged 8-18 years, admitted to the hospital, were enrolled in this cross-sectional study. Serum concentrations of these molecules were determined by enzyme-linked immunosorbent assays, and clinical features and their possible diagnostic value were analyzed. Serum levels of HIF-1α (252.4 ± 51.9 [mean ± standard deviation]) pg/mL), GDF-15 (233.7 ± 24.7 pg/mL), FGF-21 (96.1 ± 13.1 pg/mL), CGRP (44.5 ± 11.3), and PACAP-38 (504.7 ± 128.9) were significantly higher in migraine patients compared to healthy controls (199.8 ± 26.8, 192.8 ± 20.7, 79.3 ± 4.1, 34.1 ± 3.5 and 361.2 ± 86.3 pg/mL, respectively). The serum levels of these peptides were also higher in patients with chronic migraine than in patients with episodic migraine, and higher in the ictal period than in the interictal period. A positive correlation was found between attack frequency and both HIF-1α and FGF-21 levels in migraine patients. Serum levels of VIP and SP were not different between the migraine patients and healthy controls. Migraine attacks are accompanied by elevated HIF-1α, FGF-21, GDF-15, CGRP, and PACAP-38 in medication-naive pediatric patients with migraine. Elevated circulating mitochondrial metabolism/ROS-related peptides suggest a mitochondrial stress in pediatric migraine attacks and may have potential diagnostic value in monitoring disease progression and treatment response in children. Novel approaches intervening with mitochondrial metabolism need to be investigated.

Effective substances and mechanism of red ginseng on rats with spleen-deficiency syndrome based on the substance and energy metabolism as well as the "brain-gut" axis.

Red ginseng (RG), a processed product of ginseng (GS), is a generally used qi-tonifying medicine in Traditional Chinese Medicine (TCM). According to the TCM principle, RG is also generally applied to spleen-deficiency syndrome (SDS) clinically for its warmer property. However, the effective substances and mechanism of RG on SDS have not been well investigated. The aim of this study was to explore the effective substances and their mechanism of RG on SDS. The SDS model was established with a compound factor method involving an irregular diet, excessive fatigue and sennae folium with a bitter-cold property. The medicine of RG was split by multi-mode separation methods and analyzed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). The appearance indexes such as body weight, body temperature, swimming endurance, urine output, and water content of fecal were determined. The biochemical indexes such as D-xylose, SP, VIP and AChE in the digestive system, CRH, ACTH, CORT, E, T3, T4, T, E2 and 5-HT in the endocrine system, CS, NCR, IDH1, COX and Na+-K+-ATPase in the metabolism of substance and energy, cAMP and cGMP in the cyclic nucleotide system were analyzed by Enzyme-linked immunosorbent assay (ELISA) kits and biochemical kits. The serum metabolites were analyzed by UPLC-QTOF/MS. Furthermore, the gut microbiota and short-chain fatty acids (SCFAs) in feces were analyzed by 16S rRNA sequencing and headspace gas chromatography-mass method. The pharmacological experiments showed that total saponin fraction (RGTSF), less polar fraction (RGLPF), and polysaccharides faction (RGPSF) significantly modulated the "brain-gut" axis-related indexes (the levels of VIP, AChE, and 5-HT). Besides, RGTSF also significantly modulated the hypothalamic-pituitary-adrenal (HPA) axis-related indexes as well as the substance and energy metabolism-related indexes (the levels of ACTH, CORT, A, Na+-K+-ATPase, COX, NCR and CS). RGPSF also significantly modulated the hypothalamus-pituitary-thyroid (HPT) axis-related indexes (the levels of T3 and T4). Secondly, metabolomics indicated that RGTSF could significantly regulate the abnormal metabolic pathways associated with the development of SDS, which involved steroid hormone biosynthesis, taurine and hypotaurine metabolism, primary bile acid biosynthesis, and amino acid metabolism. Subsequently, the study of gut microbiota indicated that RGLPF could increase the diversities of the gut microbiota and the relative abundance of Firmicutes in rats with SDS, while RGWEF significantly increased the relative abundance of Bacteroidetes. At the genus level, RGLPF could increase the relative abundance of Lactobacillus in rats with SDS and decrease that of Akkermansia. Meanwhile, the water-eluted fraction (RGWEF) showed a stronger regulation in SCFAs. It is for the first time that the effective substances of red ginseng on spleen-deficiency syndrome were studied systematically, and the different mechanisms of the RG fractions involved in substance and energy metabolism as well as the "brain-gut" axis were revealed. The present study demonstrated that RGTSF, RGPSF, and RGLPF were the effective substances of red ginseng for ameliorating spleen-deficiency syndrome, indicating that ginsenosides composed of primary and secondary saponins as well as polysaccharides were the main effective substances for red ginseng in ameliorating spleen-deficiency syndrome.

Evaluation of the effectiveness and mechanism of action of the Chang-Kang-Fang formula combined with bifid triple viable capsules on diarrhea-predominant irritable bowel syndrome.

The Chang-Kang-Fang (CKF) formula, a traditional Chinese herbal formula, can decrease serotonin (5-HT) levels and treat irritable bowel syndrome (IBS). Probiotics have a better synergistic effect on diarrhea-predominant IBS (IBS-D) when combined with 5-HT3 receptor antagonists. The present study aimed to elucidate the efficacy and the mechanisms of action of the CKF formula combined with bifid triple viable capsules (PFK) against IBS-D. The rat models of IBS-D were induced by gavage with senna decoction plus restraint stress. The CKF formula, PFK and their combination were administered to the rats. Their effects were evaluated based on general condition of the rats and the AWR score. The levels of 5-HT and fos protein in the colon and hippocampus were measured by immunohistochemistry. The levels of SP and VIP, as well as ZO-1 and occludin in the colon, were determined by enzyme-linked immunosorbent assay and immunohistochemistry. The intestinal microbiota in faeces was analyzed by 16S rRNA high-throughput sequencing. The results showed that the oral CKF formula combined with PFK (CKF + PFK) could significantly relieve the symptoms of IBS-D, including elevating the weight rate and decreasing the AWR score. Compared with the MC group, administration of CKF + PFK significantly reduced the expression of fos in the colon and hippocampus and that of 5-HT, SP and VIP in the colon and increased the levels of 5-HT in the hippocampus and ZO-1 and occludin in the colon. The above indexes exhibited statistical significance in the CKF + PFK group relative to those in the other groups. Moreover, treatment with CKF + PFK improved the diversity of intestinal microbiota and the abundance of Firmicutes, Lachnospiraceae and Ruminococcaceae but decreased those of Bacteroidetes and Prevotellaceae. The CKF formula combined with PFK may have a synergistic effect on IBS-D by slowing gastrointestinal motility, lowering visceral hypersensitivity, enhancing the intestinal barrier function and modulating the composition of intestinal microbiota.

Postprandial effect of gastrointestinal hormones and gastric activity in patients with irritable bowel syndrome

Altered gut regulation, including motor and secretory mechanisms, is characteristic of irritable bowel syndrome (IBS). The severity of postprandial symptoms in IBS patients is associated with discomfort and pain; gas-related symptoms such as bloating and abdominal distension; and abnormal colonic motility. The aim of this study was to assess the postprandial response, i.e., gut peptide secretion and gastric myoelectric activity, in patients with constipation-predominant IBS. The study was conducted on 42 IBS patients (14 males, 28 females, mean age 45.1 ± 15.3 years) and 42 healthy participants (16 males, 26 females, mean age 41.1 ± 8.7 years). The study assessed plasma gut peptide levels (gastrin, CCK—Cholecystokinin, VIP—Vasoactive Intestinal Peptide, ghrelin, insulin) and gastric myoelectric activity obtained from electrogastrography (EGG) in the preprandial and postprandial period (meal–oral nutritional supplement 300 kcal/300 ml). Mean preprandial gastrin and insulin levels were significantly elevated in IBS patients compared to the control group (gastrin: 72.27 ± 26.89 vs. 12.27 ± 4.91 pg/ml; p < 0.00001 and insulin: 15.31 ± 12.92 vs. 8.04 ± 3.21 IU/ml; p = 0.0001), while VIP and ghrelin levels were decreased in IBS patients (VIP: 6.69 ± 4.68 vs. 27.26 ± 21.51 ng/ml; p = 0.0001 and ghrelin: 176.01 ± 88.47 vs. 250.24 ± 84.55 pg/ml; p < 0.0001). A nonsignificant change in the CCK level was observed. IBS patients showed significant changes in postprandial hormone levels compared to the preprandial state—specifically, there were increases in gastrin (p = 0.000), CCK (p < 0.0001), VIP (p < 0.0001), ghrelin (p = 0.000) and insulin (p < 0.0001). Patients with IBS showed reduced preprandial and postprandial normogastria (59.8 ± 22.0 vs. 66.3 ± 20.2%) compared to control values (83.19 ± 16.7%; p < 0.0001 vs. 86.1 ± 9.4%; p < 0.0001). In response to the meal, we did not observe an increase in the percentage of normogastria or the average percentage slow-wave coupling (APSWC) in IBS patients. The postprandial to preprandial power ratio (PR) indicates alterations in gastric contractions; in controls, PR = 2.7, whereas in IBS patients, PR = 1.7, which was significantly lower (p = 0.00009). This ratio reflects a decrease in gastric contractility. Disturbances in the postprandial concentration of gut peptides (gastrin, insulin and ghrelin) in plasma may contribute to abnormal gastric function and consequently intestinal motility, which are manifested in the intensification of clinical symptoms, such as visceral hypersensitivity or irregular bowel movements in IBS patients.