Search Results (86)

Short-chain fatty acids (SCFAs) are the major microbial metabolites produced from the fermentation of dietary fiber in the gut. They are recognised as secretagogues of the glucagon-like peptides, GLP-1 and GLP-2, likely mediated by the activation of free fatty acid receptors 2 and 3 (FFAR2 and 3) expressed on enteroendocrine L-cells. Fiber-deficient diets are associated with decreased intestinal function and decreased colonic GLP-1 and GLP-2 content. Here, we speculated that the lowered colonic GLP-1 observed following a fiber-free diet was a consequence of decreased SCFA production and a subsequent decrease in FFAR2/3 activation. Furthermore, we explored the consequences of a fiber-free diet followed by intestinal injury, and we mechanistically explored the SCFA-FFAR2/3-GLP-1 pathway to explain the increased severity. Colonic luminal content from mice fed either a fiber-free or chow diet were analysed for SCFA content by LC–MS. FFAR2/3 receptor contributions to SCFA-mediated colonic GLP-1 secretion were assessed in isolated perfused preparations of the colon from FFAR2/3 double knockout (KO) and wild-type (WT) mice. Colitis was induced by the delivery of 3% dextran sulfate sodium (DSS) for 4 days in the drinking water of mice exposed to a fiber-free diet for 21 days. Colitis was induced by the delivery of 3% DSS for 7 days in FFAR2/3 KO mice. The removal of dietary fiber significantly decreased SCFA concentrations in the luminal contents of fiber-free fed mice compared to chow-fed mice. In the perfused colon, luminal SCFAs significantly increased colonic GLP-1 secretion in WT mice but not in FFAR2/3 KO mice. In the DSS-induced colitis model, the removal of dietary fiber increased the severity and prevented the recovery from intestinal injury. Additionally, colitis severity was similar in FFAR2/3 KO and WT mice after DSS application. In conclusion, the results confirm that the removal of dietary fiber is sufficient to decrease the colonic concentrations of SCFAs. Additionally, we show that a fiber-free diet predisposes the colon to increased intestinal injury, but this effect is independent of FFAR2 and FFAR3 signalling; therefore, it is unlikely that a fiber-free diet induces a decrease in luminal SCFAs and sensitivity to intestinal disease involves the SCFA-FFAR2/3-GLP-1 pathway. Full article

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock. Full article

In pediatric colorectal surgery, achieving and visualizing adequate perfusion during complex reconstructive procedures are paramount to ensure postoperative success. However, intraoperative identification of proper perfusion remains a challeng. This review synthesizes findings from the literature spanning from January 2010 to March 2024, sourced from Medline/PubMed, EMBASE, and other databases, to evaluate the role of indocyanine green (ICG) fluorescence imaging in enhancing surgical outcomes. Specifically, it explores the use of ICG in surgeries related to Hirschsprung disease, anorectal malformations, cloacal reconstructions, vaginal agenesis, bladder augmentation, and the construction of antegrade continence channels. Preliminary evidence suggests that ICG fluorescence significantly aids in intraoperative decision-making by improving the visualization of vascular networks and assessing tissue perfusion. Despite the limited number of studies, initial findings indicate that ICG may offer advantages over traditional clinical assessments for intestinal perfusion. Its application has demonstrated a promising safety profile in pediatric patients, underscoring the need for larger, prospective studies to validate these observations, quantify benefits, and further assess its impact on clinical outcomes. The potential of ICG to enhance pediatric colorectal surgery by providing real-time, accurate perfusion data could significantly improve surgical precision and patient recovery. Full article

Few studies have explored the biological mechanism by which probiotics alleviate adverse reactions to chemotherapy drugs after local hepatic chemotherapy perfusion by regulating the intestinal flora. This study investigates the effects of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets on the intestinal microbial structure and intestinal barrier function, as well as the potential mechanism in rabbits after local hepatic chemotherapy infusion. Eighteen New Zealand White rabbits were randomly divided into a control group, a hepatic local chemotherapy perfusion group, and a hepatic local chemotherapy perfusion + Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets group to assess the effects of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets on the adverse reactions. The administration of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets alleviated the intestinal flora disorder caused by local hepatic perfusion chemotherapy, promoted the growth of beneficial bacteria, and inhibited the growth of harmful bacteria. The Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets also reduced the levels of serum pro-inflammatory cytokines and liver injury factors induced by local hepatic perfusion chemotherapy. Our findings indicate that Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets can ameliorate the toxicity and side effects of chemotherapy by regulating intestinal flora, blocking pro-inflammatory cytokines, reducing liver injury factors, and repairing the intestinal barrier. Probiotics may be used as a potential alternative therapeutic strategy to prevent the adverse reactions caused by chemotherapy with local hepatic perfusion. Full article

Background and Objective: The dynamic assessment of disease activity during the follow-up of patients with Crohn’s disease (CD) remains a significant challenge. In this study, we aimed to identify the role of dynamic contrast-enhanced ultrasound (DCE-US) in the evaluation of activity of CD. Methods: In the retrospective study, patients diagnosed with CD in our hospital were included. All the diagnoses were confirmed by clinical symptoms and ileocolonoscopical results. All patients underwent intestinal ultrasound and contrast-enhanced ultrasound (CEUS) examinations within 1 week of the ileocolonoscopy examinations. Acuson Sequoia (Siemens Healthineers, Mountain View, CA, USA) and Resona R9 Elite (Mindray Medical Systems, China) with curved array and Line array transducers were used. The CEUS examination was performed with SonoVue (Bracco SpA, Milan, Italy). DCE-US analysis was performed by UltraOffice (version: 0.3-2010, Mindray Medical Systems, China) software. Two regions of interest (ROIs) were set in the anterior section of the infected bowel wall and its surrounding normal bowel wall 2 cm distant from the inflamed area. Time–intensity curves (TICs) were generated and quantitative perfusion parameters were obtained after curve fittings. The Simple Endoscopic Score for Crohn’s disease (SES-CD) was regarded as the reference standard to evaluate the activity of CD. The receiver operating characteristic curve (ROC) analyses were used to determine the diagnostic efficiency of DCE-US quantitative parameters. Results: From March 2023 to November 2023, 52 CD patients were included. According to SES-CD score, all patients were divided into active group with the SES-CD score > 5 (n = 39) and inactive group SES-CD score < 5 (n = 13). Most of the active CD patients showed bowel wall thickness (BWT) > 4.2 mm (97.4%, 38/39) or mesenteric fat hypertrophy (MFH) on intestinal ultrasound (US) scan (69.2%, 27/39). Color Doppler signal of the bowel wall mostly showed spotty or short striped blood flow signal in active CD patients (56.4%, 22/39). According to CEUS enhancement patterns, most active CD patients showed a complete hyperenhancement of the entire intestinal wall (61.5%, 24/39). The TICs of active CD showed an earlier enhancement, higher peak intensity, and faster decline. Among all CEUS quantitative parameters, amplitude-derived parameters peak enhancement (PE), wash-in area under the curve (WiAUC), wash-in rate (WiR), wash-in perfusion index (WiPI), and wash-out rate (WoR) were significantly higher in active CD than in inactive CD (p < 0.05). The combined AUROC of intestinal ultrasound features and DCE-US quantitative perfusion parameters in the diagnosis of active CD was 0.987, with 97.4% sensitivity, 100% specificity, and 98.1% accuracy. Conclusions: DCE-US with quantitative perfusion parameters is a potential useful noninvasive imaging method to evaluate the activity of Crohn’s disease. Full article

Mesenteric ischemia is a challenging condition characterized by insufficient blood perfusion to the mesentery and, consequently, intestinal tissues that continues to perplex clinicians. Despite its low prevalence, the condition’s variable clinical presentation and elusive radiographic diagnosis can delay life-saving interventions in the acute setting and deteriorate the quality of life of patients when left undiagnosed or misdiagnosed. Purpose: Review and summarize recent diagnostic updates and emergent intervention strategies for acute and chronic mesenteric ischemia. Methods: A narrative review of all relevant studies from January 2022 through September 2023. Results: A total of 11 studies from MEDLINE, supplemented with 44 studies from Google Scholar, were included in the review. Conclusions: Both acute and chronic mesenteric ischemia propose diagnostic and therapeutic challenges for interventionalists. Computed tomographic angiography remains the diagnostic modality of choice for both. Open surgical intervention remains the gold standard for acute mesenteric ischemia, while endovascular techniques are preferred for chronic mesenteric ischemia. Full article

Metformin plasma exposure is increased in rats with thioacetamide (TAA)-induced liver failure. The absorption, distribution, and excretion process of metformin is mainly mediated by organic cation transporters (OCTs) and multidrug and toxin extrusion transporters (MATEs). To investigate the mechanisms of the increase in TAA-induced metformin plasma exposure, we employed intestinal perfusion and urinary excretion assays to evaluate the changes in the absorption and excretion of metformin and used Western blotting to investigate the metformin-related transport proteins’ expression changes and mechanisms. The results showed that neither intestinal OCT2 expression nor metformin intestinal absorption were significantly altered by TAA-induced liver failure, while significantly decreased expression and function of renal OCT2 and MATE1 as well as impaired metformin excretion were observed in TAA rats. HK-2 cells were used as an in vitro model to explore the mechanism of liver-failure-mediated downregulation in renal OCT2 and MATE1. The results demonstrated that among numerous abnormal substances that changed in acute liver failure, elevated estrogen levels and tumor necrosis factor-α were the main factors mediating the downregulation of OCT2 and MATE1. In conclusion, this study highlights the downregulation of renal OCT2 and MATE1 in liver injury and its regulatory mechanism and reveals its roles in the increase in TAA-mediated metformin plasma exposure. Full article

Traditional Chinese medicine (TCM) possesses unique advantages in the management of blood glucose and lipids. However, there is still a significant gap in the exploration of its pharmacologically active components. Integrated strategies encompassing deep-learning prediction models and active validation based on absorbable ingredients can greatly improve the identification rate and screening efficiency in TCM. In this study, the affinity prediction of 11,549 compounds from the traditional Chinese medicine system’s pharmacology database (TCMSP) with dipeptidyl peptidase-IV (DPP-IV) based on a deep-learning model was firstly conducted. With the results, Gardenia jasminoides Ellis (GJE), a food medicine with homologous properties, was selected as a model drug. The absorbed components of GJE were subsequently identified through in vivo intestinal perfusion and oral administration. As a result, a total of 38 prototypical absorbed components of GJE were identified. These components were analyzed to determine their absorption patterns after intestinal, hepatic, and systemic metabolism. Virtual docking and DPP-IV enzyme activity experiments were further conducted to validate the inhibitory effects and potential binding sites of the common constituents of deep learning and sequential metabolism. The results showed a significant DPP-IV inhibitory activity (IC₅₀ 53 ± 0.63 μg/mL) of the iridoid glycosides’ potent fractions, which is a novel finding. Genipin 1-gentiobioside was screened as a promising new DPP-IV inhibitor in GJE. These findings highlight the potential of this innovative approach for the rapid screening of active ingredients in TCM and provide insights into the molecular mechanisms underlying the anti-diabetic activity of GJE. Full article

Self-double emulsifying drug delivery systems have the potential to enhance the intestinal permeability of drugs classified under the Biopharmaceutics Classification System (BCS) class III. One such example is the antiviral agent zanamivir, exhibiting suboptimal oral absorption (with a bioavailability range of 1–5%). To address this challenge, we have developed an innovative oral formulation for zanamivir: a self-double nanoemulsifying Winsor delivery system (SDNE-WDS) consisting of the microemulsion, which subsequently yields final double nanoemulsion (W₁/O/W₂) upon interaction with water. Two distinct formulations were prepared: SDNE-WDS1, classified as a W/O microemulsion, and SDNE-WDS2, discovered to be a bicontinuous microemulsion. The inner microemulsions displayed a consistent radius of gyration, with an average size of 35.1 ± 2.1 nm. Following self-emulsification, the resultant zanamivir-loaded nanoemulsion droplets for zSDNE-WDS1 and zSDNE-WDS2 measured 542.1 ± 36.1 and 174.4 ± 3.4 nm, respectively. Both types of emulsions demonstrated the ability to enhance the transport of zanamivir across a parallel artificial membrane. Additionally, in situ rat intestinal perfusion studies involving drug-loaded SDNE-WDSs revealed a significantly increased permeability of zanamivir through the small intestinal wall. Notably, both SDNE-WDS formulations exhibited effective permeability (P_eff) values that were 3.5–5.5-fold higher than those of the low/high permeability boundary marker metoprolol. This research emphasizes the success of SDNE-WDSs in overcoming intestinal permeability barriers and enabling the effective oral administration of zanamivir. These findings hold promise for advancing the development of efficacious oral administration of BCS class III drugs. Full article

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor β (TGF-β) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc. Full article

There is an increasing need to develop alternatives to animal modeling and testing for pre-clinical studies as researchers face major challenges, such as the study of dynamic systems in laboratory settings. Microphysiological system (MPS) technology has recently shown great potential for addressing such limitations. We developed a perfusing small intestine–liver-connected device that is easy to operate and highly reproducible. In non-clinical pharmacokinetics and safety studies, the use of human-derived materials is necessary. We used human iPS cell-derived small intestinal epithelial cells (HiEs) and cryopreserved human primary hepatocytes. Hepatocytes in 3D culture were co-cultured with swiss-albino 3T3 cells as feeder cells. We evaluated the effects of co-culturing hepatocytes and HiEs using our small intestine–liver device. The mRNA expression levels of CYP1A2 and CYP3A4 in hepatocytes were significantly increased in the 3D culture. The TEER values were increased in HiEs co-cultured with hepatocytes in the 3D culture. We evaluated the differential proliferation and function characteristics of the hepatocytes and HiEs following perfusion and verified the utility of our proposed small intestine–liver device for evaluating multiple cell populations. The perfusion culture system of our small intestine–liver device can be used to investigate distinct effects on co-cultured hepatocytes and HiEs. Full article

Modern smartphones have been employed as key elements in point-of-care (POC) devices due to remarkable advances in their form factor, computing, and display performances. Recently, we reported a combination of the smartphone with a handheld endoscope using laser speckle contrast imaging (LSCI), suggesting potential for functional POC endoscopy. Here, we extended our work to develop a smartphone-combined multifunctional handheld endoscope using dual-wavelength LSCI. Dual-wavelength LSCI is used to monitor the changes in dynamic blood flow as well as changes in the concentration of oxygenated (HbO₂), deoxygenated (Hbr), and total hemoglobin (HbT). The smartphone in the device performs fast acquisition and computation of the raw LSCI data to map the blood perfusion parameters. The flow imaging performance of the proposed device was tested with a tissue-like flow phantom, exhibiting a speckle flow index map representing the blood perfusion. Furthermore, the device was employed to assess the blood perfusion status from an exteriorized intestine model of rat in vivo during and after local ischemia, showing that blood flow and HbO₂ gradually decreased in the ischemic region whereas hyperemia and excess increases in HbO₂ were observed in the same region right after reperfusion. The results indicate that the combination of LSCI with smartphone endoscopy delivers a valuable platform for better understanding of the functional hemodynamic changes in the vasculatures of the internal organs, which may benefit POC testing for diagnosis and treatment of vascular diseases. Full article

It has been demonstrated that the disturbance of gut microbiota (GM) is closely related to the reduction of bone mass and incidence of osteoporosis (OP). The aim of this study is to investigate whether the supplementation of Prevotella histicola (Ph) can prevent the bone loss in mice with ovariectomy (OVX)-mediated OP, and further explore relevant mechanisms. Regular (once a day for 8 consecutive weeks) and quantitative (200 µL/d) perfusion of Ph (the bacteria that orally gavaged) was conducted starting from 1 week after the construction of mice models. Bone mass and bone microstructure were detected by Micro-computed tomography (Micro-CT). Expressions of intestinal permeability, pro-inflammatory cytokines, and osteogenic and osteoclastic activities of mice were analyzed by histological staining and immunohistochemistry (IHC). 16S rRNA high throughput sequencing technique was applied to analyze the alterations of composition, abundance, and diversity of collected feces. Regular and quantitative perfusion of Ph mitigated the bone loss in mice with OVX-mediated OP. Compared with OVX + PBS group, perfusion of Ph repressed osteoclastogenesis and promoted osteogenesis, reduced release of pro-inflammatory cytokine cytokines (interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)), and reversed expressions of tight junction proteins (zonula occludens protein 1 (ZO-1) and Occludin). Besides, the perfusion of Ph improved the composition, abundance, and diversity of GM. Collectively, this study revealed that regular and quantitative perfusion of Ph can improve the bone loss in mice with OVX-mediated OP by repairing intestinal mucosal barrier damage, optimizing intestinal permeability, inhibiting release of pro-osteoclastogenic cytokines, and improving disturbance of GM. Full article

Gastrointestinal tuberculosis (GITB) and Crohn’s disease (CD) are close mimics. This prospective study aimed to evaluate the diagnostic performance of perfusion computed tomography (CT) in differentiating GITB from CD. Consecutive patients with ileocaecal thickening underwent perfusion CT of the ileocaecal region between January 2019 and July 2020. Two radiologists (blinded to the final diagnosis) independently assessed blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability at perfusion CT. These parameters were compared among the patients with GITB as well as active and inactive CD. Receiver operating characteristic curves were utilized for determining the diagnostic performance of perfusion CT. Interclass correlation coefficient and Bland–Altman analysis were performed to compare the observations of the two radiologists. During the study period, 34 patients underwent perfusion CT. Eight patients had diagnoses other than intestinal tuberculosis or CD. Thus, 26 patients (mean age 36 ± 14 years, 18 males) with GITB (n = 11), active CD (n = 6), and inactive CD (n = 9) were evaluated. BF, MTT, and permeability showed significant differences among the groups, while BV did not differ significantly among the groups. BF and permeability had 100% sensitivity and 100% specificity, while MTT had 61.5–100% sensitivity and 70–100% specificity for differentiating GITB from active CD and active from inactive CD. The interclass correlation coefficient for perfusion CT parameters was 0.88–1. Perfusion CT is a novel imaging technique that can improve the diagnostic performance of differentiating tuberculosis from CD. Full article

The drug efflux transporter permeability glycoprotein (P-gp) plays an important role in oral drug absorption and distribution. Under microgravity (MG), the changes in P-gp efflux function may alter the efficacy of oral drugs or lead to unexpected effects. Oral drugs are currently used to protect and treat multisystem physiological damage caused by MG; whether P-gp efflux function changes under MG remains unclear. This study aimed to investigate the alteration of P-gp efflux function, expression, and potential signaling pathway in rats and cells under different simulated MG (SMG) duration. The altered P-gp efflux function was verified by the in vivo intestinal perfusion and the brain distribution of P-gp substrate drugs. Results showed that the efflux function of P-gp was inhibited in the 7 and 21 day SMG-treated rat intestine and brain and 72 h SMG-treated human colon adenocarcinoma cells and human cerebral microvascular endothelial cells. P-gp protein and gene expression levels were continually down-regulated in rat intestine and up-regulated in rat brain by SMG. P-gp expression was regulated by the Wnt/β-catenin signaling pathway under SMG, verified by a pathway-specific agonist and inhibitor. The elevated intestinal absorption and brain distribution of acetaminophen levels also confirmed the inhibited P-gp efflux function in rat intestine and brain under SMG. This study revealed that SMG alters the efflux function of P-gp and regulates the Wnt/β-catenin signaling pathway in the intestine and the brain. These findings may be helpful in guiding the use of P-gp substrate drugs during spaceflight. Full article