Rat Intestine Research Articles

Oral amoxicillin treatment disrupts the gut microbiome and metabolome without interfering with luminal redox potential in the intestine of Wistar Han rats.

Oral antibiotic treatment is well known to be one of the main factors affecting gut microbiota composition by altering bacterial diversity. It decreases the abundance of butyrate-producing bacteria such as Lachnospiraceae and Ruminococcaceae, while increasing abundance of Enterobacteriaceae. The recovery time of commensal bacteria post-antibiotic treatment varies among individuals, and often, complete recovery is not achieved. Recently, gut microbiota disruption has been associated with increased gut oxygen levels and higher redox potential in faecal samples. Given that redox balance is crucial for microbial metabolism and gut health, influencing fermentation processes and maintaining anaerobic conditions, we investigated the impact of oral amoxicillin treatment on the redox potential in the caecum. We used 24 Wistar Han male rats and measured caecal redox potential in situ with a probe, before and after 7 days of amoxicillin treatment, as well as after 7 days of recovery. Additionally, we analysed caecal weight, pH, antioxidant capacity, caecal microbiota, metabolome, and colonic tissue expression of relevant genes involved in the redox potential state. Our findings show that oral amoxicillin treatment significantly reduced archaeal load, and decreased the bacterial alpha diversity and affected bacterial composition of the caecal microbiome. The caecal metabolome was also significantly affected, exemplified by reduced amounts of short chain fatty acids during amoxicillin treatment. While the caecal metabolome fully recovered seven days post amoxicillin treatment, the microbiome did not fully recover within this time frame. However, amoxicillin did not lead to an increase in luminal redox potential in the cecum during or post amoxicillin treatment. Limited differences were observed for colonic expression of genes involved in intestinal barrier function and generation of reactive oxygen species, except for the catalase gene, which was significantly upregulated post-amoxicillin treatment. Our results suggest that while oral amoxicillin disrupts the gut microbiome and metabolome, it does not directly interfere with gut luminal redox state.

Comparative drug-drug interactions of berberine and astragaloside IV in normal and type 2 diabetes mellitus rats based on UPLC-QqQ-MS/MS

The UPLC-QqQ-MS/MS method was established, validated, and used for the simultaneous detection of berberine (BBR), astragaloside IV (AST), and the main metabolites to demonstrate the comparative pharmacokinetics of BBR and AST in normal and T2DM rats. BBR and AST had reduced the internal exposure of each other and their main metabolites in normal rats. However, AST had few significant effects on the pharmacokinetic parameters of BBR and the main metabolites in T2DM rats. Similarly, BBR had no significant effect on the pharmacokinetic parameters of AST but significantly increased the exposure to cycloastragenol (CAG) in vivo. Molecular docking of BBR and AST with the P-glycoprotein (P-gp) was performed, which indicated that both BBR and AST are potential substrates for P-gp. The differences in gut microbiota between normal and T2DM rats were compared by 16S rRNA sequencing. Git microbiota that could produce β-glucosidase and β-xylosidase were highly abundant in T2DM rats. The current study indicated that BBR and AST had reduced oral bioavailability. The gut microbiota was enriched in the intestines of T2DM rats and promoted the hydrolysis of AST to produce CAG, while the drug-drug interaction between AST and BBR was blocked.

Investigation of the Effect of Wheat and Corn Gluten on Inflammation, Transglutaminase, Gliadin and IgA Levels in Healthy Rat Intestines

The aim of this study was to evaluate the effects of wheat and corn gluten on some histopathologic parameters such as villus atrophy, crypt hyperplasia, lymphocyte plasma neutrophils and immunohistochemical parameters such as trans glutaminase, gliadin and IgA in the small intestine of healthy male rats without HLA-DQ2 and HLA-DQ8 genes. In the study, 21 healthy newborn male Sprague Dawley rats were fed wheat, corn and soy with the addition of 7 rats in each group from one-day age to 60 days of age. Histopathological (villous atrophy, lymphocyte plasma neutrophil, crypt hyperplasia) and immunohistochemical (transglutaminase, gliadin, IgA) parameter analyses were performed in small intestinal tissue samples. As a result of the study, it was found that the small intestinal villus lengths of the wheat gluten group were longer than the other groups (P < .05). Cryptic hyperplasia was detected most in the soybean group and the lowest in the wheat group (P < .05). Gliadin antibody levels were found to be in the soybean group with the highest and the lowest in the wheat group (P < .05). In healthy male rats lacking HLA-DQ2 and HLA-DQ8 genes, the effect of wheat gluten on crypt hyperplasia and gliadin levels in small intestinal tissue was significantly lower than in soy and corn gluten groups, while its effect on villous atrophy, lymphocyte plasma neutrophil and transglutaminase was limited. In addition, the intestinal villus lengths of the wheat gluten group were significantly higher than those of the corn and soybean groups.

Prediction of SPT-07A Pharmacokinetics in Rats, Dogs, and Humans Using a Physiologically-Based Pharmacokinetic Model and In Vitro Data.

Background/Objectives: SPT-07A, a D-borneol, is currently being developed in China for the treatment of ischemic stroke. We aimed to create a whole-body physiologically-based pharmacokinetic (PBPK) model to predict the pharmacokinetics of SPT-07A in rats, dogs, and humans. Methods: The in vitro metabolism of SPT-07A was studied using hepatic, renal, and intestinal microsomes. The pharmacokinetics of SPT-07A in rats were simulated using the developed PBPK model and in vitro data. Following validation using pharmacokinetic data in rats, the developed PBPK model was scaled up to dogs and humans. Results: Data from hepatic microsomes revealed that SPT-07A was primarily metabolized by UDP-glucuronosyltransferase (UGTs). Glucuronidation of SPT-07A also occurred in the kidney and intestine. The in vitro to in vivo extrapolation analysis showed that hepatic clearance of SPT-07A in rats, dogs, and humans accounted for 62.2%, 87.3%, and 76.5% of the total clearance, respectively. The renal clearance of SPT-07A in rats, dogs, and humans accounted for 32.6%, 12.7%, and 23.1% of the total clearance, respectively. Almost all of the observed concentrations of SPT-07A following single or multi-dose to rats, dogs, and humans were within the 5th-95th percentiles of simulations from 100 virtual subjects. Sensitivity analysis showed that hepatic metabolic velocity, renal metabolic velocity, and hepatic blood flow remarkably affected the exposure to SPT-07A in humans. Dedrick plots were also used to predict the pharmacokinetics of SPT-07A in humans. Prediction accuracy using the PBPK model is superior to that of Dedrick plots. Conclusions: We elucidate UGT-mediated SPT-07A metabolism in the liver, kidney, and intestine of rats, dogs, and humans. The pharmacokinetics of SPT-07A were successfully simulated using the developed PBPK model.

Inhibition of AhR disrupts intestinal epithelial barrier and induces intestinal injury by activating NF-κB in COPD.

Chronic obstructive pulmonary disease (COPD) is frequently associated with intestinal comorbidities. Damage to the intestinal barrier plays a crucial role in these disorders, leading to increased intestinal and systemic inflammation, and thereby promoting the progression of COPD. This study aims to investigate the mechanism of intestinal epithelial barrier damage, focusing on the roles of the Aryl hydrocarbon Receptor (AhR) and NF-κB in COPD-related intestinal damage. A COPD rat model was induced by cigarette smoke and bacterial infection, while Caco-2/HT29 intestinal epithelial cells were treated with TNF-α or IL-1β to assess intestinal disorder and the underlying mechanisms of barrier damage. COPD rats exhibited significant lung function decline, pathological damage, and inflammatory response in lung tissues. Additionally, significant intestinal injury was observed, accompanied by pronounced colonic pathological damage, an enhanced inflammatory response, and intestinal barrier disruption. This was evidenced by decreased expression of apical junction proteins and elevated serum diamine oxidase levels. Pro-inflammatory cytokines TNF-α or IL-1β significantly downregulated the expression of apical junction proteins in Caco-2/HT29 cells, reduced transepithelial electrical resistance of Caco-2 cells, and increased FD-4 permeability. Moreover, TNF-α or IL-1β induction activated NF-κB in Caco-2/HT29 cells, with a similar activation observed in the colonic tissues of COPD rats. The NF-κB inhibitor PDTC suppressed this activation and protected against intestinal epithelial barrier damage. Furthermore, AhR inhibition was observed both invitro and invivo. The AhR activator FICZ inhibited NF-κB activation and mitigated intestinal epithelial barrier damage, whereas the AhR inhibitor CH223191 inhibited AhR and exacerbated intestinal epithelial barrier damage by facilitating NF-κB activation. However, the NF-κB inhibitor PDTC did not significantly affect AhR. Additionally, TNF-α/IL-1β inhibited the binding of AhR and p-NF-κB. Consequently, AhR inhibition can downregulate the expression of apical junction proteins, probably through activation of NF-κB signaling leading to intestinal epithelial barrier damage. This study confirmed the presence of lesions in the lungs and intestines of COPD rats, as well as the associated damage to the intestinal epithelial barrier. The inhibition of AhR followed by the activation of NF-κB has been identified as a critical mechanism underlying the injury to the intestinal epithelial barrier.

Effects of 3,4-methylenedioxymethamphetamine on the gut microbiota and metabolites in the small intestine, cecum, and colon of male rats.

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a widely abused recreational drug that has also gained interest for potential clinical applications in mental health. With the growing recognition of gut microbiota's role in mental health, this study examined whether repeated oral MDMA administration could affect gut microbiota in the small intestine, cecum, and colon of male rats. Repeated oral MDMA administration (10mg/kg/day for 14days) caused significant changes in the gut microbiota across these regions, with distinct effects observed in each. PICRUSt2 analysis revealed significant alterations in several metabolic pathways in these regions, indicating potential shifts in microbial functional capabilities associated with MDMA treatment. Untargeted metabolomics analysis revealed that MDMA significantly altered levels of two metabolites-ferulic acid and methylmalonic acid-in the colon, without changes in the blood, small intestine, or cecum. Notably, methylmalonic acid levels in the colon positively correlated with Lawsonibacter and Oscillibacter. These findings suggest that repeated oral MDMA treatment can alter gut microbiota composition across intestinal regions, potentially contributing to its pharmacological effects.

Altered purine and pentose phosphate pathway metabolism in uteroplacental insufficiency-induced intrauterine growth restriction offspring rats impairs intestinal function

BackgroundThis study aimed to identify metabolic alterations in the small intestine of newborn rats with intrauterine growth restriction (IUGR), a condition linked to intestinal dysfunction. MethodsPregnant Sprague Dawley rats underwent bilateral uterine artery ligation on gestational day 17 to induce intrauterine growth restriction or sham surgery. Rat pups were delivered spontaneously on gestational day 22. Small intestine tissues were collected on postnatal days 0 and 7 from offspring. Liquid chromatography-mass spectrometry analysis was performed to investigate untargeted metabolomic profiles. Western blot analysis assessed protein expression of key regulators. ResultsNewborn rats with intrauterine growth restriction exhibited distinct small intestine metabolic profiles compared to controls on postnatal day 0. Notably, significant alterations were observed in purine metabolism, the pentose phosphate pathway, and related pathways. Western blot analysis revealed a decrease expression in transketolase, a key enzyme of the pentose phosphate pathway, suggesting impaired activity of the pentose phosphate pathway. Additionally, decreased expression of tight junction proteins ZO-1 and occludin indicated compromised intestinal barrier function in rats with intrauterine growth restriction. Similar metabolic disruptions persisted on postnatal day 7, with further reductions in tricarboxylic acid cycle intermediates and folate biosynthesis precursors. Interestingly, lysyl-glycine, a protein synthesis marker, was elevated in rats with intrauterine growth restriction. ConclusionsOur findings reveal a distinct metabolic signature in the small intestine of neonatal rats with intrauterine growth restriction, characterized by disruptions in the pentose phosphate pathway, purine metabolism, and energy production pathways. These novel insights suggest potential mechanisms underlying IUGR-associated intestinal dysfunction and impaired growth.

Long-term copper exposure induced pyroptosis and inflammation of rat spleen through intestinal-splenic axis

Copper is an essential micro-element in animal growth. Tribasic copper chloride (TBCC), as an important source of animal feed copper, is widely used in agricultural production. Multiple studies have shown that excessive intake of copper can affect the immune function of animals and lead to disease or death. The intestine-spleen axis, which is the interaction between the spleen, intestines and gut microbiota, is closely linked to immune function in the body. However, the mechanism of intestine-spleen axis affecting TBCC induced immune dysfunction in rats has not been revealed. In this study, we analyzed the impacts of different doses of TBCC on the intestine, gut microbiota and spleen of rats, and investigated their relationship in the process. Our results demonstrated that under copper exposure, the structural integrity of the intestinal epithelium was compromised, resulting in a significant downregulation of genes and proteins expression levels related to the intestinal barrier (Zonula occludens-1, Claudin-1 and Occludin). Additionally, copper perturbed the composition of the rat intestinal microbiota, altered the abundance and diversity of the microbial community. Copper entered the spleen via the intestine-spleen axis, leading to structural damage in the spleen and activation of the NFκB signaling pathway, and increased pro-inflammatory cytokines (IFN-γ, TNF-α, IL-18, and IL-1β), ultimately causing pyroptosis and inflammation in the spleen. These findings offer a novel perspective on how copper may induce spleen injury through the intestine-spleen axis.

Expression of Somatostatin Receptors in the Small Intestine during Postnatal Ontogenesis.

The expression of somatostatin receptors (SSTRs) of types 1, 2, and 5 was studied in the small intestine of rats from different age groups (1, 10, 20, 30, 60 days, and 2-year-old) using Western blotting. The expression of SSTR1, SSTR2, and SSTR5 increased in the first 30 days of life, but decreased in older rats compared to 2-month-old animals. These findings suggest that there is differential expression of SSTRs during age-related development of the small intestine. Further studies will determine the role of individual SSTRs in the growth and development of target organs.

Case Report: Hymenolepis diminuta in an asymptomatic Ecuadorian child.

Background The cestode Hymenolepis diminuta is a cosmopolitan parasite, which in the adult stage is usually found in the small intestine of rats and accidentally in humans. Case report We describe the finding of eggs of this parasite in an asymptomatic 3-year-old child. The child had extremely high IgE values of 1,376 IU/ml. After receiving treatment with Albendazole suspension 400mg/20mL, on the 10th day post-treatment, he showed no H. diminuta eggs in his fecal matter Conclusions Detailed morphological review of Hymenolepis nana-like eggs is recommended to distinguish them from H. diminuta eggs.

Type 3 immune response protects against Salmonella Typhimurium infection in the small intestine of neonatal rats

ABSTRACT Bacterial infections, particularly Salmonella, pose a significant health risk to neonates due to their underdeveloped immune systems. Understanding the immune responses in the neonatal intestine during S. Typhimurium infection is crucial for developing effective therapeutic and prevention strategies. This study found neonatal rats exhibited severe symptoms, including significant mortality, body weight loss, diarrhea, and bacterial load increases in the gastrointestinal tract and various organs, particularly in the ileum. Moreover, neonatal rats exhibited a high percentage of type 3 immune cells including Th17, γδT17, and ILC3 after S. Typhimurium infection. Furthermore, cintirorgon treatment during early life, the agonist of RORγt, significantly enhanced IL-17A-secreting type 3 immune response and alleviated the symptoms. Our data reveal targeting RORγt and IL-17A pathways may offer a promising therapeutic strategy for bacterial infections in neonatal populations.

Apoptotic and proliferative processes in the small intestine of rats with type 2 diabetes mellitus after metformin and propionic acid treatment.

Propionic acid (PA) is an intermediate product of metabolism of intestinal bacteria and may protect the intestinal barrier from disruption. The aim of the study was to investigate the apoptotic and proliferative processes in the small intestine (SI) of rats with type 2 diabetes mellitus (T2DM) on the background of metformin monotherapy and its combination with PA. Male Wistar rats were divided: 1) control; 2) T2DM (3-month high-fat diet followed by streptozotocin injection of 25mg/kg of body weight); 3) T2DM + metformin (60mg/kg, 14days, orally); 4) T2DM + PA (60mg/kg, 14days, orally); 5) T2DM + PA + metformin. Western blotting, RT-PCR, and scanning electron microscopy were performed. We observed profound changes in the SI of diabetic rats suggesting the disturbed intestinal homeostasis: impaired mitochondrial ultrastructure, increased cristae volume, and decreased content of proliferative marker Ki67 with almost unchanged proapoptotic caspase-3 and its p17 subunit levels. Metformin and PA monotherapies also led to an increased cristae volume, however, after their combination, a tendency to normalization of ultrastructure of mitochondria was observed. While there was a significant inhibition of proliferation in T2DM and, in greater extent, after metformin and PA monotherapies, differential influence on apoptosis in the SI was observed. While metformin inhibited apoptosis via Bax declining, PA mainly acted via caspase-3-dependent mechanism elevating its active p17 subunit. PA supplementation for the improvement of diabetes-induced gastrointestinal complications concurrently with metformin may be consider as a perspective supportive therapy. Data related to PA action on SI may be valuable during the development of new treatment strategies for diabetes-induced intestinal disturbances raised after metformin treatment.

Intestinal Region-Dependent Impact of NFκB-Nrf Crosstalk in Myenteric Neurons and Adjacent Muscle Cells in Type 1 Diabetic Rats.

Type 1 diabetes affects cytokines as potential inducers of NFκB signalling involved in inflammation and neuronal survival. Our goal was to assess the expression of NFκB p65 and its negative regulator, Nrf2, in myenteric neurons and adjacent smooth muscle of different gut segments after chronic hyperglycaemia and immediate insulin treatment. After ten weeks of hyperglycaemia, intestinal samples of control, streptozotocin-induced diabetic and insulin-treated diabetic rats were prepared for fluorescent immunohistochemistry, immunogold electron microscopy, ELISA and qPCR. In the diabetic rats, the proportion of NFκB p65-immunoreactive myenteric neurons decreased significantly in the duodenum and increased in the ileum. The density of NFκB p65-labelling gold particles increased in the ileal but remained unchanged in the duodenal ganglia. Meanwhile, both total and nuclear Nrf2 density increased in the myenteric neurons of the diabetic duodenum. In smooth muscle, NFκB p65 and Nrf2 density increased in the small intestine of diabetic rats. While on the mRNA level, NFκB p65 and Nrf2 were induced, on the protein level, NFκB p65 increased and Nrf2 decreased in muscle/myenteric plexus homogenates. Insulin treatment had protective effects. Our findings reveal a segment-specific NFκB and Nrf expression in myenteric neurons and ganglionic muscular environments, which may contribute to regional neuronal survival and motility disturbances in diabetes.

Case Report: Hymenolepis diminuta in an asymptomatic Ecuadorian child.

Background The cestode Hymenolepis diminuta is a cosmopolitan parasite, which in the adult stage is usually found in the small intestine of rats and accidentally in humans. Case report We describe the finding of eggs of this parasite in an asymptomatic 3-year-old child. The child had extremely high IgE values of 1,376 IU/ml. After receiving treatment with Albendazole suspension 400mg/20mL, on the 10th day post-treatment, he showed no H. diminuta eggs in his fecal matter Conclusions Detailed morphological review of Hymenolepis nana-like eggs is recommended to distinguish them from H. diminuta eggs.

Effect of dimephosphone in a course administration on the mechanical activity of the intestine of rats with an autism model

BACKGROUND: Gastrointestinal tract dysfunctions are a very common problem in patients with autism spectrum disorders, which aggravates the underlying course of the disease, and therefore there is a need to find safe drugs to correct gastrointestinal dysfunctions. AIM: Evaluation of intestinal contractile activity in rats with an autism model after a course of intragastric administration of dimephosphone. MATERIAL AND METHODS: The mechanical activity of the duodenum and ileum of rats with the valproate model of autism after the administration of dimephosphone was studied in vitro. To model autism, female rats were given a single subcutaneous injection of sodium valproate at a dose of 500 mg/kg in the withers area on the 13th day of pregnancy. The offspring of these rats were divided into two groups. The experimental group of rats (n=12) was given dimephosphone at a dose of 50 mg/kg for 30 days, starting from the age of 2 months, control rats (n=12) were given physiological saline in an equal volume. Another group of rats was intact (n=9), which were born from female rats not exposed to valproic acid. The effect of carbachol (10–8–10–5 M), ATP (10–7–10–4 M), 2-methylthio-ATP (10–7–10–5 M) and electrical stimulation (1–5 Hz) on the mechanical activity of isolated intestinal smooth muscle preparations was assessed. Statistical processing was performed in IBM SPSS Statistics 26.0 using one-way analysis of variance. RESULTS: It was found that in rats with autism modeling, carbachol-induced intestinal contractions and ATP-induced intestinal relaxation increased. A course of intragastric administration of dimephosphone for 30 days normalized these changes, which became indistinguishable from the corresponding indices in intact animals. Thus, ATP at a concentration of 10–4 caused relaxation of the smooth muscles of the duodenum of rats with autism modeling after a course of dimephosphone administration by 77.1±14.7%, which significantly differed from the corresponding indices in control animals — 34.4±9.4% (p 0.05) and did not differ from the indices in intact rats. Similar changes occurred in the mechanical activity of the ileum. Intestinal relaxation in rats caused by 2-methylthio-ATP did not change significantly either in the control or in the group of animals receiving dimephosphone. CONCLUSION: Dimephosphone, when administered intragastrically, normalizes the disturbances in the mechanical activity of the intestines of rats with an autism model.

Changes in the Tissue Barrier after Exposure to Lipopolysaccharide on the Apical Side of Enterocytes and the Follicle-Associated Epithelium in Peyer's Patches of the Rat Intestine.

To study the para- and transcellular permeability of columnar epithelium and follicle-associated epithelium of Peyer's patches in the rat intestine, LPS was applied from the mucosal side to simulate the action of endotoxins from gram-negative bacteria of gut microbiota. LPS did not affect transepithelial resistance or sodium fluorescein permeability, but increased the levels of claudin-3 and claudin-4 in enterocytes, suggesting strengthening of the paracellular intestinal barrier. Transcellular permeability was evaluated by electron microscopy based on the number of vesicular structures in the cytoplasm of different cell types. LPS increased the number of small vesicles in follicle-associated epithelium of Peyers' patches. In columnar epithelial cells, LPS reduced the number of smaller vesicles and increased the number of larger ones. LPS did not damage the tissue barrier, but enhanced transcytosis, which could potentiate the effects of endotoxin on its receptors in the intestinal mucosa.

Design, Synthesis, and Biological Evaluation of Covalently Mucoadhesive Derivatives as Nonsystemic Intestine-Targeted TGR5 Agonists.

Takeda G-protein-coupled receptor 5 (TGR5) is considered a promising therapeutic target for treating type 2 diabetes mellitus (T2DM), obesity, and other metabolism-related diseases. Although many TGR5 agonists have been identified, they might cause some side effects in the gallbladder and the heart. To reduce these side effects and improve glucose-lowering capability, we first designed and synthesized a series of 4-phenoxynicotinamide intestine-targeted TGR5 agonist derivatives containing maleimides in the side chains with different linker lengths. All of the target compounds demonstrated significant TGR5 agonistic activity, among which compound 22b displayed the best TGR5 agonistic activity. Additionally, compound 22b displayed low Caco-2 cell permeability and strong mucoadhesion to mucin and the rat intestine. In C57BL/6J, diet-induced obese, and db/db mice, compound 22b demonstrated a robust and prolonged hypoglycemic effect along with an acceptable safety profile.

Electroacupuncture Promotes the Generation of Intestinal Treg Cells After Ischemic Stroke by Foxp3 Acetylation Regulation.

Electroacupuncture (EA) has been shown to ameliorate brain injury and protect against intestinal injury after ischemic stroke. These protective effects are closely associated with the enhancement of regulatory T (Treg) cell numbers and function in the intestine, as well as the inhibition of intestinal γδ T cell production and their migration to the brain. This study aimed to elucidate the potential mechanism by which EA regulates intestinal Treg cell differentiation after stroke. Sprague-Dawley rats were divided into three groups: the sham group, the middle cerebral artery occlusion (MCAO) group, and the MCAO plus EA (MEA) group. The MCAO model was generated by occluding the middle cerebral artery. EA was applied to Baihui (GV20) acupoint once daily. Samples were collected 3days after reperfusion. Our results showed that EA reduced the inflammatory response in the brain and intestine after ischemic stroke. EA treatment increased the percentage of Treg cells in the small intestine of rats. EA increased the levels of SCFAs, while also inhibiting histone deacetylase activity (HDAC). Additionally, acetylated Foxp3 protein in the small intestine was increased after EA treatment. These results suggest that EA at GV20 alleviates brain and intestinal inflammatory injury in stroke rats, potentially through the enhancement of SCFA-mediated Foxp3 acetylation in Treg cells.

The pharmacokinetics of dabigatran in a rat model of hyperlipidaemia induced by poloxamer 407

Various pharmacokinetic changes have been reported in experimental hyperlipidemic (HL) animal models. To evaluate whether P-glycoprotein (P-gp) activity was affected in HL rats, we assessed the pharmacokinetics of dabigatran after oral administration of dabigatran etexilate (DABE); this is a dabigatran prodrug and a well-known P-gp substrate. HL and control rats exhibited similar area under the plasma concentration-time curve (AUC), total body clearance (CL), and steady state volume of distribution (Vss) values following intravenous administration of dabigatran (1 mg/kg). This suggested that the distribution and elimination of dabigatran were similar in control and HL rats. The hepatic and intestinal P-gp protein levels did not differ significantly between control and HL rats. The dabigatran AUC and extent of absolute oral bioavailability (F) values were similar in control and HL rats following oral administration of DABE (10 mg/kg as dabigatran). Therefore, there was no apparent change in intestinal P-gp activity in HL rats compared to control rats. This study revealed no significant change in P-gp expression or activity in the intestine or liver of HL rats, and similar pharmacokinetics of dabigatran. Hyperlipidaemia may not directly affect the oral absorption of P-gp substrate drugs.

Whole-body mass spectrometry imaging reveals the systemic metabolic disorder and catecholamines biosynthesis alteration on heart-gut axis in heart failure rat

IntroductionHeart failure (HF) is a systemic metabolic disorder disease, across multiorgan investigations advancing knowledge of progression and treatment of HF. Whole-body MSI provides spatiotemporal information of metabolites in multiorgan and is expected to be a potent tool to dig out the complex mechanism of HF. ObjectivesThis study aimed at exploring the systemic metabolic disorder in multiorgan and catecholamines biosynthesis alteration on heart-gut axis after HF. MethodsWhole-body MSI was used to characterize metabolic disorder of the whole rat body after HF. An integrated method by MSI, LC-MS/MS and ELISA was utilized to analyze key metabolites and enzymes on heart, small intestine, cecum and colon tissues of rat. Gut microbiota dysbiosis was investigated by 16S rDNA sequencing and metagenomic sequencing. Validation experiments and in vitro experiments were performed to verify the effect of catecholamines biosynthesis alteration on heart-gut axis after HF. ResultsWhole-body MSI exhibited varieties of metabolites alteration in multiple organs. Remarkably, catecholamine biosynthesis was significantly altered in the serum, heart and intestines of rats. Furthermore, catecholamines and tyrosine hydroxylase were obviously upregulated in heart and colon tissue. Turicibacter_sanguinis was relevant to catecholamines of heart and colon. Validation experiments demonstrated excessive norepinephrine induced cardio-intestinal injury, including significantly elevating the levels of BNP, pro-BNP, LPS, DAO, and increased the abundance of Turicibacter_sanguinis. These alterations could be reversed by metoprolol treatment blocking the effect of norepinephrine. Additionally, in vitro studies demonstrated that norepinephrine promoted the growth of Turicibacter_sanguinis and Turicibacter_sanguinis could import and metabolize norepinephrine. Collectively, excessive norepinephrine exerted bidirectional effects on cardio-intestinal function to participate in the progression of HF. ConclusionOur study provides a new approach to elucidate multiorgan metabolic disorder and proposes new insights into heart-gut axis in HF development.