Search Results (24)

Gut microbiota regulate the intestinal expression of drug-metabolizing enzymes, transporters, and barrier properties that determine oral drug absorption and disposition. This study compares germ-free Swiss Webster mice to mice colonized with fecal microbiota from a single human donor, evaluating microbiota-driven differences in colonic gene expression and P-gp protein expression, as well as small intestinal mucosal permeability. Transcriptomic analysis of colonic tissue revealed microbiota-induced upregulation of genes encoding P-gp and other drug transporters, including MCT1 and OCTN2. Immunofluorescence also indicated greater P-gp expression and apical localization in colonized mice. Gene expression of drug-metabolizing enzymes was also higher in colonized mice, including phase I enzymes (carboxylesterase 2 paralogs), phase II enzymes (UDP-glucuronosyltransferases and glutathione S-transferases), and enzymes responsible for synthesizing their co-substrates, UDP-glucuronic acid and glutathione. Small intestinal mucosal explants demonstrated lower permeability to ¹⁴C-labeled polyethylene glycol 4000 in colonized mice compared to germ-free mice. In the colon, transcriptomic analysis identified microbiota-dependent changes in genes regulating paracellular tight junctions and actomyosin contractility. These results show that human-derived gut microbiota alter gene expression in the mouse colon, identifying candidate microbiota-responsive genes relevant to oral drug absorption and disposition. Full article

Background and Aims: Postoperative ileus (POI) is a motility dysfunction associated with inflammation in the gastrointestinal (GI) tract after abdominal surgery. Management relies on supportive care, as there is no effective medical treatment. Clinical trials found that coffee consumption improves bowel movement and shortens hospital stays in POI. We aimed to investigate the mechanisms underlying the beneficial effect of coffee in an animal model of POI. Methods: Mouse POI was established by manipulation of the small intestine with wet swab applicators for 5 min. Mice were then treated with water, regular or decaffeinated coffee (10 mg per day) by oral gavage and euthanized 24 h after the operation. Key Results: Intestinal manipulation slowed GI transit rate from 5.64 ± 0.47 to 3.77 ± 0.16 (N = 6, measured by geometric center), reduced intestinal muscle contractility, and induced an acute inflammatory response with increased expression of proinflammatory mediators such as IL-6, IL-1, CCL2, and CXCL-1 in the POI intestine. Coffee treatment (regular or decaffeinated) did not reduce inflammation or the expression of inflammatory mediators but significantly improved muscle contractility and increased GI transit to 4.59 ± 0.31 (N = 5) and 4.80 ± 0.29 (N = 5) in POI mice (regular and decaffeinated coffee, respectively). Regular or decaffeinated coffee dose-dependently (0.1–10 mg/mL) increased contractility of intestinal muscle strips. The contractile effect was not affected by neural toxin tetrodotoxin (10⁻⁶ M) or cholinergic nicotinic antagonist hexamethonium (10⁻⁴ M) but was completely abolished by muscarinic receptor antagonist atropine (10⁻⁶ M). Conclusions: Coffee consumption does not attenuate inflammatory response but improves GI motor function and stimulates intestinal smooth muscle contractions in the mouse model of POI. Coffee stimulates contractions in a caffeine-independent manner through a cholinergic muscarinic receptor-dependent mechanism. Full article

Salvia guaranitica A.St.-Hil. Ex Benth. (Lamiaceae) is native from South America, traditionally used for releasing tension and treating gastrointestinal cramps. It was evaluated for the presence of flavonoids and isoflavones in the extract, and the hypothesis of being cardioprotective under ischemia and reperfusion (I/R), antidiarrheal, antispasmodic and anxyolitic in respective models. For phytochemistry, GC-MS and HPLC-DAD methodologies were used. Cardiac performance after subchronic oral administration of S. guaranitica tincture (S.g-T, 0.95 mg extract/mL) was evaluated in rat isolated perfused hearts exposed to I/R, and mechanisms were characterized. Antispasmodic effects of S.g-T were evaluated on contractile concentration–response curves (CRCs) of carbachol (CCh) and calcium (Ca²⁺) in rat isolated intestinal tissue. In vivo tests of ricin-oil diarrhea models, open-field (OFT), novel-suppressed feeding (NFT) and tail suspension (TST) tests were performed on mice. Phenolic acids, genistin, luteolin, kaempferol and quercetin glycosides, genins, loliolide, dodecane, farnesene, phytol and isochiapin B were identified. Post-ischemic cardiac recovery was improved by S.g.-T, associated to activation of phosphatidylinositol-3-kinase and β-estrogenic receptor. S.g.-T also induced antispasmodic effects, as a non-competitive inhibitor of the CCh-CRC and Ca²⁺-CRC in the intestine. In vivo, S.g.-T showed antidiarrheal activity (95 mg extract/kg) and anxiolytic-like effects (0.95–9.5 mg extract/kg) without sedation or antidepressant-like effects. Therefore, S. guaranitica leaves have potential therapeutic cardioprotective, antidiarrheal, antispasmodic and anxiolytic effects. Full article

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted in response to food intake that acts biologically by binding to GLP-1 receptors. The primary function of GLP-1 is to stimulate insulin secretion and inhibit glucagon secretion, which helps limit after-meal spikes in blood glucose. GLP-1 reduces intestinal contractility, slows down gastrointestinal motility and emptying, and also acts directly on the hypothalamus, thereby regulating appetite and food intake. Due to its metabolic effects, GLP-1 forms the basis of medications currently used to treat type 2 diabetes (T2DM) and obesity. However, it has also been observed that the use of GLP-1 agonists in the treatment of obesity or diabetes has a beneficial effect on comorbid respiratory conditions. This narrative review analyzes the scientific literature and describes the most recent information on the impact of GLP-1 receptor agonist (GLP-1 RA) therapies on the most common respiratory disorders—both the beneficial and undesirable effects. We discuss evidence that acute lung injury, COVID-19, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea can benefit from therapies with various GLP-1 RAs. They can complement existing lung-targeted treatments, but as research progresses, they are likely to play an ever more important role in the treatment of respiratory diseases. Full article

Background/Objectives: Inflammatory bowel diseases (IBD) are conditions of the gastrointestinal tract with treatments linked to side effects and relapses. Spondias mombin L. is a species with anti-inflammatory action, but there is little information in the literature about its application in the treatment of IBD. The aim of this study was to evaluate the intestinal anti-inflammatory activity of hydroalcoholic extract of Spondias mombin L. (HESm) in a rat model of ulcerative colitis (UC). Methods: Hydroalcoholic extract was obtained using the turboextraction technique, followed by identification of its major components using ultra-high performance liquid chromatography (UFLC). Intestinal anti-inflammatory activity was evaluated in an acute model of UC induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Groups received a vehicle, prednisolone (2 mg/kg), or HESm (125, 250 or 500 mg/kg) before and after UC induction. Ulcerated area, score, and intestinal weight/length ratio were analyzed. Histopathological analysis and the extract’s effect on the contractility of the intestinal segment were carried out. Results: UFLC identified the presence of quercetin, a flavonoid widely cited for the species. At doses of 125, 250, and 500 mg/kg, the extract reduced areas of injury by 86.82, 92.67, and 85.06%, respectively, compared to the control, in addition to reducing scores and weight/length ratio of the colons. Histopathological analysis confirmed the results. In contractility, the extract at the highest concentration tested reduced the response of the muscarinic agonist carbamylcholine to 53.7 ± 4.2% of control contraction. Conclusions: Results demonstrate the species’ ability to reduce injuries caused by colitis, suggesting its potential to contribute to the clinical management of IBD in the future. Full article

Glucagon-like peptide-2 (GLP-2) has been reported to cause gastrointestinal relaxation by interfering with enteric inhibitory neurotransmitters, including vasoactive intestinal peptide (VIP). However, the involvement of VIP in the GLP-2’s actions on isolated ileal preparations has never been explored. In this study, we investigated whether VIP contributes to the inhibitory effects of GLP-2 on spontaneous and neurally evoked contractions in mouse ileal segments. Functional experiments showed that VIP, as well as GLP-2, depresses both spontaneous and electrically induced contractile responses. The VIP antagonist, VIP 6–28, slightly increased the amplitude of the neurally induced contractile responses. VIP 6–28 did not alter the hormone’s effects on the spontaneous activity, but reduced its inhibitory action on the neurally evoked contractions. In GLP-2-exposed specimens, immunohistochemistry showed a significant decrease in VIP-positivity in nerve fibers located in the muscle layers. These results provide the first evidence that in isolated mouse ileal preparations VIP contributes to the inhibitory effects of GLP-2 on the neurally induced contractile responses. From a physiological point of view, such depressant effects of the hormone may represent a mechanism aimed at slowing intestinal transit and optimizing nutrient absorption. Full article

Postbiotics, as a novel class of functional components, have garnered considerable scholarly and industrial interest due to their distinctive advantages in food processing applications and their positive impact on human health. Although postbiotics have demonstrated potential in alleviating constipation, their specific mechanism of action and bioactive components remain unclear. This study aimed to investigate the ameliorative effects and potential mechanisms of postbiotics derived from Bifidobacterium animalis subsp. lactis BL-99 (BL-99) on FC using both in vivo and in vitro models. The findings revealed that both BL-99 and its postbiotics significantly mitigated FC symptoms, as evidenced by enhanced intestinal motility, and elevated fecal water content. Additionally, treatment with BL-99 postbiotics was associated with an increase in the thickness of the intestinal muscular layer and a reduction in apoptosis of intestinal smooth muscle cells (SMCs). Mechanistically, BL-99 postbiotics were found to enhance the contractile response and promote the proliferation of intestinal SMCs. Furthermore, untargeted metabolomics analysis identified two key bioactive peptides, Glu-Val and Glu-Leu, as the active components in BL-99 responsible for regulating SMC function. Collectively, these findings highlight the potential of BL-99 postbiotics as a promising functional food ingredient for alleviating FC, providing a novel and effective strategy for the developing dietary interventions targeting this condition. Full article

Background/Objectives: Mebeverine hydrochloride (MBH) is an antispasmodic agent used to regulate bowel movements and relax intestinal smooth muscle, but its application is limited by specific side effects; therefore, this study investigates the effects of previously synthesized MBH-loaded silver nanoparticles (AgNPs) on smooth muscle contractile activity and their anti-inflammatory potential as an alternative delivery system. Methods: The interactions of AgNPs with cholinergic inhibitors, selective antagonists, Ca²⁺ blockers, and key neurotransmitters were analyzed. In vitro, albumin denaturation suppression and ex vivo assays evaluated the anti-inflammatory effects of AgNPs-MBH, validated using a DFT in silico approach. To comprehensively assess the systemic impact and IBS treatment potential of AgNPs-MBH, we also examined in vitro their antimicrobial activity and hepatic cell responses, as the liver is a key organ in evaluating the overall safety and efficacy of nanoparticles. Additionally, the drug-release capabilities of Ag NPs were established. Results: Our findings indicate that AgNPs with MBH do not affect blocked cholinergic receptors, but their effects are more pronounced and distinct in amplitude and character than MBH. MBH-loaded AgNPs showed a lower anti-inflammatory effect than MBH but were still better than diclofenac. They also affected hepatic cell morphology and proliferation, suggesting potential for enhanced therapeutic efficacy. Drug-loaded AgNPs are considered not bactericidal. Conclusions: Based on our results, drug-loaded AgNPs might be a promising medication delivery system for MBH and a useful treatment option for IBS. Future in vivo and preclinical experiments will contribute to the establishment of drug-loaded AgNPs in IBS treatment. Full article

Recent discoveries have shown that enteric glial cells play an important role in different neurodegenerative disorders, such as Parkinson’s disease (PD), which is characterized by motor dysfunctions caused by the progressive loss of dopaminergic neurons in the substance nigra pars compacta and non-motor symptoms including gastrointestinal dysfunction. In this study, we investigated the modulatory effects of the flavonoid rutin on the behavior and myenteric plexuses in a PD animal model and the response of enteric glia. Adult male Wistar rats were submitted to stereotaxic injection with 6-hydroxydopamine or saline, and they were untreated or treated with rutin (10 mg/kg) for 14 days. The ileum was collected to analyze tissue reactivity and immunohistochemistry for neurons (HuC/HuD) and enteric glial cells (S100β) in the myenteric plexuses. Behavioral tests demonstrated that treatment with rutin improved the motor capacity of parkinsonian animals and improved intestinal transit without interfering with the cell population; rutin treatment modulated the reactivity of the ileal musculature through muscarinic activation, reducing relaxation through the signaling pathway of nitric oxide donors, and increased the longitudinal contractility of the colon musculature in parkinsonian animals. Rutin revealed modulatory activities on the myenteric plexus, bringing relevant answers regarding the effect of the flavonoid in this system and the potential application of PD adjuvant treatment. Full article

Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3^R451C mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3^R451C mice bred on a mixed genetic background. Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3^R451C mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3^R451C mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3^R451C mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABA_A antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3^R451C p = 0.002), but not the ileum, in both wild-type and Nlgn3^R451C mice. These findings demonstrate that changes in enteric nervous system function contribute to gastrointestinal dysmotility in mice expressing the autism-associated R451C missense mutation in the Neuroligin-3 protein. Full article

Infusions of Valeriana pilosa are commonly used in Peruvian folk medicine for treating gastrointestinal disorders. This study aimed to investigate the spasmolytic and antispasmodic effects of Valeriana pilosa essential oil (VPEO) on rat ileum. The basal tone of ileal sections decreased in response to accumulative concentrations of VPEO. Moreover, ileal sections precontracted with acetylcholine (ACh), potassium chloride (KCl), or barium chloride (BaCl₂) were relaxed in response to VPEO by a mechanism that depended on atropine, hyoscine butylbromide, solifenacin, and verapamil, but not glibenclamide. The results showed that VPEO produced a relaxant effect by inhibiting muscarinic receptors and blocking calcium channels, with no apparent effect on the opening of potassium channels. In addition, molecular docking was employed to evaluate VPEO constituents that could inhibit intestinal contractile activity. The study showed that α-cubebene, β-patchoulene, β-bourbonene, β-caryophyllene, α-guaiene, γ-muurolene, valencene, eremophyllene, and δ-cadinene displayed the highest docking scores on muscarinic acetylcholine receptors and voltage-gated calcium channels, which may antagonize M₂ and/or M₃ muscarinic acetylcholine receptors and block voltage-gated calcium channels. In summary, VPEO has both spasmolytic and antispasmodic effects. It may block muscarinic receptors and calcium channels, thus providing a scientific basis for its traditional use for gastrointestinal disorders. Full article

In terms of the global burden of disease, helminthiasis is the most common infectious disease in the world. In response to the disease, the human host develops an immunological response that occurs predominantly through the action of T helper 2 (Th2) cells and the interleukins IL-4, IL-5 and IL-13. However, other types of Th cells, such as Th9, are also involved in the defense against helminths, with the IL-9 produced by these cells promoting the induction of mastocytosis and the increased production of IgG1 and IgE, in addition to the increase in intestinal contractility that promotes the expulsion of worms. Together, IL-9 and IL-10, which is also produced by Th9, induce a type 2 inflammatory response characterized by the coordinated actions of innate lymphoid cells, mast cells, basophils and other cells that work together toward a single objective: the reduction of the parasitic burden. This review presents the latest findings on Th9 effector mechanisms in helminthic infections. Full article

Irritable Bowel syndrome (IBS) is a highly widespread gastrointestinal disorder whose symptomatology mainly affect the large intestine. Among the risk factors, psychosocial stress is the most acknowledged. The repeated water avoidance stress (rWAS) is considered an animal model of psychosocial stress that is capable of mimicking IBS. Otilonium bromide (OB), which is orally administered, concentrates in the large bowel and controls most of the IBS symptoms in humans. Several reports have shown that OB has multiple mechanisms of action and cellular targets. We investigated whether the application of rWAS to rats induced morphological and functional alterations of the cholinergic neurotransmission in the distal colon and whether OB prevented them. The results demonstrated that rWAS affects cholinergic neurotransmission by causing an increase in acid mucin secretion, in the amplitude of electrically evoked contractile responses, abolished by atropine, and in the number of myenteric neurons expressing choline acetyltransferase. OB counteracted these changes and also showed an intrinsic antimuscarinic effect on the post-synaptic muscular receptors. We assume that the rWAS consequences on the cholinergic system are linked to corticotrophin-releasing factor-1 (CRF1) receptor activation by the CRF hypothalamic hormone. OB, by interfering with the CFR/CRFr activation, interrupted the cascade events responsible for the changes affecting the rWAS rat colon. Full article

In mice, oral Toxoplasma gondii infection induces severe ileitis. The aim of the present study was to investigate the impact of the P2X7 receptor (P2X7) on the inflammatory response to T. gondii-induced ileitis. Cysts of the ME49 strain of T. gondii were used to induce ileitis. The infected mice were euthanized on day 8 and ileal tissue and peripheral blood were collected for histopathological and immunohistochemical analyses. Ileal contractility, inflammatory mediators, inflammasome activation, quantitative PCR analysis of gene expression, and fecal microbiota were assessed using appropriate techniques, respectively. The infected P2X7−/− mice had greater disease severity, parasitic burden, liver damage, and intestinal contractility than the infected wild-type (WT) mice. Infection increased serum IL-6 and IFN-γ and tissue caspase-1 but not NLRP3 in P2X7−/− mice compared to WT mice. Bacteroidaceae, Rikenellaceae, and Rhodospirillales increased while Muribaculaceae and Lactobacillaceae decreased in the infected WT and P2X7−/− mice. Bacteroidia and Tannerellaceae increased in the P2X7−/− mice with ileitis. By contrast, Clostridiales and Mollicutes were absent in the P2X7−/− mice but increased in the WT mice. P2X7 protects mice against T. gondii infection by activating the inflammasome and regulating the local and systemic immune responses. Specific gut bacterial populations modulated by P2X7 determine disease severity. Full article

Diabetes mellitus (DM) is a chronic progressive metabolic disorder associated with several gastrointestinal complications, affecting up to 75% of patients. Knowing that Angiotensin II (AngII) also regulates intestinal contraction, we decided to evaluate changes in ileum and colon histomorphometry and AngII reactivity in a rat model of DM. Streptozotocin (STZ, 55 mg/kg) was administered to induce DM to 24 adult male Wistar rats. Diabetic rats displayed all the characteristic signs of type 1 DM (T1DM) and fecal excretion increased about 4-fold over 14 days, while the excretion of controls remained unaltered. Compared to controls, diabetic ileum and colon presented an increase in both macroscopic (length, perimeter and weight) and microscopic (muscular wall thickness) parameters. Functionally, AngII-induced smooth muscle contraction was lower in diabetic rats, except in the distal colon. These differences in the contractile response to AngII may result from an imbalance between AngII type 1 (antagonized by candesartan, 10 nM) and type 2 receptors activation (antagonized by PD123319, 100 nM). Taken together, these results indicate that an early and refined STZ-induced T1DM rat model already shows structural remodelling of the gut wall and decreased contractile response to AngII, findings that may help to explain diabetic dysmotility. Full article