Gastrointestinal Permeability Research Articles

Application of validated spectrophotometric method to quantify metformin in the development of glucose-responsive microparticles loaded dissolving microneedles

Metformin (MTF) is a first-line drug in the treatment of type 2 diabetes mellitus. Delivered through the oral route, MTF has several limitations, mainly due to the side effects in gastrointestinal, non-specific release and low intestinal permeability, resulting in the low bioavailability of MTF in the body. Here, we developed glucose-responsive microparticles (GR-MP) containing MTF delivered via dissolving microneedles (DMNs) to overcome these limitations. To support the development of the formulation, in this study, a simple analytical method was developed using a UV–visible spectrophotometer. The method was validated in four different media, namely PBS, PBS containing 1 % w/v glucose, 2 % w/v glucose and 4 % w/v glucose, to mimic the normal and hyperglycemic condition. The method was further validated as per International Conference Harmonization (ICH). This analytical method was applied to quantify the amount of MTF in the GR-MP preparation, in vitro release, drug content in DMNs and, importantly, ex vivo permeation study in in vitro hyperglycemic conditions. The results exhibited that the calibration curves in all media showed a correlation coefficient (R) of 0.998, indicating the linearity of the method. Moreover, LLOQ values in the four different media were 2.23 µg/mL, 1.95 µg/mL, 1.94 µg/mL, and 2.88 µg/mL, respectively. Importantly, the method was precise and accurate with desired dilution integrity according to ICH, implying the validity of the methods. Finally, the method was successfully applied in the development of DMNs containing GR-MP of MTF, showing that the incorporation of MTF into this combination approach could selectively control the release of the drug according to the glucose concentration both in in vitro release and ex vivo permeation studies. Therefore, this approach could be a favorable system to solve the oral administration of MTF. Further in vivo analytical methods should now be developed to explore the effectiveness of this system in a suitable animal model.

Cyclodextrin Derivatives as Promising Solubilizers to Enhance the Biological Activity of Rosmarinic Acid.

Rosmarinic acid (RA) is a natural antioxidant with neuroprotective properties; however, its preventive and therapeutic use is limited due to its slight solubility and poor permeability. This study aimed to improve RA physicochemical properties by systems formation with cyclodextrins (CDs): hydroxypropyl-α-CD (HP-α-CD), HP-β-CD, and HP-γ-CD, which were prepared by the solvent evaporation (s.e.) method. The interactions between components were determined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier Transform infrared spectroscopy (FTIR). The sites of interaction between RA and CDs were suggested as a result of in silico studies focused on assessing the interaction between molecules. The impact of amorphous systems formation on water solubility, dissolution rate, gastrointestinal (GIT) permeability, and biological activity was studied. RA solubility was increased from 5.869 mg/mL to 113.027 mg/mL, 179.840 mg/mL, and 194.354 mg/mL by systems formation with HP-α-CD, HP-β-CD, and HP-γ-CD, respectively. During apparent solubility studies, the systems provided an acceleration of RA dissolution. Poor RA GIT permeability at pH 4.5 and 5.8, determined by parallel artificial membrane permeability assay (PAMPA system), was increased; RA–HP-γ-CD s.e. indicated the greatest improvement (at pH 4.5 from Papp 6.901 × 10−7 cm/s to 1.085 × 10−6 cm/s and at pH 5.8 from 5.019 × 10−7 cm/s to 9.680 × 10−7 cm/s). Antioxidant activity, which was determined by DPPH, ABTS, CUPRAC, and FRAP methods, was ameliorated by systems; the greatest results were obtained for RA–HP-γ-CD s.e. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was increased from 36.876% for AChE and 13.68% for BChE to a maximum inhibition of the enzyme (plateau), and enabled reaching IC50 values for both enzymes by all systems. CDs are efficient excipients for improving RA physicochemical and biological properties. HP-γ-CD was the greatest one with potential for future food or dietary supplement applications.

Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia

ObjectiveFunctional dyspepsia (FD) is a complex disorder, with debilitating epigastric symptoms. Evidence suggests alterations in gastrointestinal (GI) motility, visceral hypersensitivity, permeability and low-level immune activation in the duodenum may play...

358 Gastrointestinal Permeability in Unweaned Male Holstein Calves: Colostrum Consumption and Feed Restriction Matters

Abstract Male Holstein calves (n = 80; 42.7 ± 1.44 kg and 14.2 ± 0.81 days of age) were used to evaluate the effects of colostrum consumption and feed restriction on gut functionality in calves subjected to an assembly center simulation (ACS). Well-colostrated (WC) calves received 4L of colostrum within the first 2h after birth and 2L of colostrum in the next 3 feedings, and poor-colostrated (PC) calves received 2L of colostrum within the first 2h after birth. At approximately 14 d of age, calves were subjected to ACS (d-4 to d-1) before a 19h-transport (d0) where they were fed 4L of milk replacer/d (moderate restriction; MO) or 4L of a rehydration solution/d (severe restriction; SV). Treatments were: WCMO, WCSV, PCMO, PCSV and a group of control calves (WCCT) also fed concentrate ad-libitum during ACS and not transported. Twenty-four hours after transportation, a gut permeability test using Cr-EDTA was performed and blood samples for the determination of serum citrulline concentration were collected. Afterwards, one-half of the calves/treatment were euthanized to obtain tissue samples for a gut permeability in vitro analysis and morphometry. Data were analyzed using the MIXED procedure of SAS. Serum Cr-EDTA concentration was greater (P< 0.01) for the WCSV and PCSV compared with the WCMO, PCMO, and WCCT had the least Cr-EDTA concentration after transportation. The PCSV, WCMO and WCSV calves had the least (P< 0.01) serum concentration of citrulline. In vitro measurements of ileum permeability tended (P=0.06) to be greater for PCSV compared with the other treatments. In WCSV, WCMO and PCSV Goblet cells numbers in the ileum were lesser (P=0.02) than in WCCT and PCMO. Feeding rehydrated solution to poor colostrated calves before transport negatively affected gut functionality as indicated by the greatest permeability to Cr-EDTA, the lest serum citrulline concentration, and ileum Globet cells numbers, these findings are supported by the in vitro gut permeability data.

Caffeine citrate effects on gastrointestinal permeability, bacterial translocation and biochemical parameters in newborn rats after long-term oral administration

BACKGROUND: Caffeine is a potent central and respiratory acting agent used in neonatology to treat apnea in premature newborns. OBJECTIVE: This study investigates the effects of caffeine orally administered to newborn rats on gastrointestinal permeability, bacterial translocation and different biochemical parameters. METHODS: Newborn rats were divided into different groups (N = 06). The treated newborn rats were orally administered with standard caffeine doses (12 mg/kg per day), and the control groups received a placebo. The animals were weighed daily until sacrifice. Blood samples, mesenteric lymph nodes (MLN) and organs were aseptically collected. Furthermore, different biochemical (D-Lactate) and oxidative stress biomarkers (MDA, CAT, SOD and GSH) were examined. Microbiological analyses were performed to assess microbiota alterations and bacterial translocation. RESULTS: Preliminary results showed that caffeine administration decreased the level of bacterial translocation over time. The treatment reduced plasma D-lactate levels (p < 0.05). Additionally, caffeine induced a disturbance in the concentrations of biochemical parameters and oxidative stress biomarkers. Indeed, liver enzymes (AST and ALT) were significantly (p < 0.05) risen after caffeine treatment. Glutathione (GSH) levels were significantly higher in caffeine treated groups (75.12±0.32; 51.98±1.12 U/mg; p < 0.05) comparing to control ones (40.82±0.25; 42.91±0.27 U/mg; p < 0.05) in the ileum and the colon, respectively. CONCLUSIONS: Thus, besides improving gastrointestinal permeability, our data show that caffeine has beneficial effects on the intestinal antioxidant system.

The effect of rugby training on indirect markers of gut permeability and gut damage in academy level rugby players

PurposeTo assess indirect markers of intestinal endothelial cell damage and permeability in academy rugby players in response to rugby training at the beginning and end of preseason.MethodsBlood and urinary measures (intestinal fatty acid binding protein and lactulose:rhamnose) as measures of gastrointestinal cell damage and permeability were taken at rest and after a standardised collision-based rugby training session in 19 elite male academy rugby players (age: 20 ± 1 years, backs: 89.3 ± 8.4 kg; forwards: 111.8 ± 7.6 kg) at the start of preseason. A subsample (n = 5) repeated the protocol after six weeks of preseason training. Gastrointestinal symptoms (GIS; range of thirteen standard symptoms), aerobic capacity (30–15 intermittent fitness test), and strength (1 repetition maximum) were also measured.ResultsFollowing the rugby training session at the start of preseason, there was an increase (median; interquartile range) in intestinal fatty acid binding protein (2140; 1260–2730 to 3245; 1985–5143 pg/ml, p = 0.003) and lactulose:rhamnose (0.31; 0.26–0.34 to 0.97; 0.82–1.07, p < 0.001). After six weeks of preseason training players physical qualities improved, and the same trends in blood and urinary measures were observed within the subsample. Overall, the frequency and severity of GIS were low and not correlated to markers of endothelial damage.ConclusionsRugby training resulted in increased intestinal endothelial cell damage and permeability compared to rest. A similar magnitude of effect was observed after six weeks of pre-season training. This was not related to the experience of GIS.

Heat stress develops with increased total-tract gut permeability, and dietary organic acid and pure botanical supplementation partly restores lactation performance in Holstein dairy cows.

To evaluate the effects of heat stress (HS) conditions and dietary organic acid and pure botanical (OA/PB) supplementation on gut permeability and milk production, we enrolled 46 multiparous Holstein cows [208 ± 4.65 dry matter intake (DMI; mean ± SD), 3.0 ± 0.42 lactation, 122 ± 4.92 d pregnant, and 39.2 ± 0.26 kg of milk yield] in a study with a completely randomized design. Cows were assigned to 1 of 4 groups: thermoneutral conditions (TN-Con, n = 12), HS conditions (HS-Con, n = 12), thermoneutral conditions pair-fed to HS-Con (TN-PF, n = 12), or HS supplemented with OA/PB [75 mg/kg of body weight (BW); 25% citric acid, 16.7% sorbic acid, 1.7% thymol, 1.0% vanillin, and 55.6% triglyceride; HS-OAPB, n = 10]. Supplements were delivered twice daily by top-dress; all cows not supplemented with OA/PB received an equivalent amount of the triglyceride used for microencapsulation of the OA/PB supplement as a top-dress. Cows were maintained in thermoneutrality [temperature-humidity index (THI) = 68] during a 7-d acclimation and covariate period. Thereafter, cows remained in thermoneutral conditions or were moved to HS conditions (THI: diurnal change 74 to 82) for 14 d. Cows were milked twice daily. Clinical assessments and BW were recorded, blood was sampled, and gastrointestinal permeability measurements were repeatedly evaluated. The mixed model included fixed effects of treatment, time, and their interaction. Rectal and skin temperatures and respiration rates were greater in HS-Con and HS-OAPB relative to TN-Con. Dry matter intake, water intake, and yields of energy-corrected milk (ECM), protein, and lactose were lower in HS-Con relative to HS-OAPB. Nitrogen efficiency was improved in HS-OAPB relative to HS-Con. Compared with TN-Con and TN-PF, milk yield and ECM were lower in HS-Con cows. Total-tract gastrointestinal permeability measured at d 3 of treatment was greater in HS-Con relative to TN-Con or TN-PF. Plasma total fatty acid concentrations were reduced, whereas insulin concentrations were increased in HS-Con relative to TN-PF. We conclude that exposure to a heat-stress environment increases total-tract gastrointestinal permeability. This study highlights important mechanisms that might account for milk production losses caused by heat stress, independent of changes in DMI. Our observations also suggest that dietary supplementation of OA/PB is a means to partly restore ECM production and improve nitrogen efficiency in dairy cattle experiencing heat stress.

Exertional, But Not Passive, Hyperthermia Increases Gastrointestinal Permeability

Exertional hyperthermia reduces splanchnic blood flow which leads to gastrointestinal ischemia. This is associated with increased gastrointestinal perturbations and endotoxemia which are potential precursors of exertional heat stroke. However, whether hyperthermia alone can result in significant disruption to gastrointestinal integrity remains unclear. PURPOSE: To determine whether exertional or passive hyperthermia contributes to greater changes in gastrointestinal permeability METHODS: 16 physically active males (mean ± SD; age: 26 ± 3, VO2max: 65 ± 6 ml/kg/min) completed three randomised trials. Blood samples were obtained at baseline and after (a) 70% VO2max run (RUN; Tdb: 30.0 ± 0.1 °C, RH: 71 ± 1%), (b) 50% VO2max walk (WALK; Tdb: 30.0 ± 0.0 °C, RH: 71 ± 0%) and (c) passive heating via warm water immersion at 42 °C (PaH). Serum concentrations of I-FABP, LPS and IL-6 were determined using ELISA. Gastrointestinal temperature (Tgi), heart rate (HR), physiological strain index (PSI) and changes in blood biomarkers were assessed using 1-way ANOVA or paired t-test with p < 0.05 as statistically significant. RESULTS: Participants observed similar baseline Tgi (37.0 ± 0.2 °C, p = 0.204) and HR (63 ± 7 bpm; p = 0.118). End Tgi was similar for RUN (39.4 ± 0.2 °C) and PaH (39.3 ± 0.3 °C, p = 0.289), but lower in WALK (37.9 ± 0.3 °C, p < 0.001). Mean PSI was greatest in RUN (7.4 ± 0.5), followed by PaH (5.2 ± 0.6) and WALK (3.1 ± 0.7, p < 0.001). Serum concentrations of I-FABP, LPS and IL-6 were similar at baseline (p > 0.05). Serum I-FABP and IL-6 concentrations increased from baseline to post-trial in RUN (I-FABP: 797 ± 467 pg/ml vs 1801 ± 1432 pg/ml, p = 0.007; IL-6: 4.3 ± 3.4 pg/ml vs 9.3 ± 5.4 pg/ml, p < 0.001) and WALK (I-FABP: 772 ± 460 pg/ml vs 1121 ± 966 pg/ml, p = 0.044; IL-6: 4.5 ± 4.1 pg/ml vs 9.1 ± 8.5 pg/ml, p = 0.004) but not in PaH (I-FABP: 888 ± 572 pg/ml vs 893 ± 550 pg/ml, p = 0.935; IL-6: 5.3 ± 5.4 pg/ml vs 5.5 ± 5.2 pg/ml, p = 0.285). No differences in post-trial serum LPS concentrations were observed (p = 0.337). CONCLUSION: Hyperthermia alone may be insufficient to trigger changes in gastrointestinal permeability. Disruptions to gastrointestinal integrity during exertional hyperthermia may instead be exercise-induced, stemming from mechanical and metabolic stress arising from physical exertion. Supported by NUS Internal Research Funding

Improving Aqueous Solubility and In Vitro Pharmacokinetic Properties of the 3-Nitroimidazo[1,2-a]pyridine Antileishmanial Pharmacophore.

An antileishmanial structure–activity relationship (SAR) study focused on positions 2 and 8 of the imidazo[1,2-a]pyridine ring was conducted through the synthesis of 22 new derivatives. After being screened on the promatigote and axenic amastigote stages of Leishmania donovani and L. infantum, the best compounds were tested against the intracellular amastigote stage of L. infantum and evaluated regarding their in vitro physicochemical and pharmacokinetic properties, leading to the discovery of a new antileishmanial6-chloro-3-nitro-8-(pyridin-4-yl)-2-[(3,3,3-trifluoropropylsulfonyl)methyl]imidazo[1,2-a]pyridine hit. It displayed low cytotoxicities on both HepG2 and THP1 cell lines (CC50 > 100 µM) associated with a good activity against the intracellular amastigote stage of L. infantum (EC50 = 3.7 µM versus 0.4 and 15.9 µM for miltefosine and fexinidazole, used as antileishmanial drug references). Moreover, in comparison with previously reported derivatives in the studied series, this compound displayed greatly improved aqueous solubility, good mouse microsomal stability (T1/2 > 40 min) and high gastrointestinal permeability in a PAMPA model, making it an ideal candidate for further in vivo studies on an infectious mouse model.

Physicochemical characteristics and in vitro bioavailability of licorice (Glycyrrhiza glabra L.) extract complexed using cyclic glucans

Licorice extract (LE), whose main ingredient is glabridin (GL), have various biological properties such as antioxidant and anticancer activities, however, their low solubility and bioavailability limit their application in the pharmaceutical and food industries. In this study, inclusion complexes (ICs) were developed using β-cyclodextrin (CD), 2-hydroxypropyl-β-cyclodextrin (HP), and cycloamylose (CA) to overcome the application limits of LE. The IC with cyclic glucans successfully enhanced the phase solubility of LE, and the stoichiometry of the complexes was investigated. After in vitro digestion, the bioaccessibility (% retention) of LE increased significantly in the IC samples, particularly with CA, compared to free LE. In vitro bioavailability, which was assessed using the results of bioaccessibility via the simulated gastrointestinal tract (GIT) model and permeability via Caco-2 monolayer assay, increased 2.5, 2.3, and 4.7-fold in the CD, HP, and CA ICs, respectively. This study provides a promising strategy to overcome the application limits of LE in various industries.

Nanocrystals as an effective strategy to improve Pomalidomide bioavailability in rodent

Pomalidomide (POM) is an FDA-approved immunomodulatory imide drug (IMiDs) an it is effectively used in the treatment of multiple myeloma. IMiDs are analogs of the drug thalidomide and they have been repurposed for the treatment of several diseases such as psoriatic arthritis and Kaposi Sarcoma. In recent years, IMiDs have been also evaluated as a new treatment for neurological disorders with an inflammatory and neuroinflammatory component. POM draws particular interest for its potent anti-TNF-α activity at significantly lower concentrations than the parent compound thalidomide. However, POM’s low water solubility underpins its low gastrointestinal permeability resulting in irregular and poor absorption. The purpose of this work was to prepare a POM nanocrystal-based formulation that could efficiently improve POM’s plasma and brain concentration after intraperitoneal injection. POM nanocrystals prepared as a nanosuspension by the media milling method showed a mean diameter of 219 nm and a polydispersity index of 0.21. POM’s nanocrystal solubility value (22.97 µg/mL) in phosphate buffer was about 1.58 folds higher than the POM raw powder. Finally, in vivo studies conducted in adult Male Sprague-Dawley rats indicated that POM nanocrystal ensured higher and longer-lasting drug levels in plasma and brain when compared with POM coarse suspension.

Effects of mixed Eimeria challenge on performance, body composition, intestinal health, and expression of nutrient transporter genes of Hy-Line W-36 pullets (0-6 wks of age)

A study was aimed to investigate the effects of mixed Eimeria challenge on performance, gastrointestinal health, oxidative stress, inflammation, and expression of nutrient transporter genes of Hy-Line W-36 pullets. A total of 540, 16-d old pullets were randomly allocated into 5 treatment groups with 6 replicate cages, including a nonchallenged control group. A mixed Eimeria species solution containing 50,000 E. maxima, 50,000 E. tenella, and 250,000 E. acervulina oocysts per mL was prepared and challenged to one group as a high-dose treatment (High). The 2-fold serial dilution was done to prepare the medium-high (Med-High: 25,000 E. maxima; 25,000 E. tenella; and 125,000 E. acervulina), the medium-low (Med-Low: 12,500 E. maxima; 12,500 E. tenella; and 62,500 E. acervulina), and the low (Low: 6,250 E. maxima; 6,250 E. tenella; and 31,250 E. acervulina) dose treatments, and these dosages were challenged to 3 remaining groups, respectively. Growth performance, daily feed intake (FI), and mortality were calculated from 0-14 d postinfection (DPI). Gastrointestinal permeability (GP) was measured on 3, 5, 6, 7, and 9 DPI. The result indicated significant linear responses to the Eimeria challenge dosage in average body weight and body weight gain (P < 0.0001). An interaction between treatment and DPI was observed for FI (P < 0.0001). Feed intake significantly dropped from 4 DPI and did not recover until 12 DPI in the challenged groups. The lowest FI for each of the challenged groups was observed on 5 DPI. Gastrointestinal permeability increased linearly, peaking at 5 DPI, and was recovered back to normal by 9 DPI in the challenged groups. Furthermore, gene expression of tight junction proteins was linearly upregulated by increased Eimeria dosages. The oxidative status of the pullets was lowered in the challenged groups than the nonchallenged control group, whereas the expression of inflammatory and proinflammatory cytokines was upregulated by Eimeria challenge on 6 DPI (P < 0.05). The highest mortality was observed in pullets challenged with the High, followed by the Med-High (P < 0.0001) on 5 DPI. In summary, the mixed Eimeria challenge linearly reduced the growth performance of pullets with an increase in oxidative stress and inflammation. A severe effect of Eimeria on gastrointestinal health was observed on 5 or 6 DPI as suggested by GP, tight junction genes, and mortality results. This study indicates that Eimeria infection can be a threat to gastrointestinal health related issues in pullets.

Anthocyanin-Rich Blackcurrant Extract Preserves Gastrointestinal Barrier Permeability and Reduces Enterocyte Damage but Has No Effect on Microbial Translocation and Inflammation After Exertional Heat Stress.

This study investigated the effects of 7days of 600mg/day anthocyanin-rich blackcurrant extract intake on small intestinal permeability, enterocyte damage, microbial translocation, and inflammation following exertional heat stress. Twelve recreationally active men (maximal aerobic capacity = 55.6 ± 6.0ml·kg-1·min-1) ran (70% VO2max) for 60min in an environmental chamber (34°C, 40% relative humidity) on two occasions (placebo/blackcurrant, randomized double-blind crossover). Permeability was assessed from a 4-hr urinary excretion of lactulose and rhamnose and expressed as a ratio of lactulose/rhamnose. Venous blood samples were taken at rest and 20, 60, and 240min after exercise to measure enterocyte damage (intestinal fatty acid-binding protein); microbial translocation (soluble CD14, lipopolysaccharide-binding protein); and interleukins 6, interleukins 10, and interleukins 1 receptor antagonist. Exercise increased rectal temperature (by ∼2.8°C) and heart rate (by ∼123 beats/min) in each condition. Blackcurrant supplementation led to a ∼12% reduction in lactulose/rhamnose ratio (p < .0034) and enterocyte damage (∼40% reduction in intestinal fatty acid-binding protein area under the curve; p < .0001) relative to placebo. No between-condition differences were observed immediately after exercise for lipopolysaccharide-binding protein (mean, 95% confidence interval [CI]; +80%, 95% CI [+61%, +99%]); soluble CD14 (+37%, 95% CI [+22%, +51%]); interleukins 6 (+494%, 95% CI [+394%, +690%]); interleukins 10 (+288%, 95% CI [+105%, +470%]); or interleukins 1 receptor antagonist (+47%, 95% CI [+13%, +80%]; all time main effects). No between-condition differences for these markers were observed after 60 or 240min of recovery. Blackcurrant extract preserves the GI barrier; however, at subclinical levels, this had no effect on microbial translocation and downstream inflammatory processes.

Lactose hydrate can increase the transcellular permeability of β-naphthol in rat jejunum and ileum.

The unstirred water layer (UWL) is an integral part of the apical surface of mucosal epithelia and comprises mucins (MUC), for which there are many molecular species. Galectins, a family of β-galactoside-bindinglectins, form a lattice barrier on surface epithelial cells by interacting with MUC. Lactose inhibits the galectin-MUC interaction. Therefore, the present study investigated the galectin-MUC interaction in the mucosa of the gastrointestinal tract and its role in intestinal barrier functions. The effects of lactose hydrate (LH) on the membrane permeability of the rat small intestine and Caco-2 cells were examined. LH enhanced the membrane permeability of the rat small intestine, which contains the UWL, via a transcellular route, for which the UWL is the rate limiting factor. The membrane permeability of Caco-2 cells, in which the UWL is insufficient, was not affected by LH. The apparent permeability coefficient (Papp) of a paracellular marker was not significantly altered in the rat small intestine or Caco-2 cells treated with LH at any concentration. Furthermore, the Papp of β-naphthol which is a transcellular marker was not significantly altered in Caco-2 cells treated with LH, but was significantly increased in the rat small intestine in a LH concentration-dependent manner. The present results demonstrate that the physical barrier has an important function in gastrointestinal membrane permeability, and LH-induced changes increase the transcellular permeability of β-naphthol in rat small intestine.

Low cerebrospinal fluid-to-plasma ratios of orally administered lenalidomide mediated by its low cell membrane permeability in patients with hematologic malignancies.

Lenalidomide is a synthetic analog of thalidomide formed by the removal of one keto group (plus the addition of an amino group); it has anti-tumor activities beneficial for the treatment of hematologic malignancies. However, lenalidomide distribution to brain in animal models is reportedly low compared with that of thalidomide. The aim of this study was to evaluate plasma and cerebrospinal fluid concentrations of lenalidomide in three patients with malignant hematologic malignancies. Lenalidomide was detected in plasma from the three Japanese patients 1.5h following oral administration of 20mg lenalidomide using liquid chromatography/mass spectrometry, despite the in vitro gastrointestinal permeability of lenalidomide being low. Clinically observed cerebrospinal fluid-to-plasma ratios of lenalidomide were low (1.3-2.4%). Observed influx permeability values for lenalidomide in monkey blood-brain barrier model and human placental cell systems were one order of magnitude lower than those of thalidomide and another second-generation drug, pomalidomide along with a positive permeability control, caffeine. Because of the low cell-barrier permeability of lenalidomide demonstrated in in vitro assays, clinically relevant pharmacokinetic profiles of lenalidomide resulted in low penetrability from plasma into cerebrospinal fluid in patients with hematologic malignancies. Lenalidomide is conclusively suggested to expert its favorable immunomodulatory effects via systemic exposures in the patients.

Resistance Exercise Increases Gastrointestinal Symptoms, Markers of Gut Permeability, and Damage in Resistance-Trained Adults.

This study aimed to determine the influence of acute resistance exercise (RE) and biological sex on subjective gastrointestinal (GI) symptoms, GI epithelial damage, and GI permeability in resistance-trained males and females. Thirty resistance-trained men ( n = 15) and women ( n = 15) completed an RE bout and a nonexercise control (CON) session in a randomized counterbalanced design. The RE protocol used a load of 70% one-repetition maximum for 4 sets of 10 repetitions with a 90-s rest period length between sets and a 120-s rest period between exercises (squat, seated shoulder press, deadlift, bent-over row, and leg press). Blood samples were collected before exercise (PRE), immediately postexercise (IP), and 15-, 30-, and 60-min postexercise. Participants completed GI symptom questionnaires to assess subjective GI symptoms PRE, IP, and 60-min postexercise. Blood samples were assayed to quantify small intestine damage (I-FABP) and GI permeability (lactulose-rhamnose [L/R] ratio). Data were analyzed via separate repeated-measures ANOVA, and area under the curve (AUC) analyses were completed via one-way ANOVA. Participants reported greater GI symptoms in RE at IP compared with CON ( P < 0.001) with 70% of participants reporting at least one GI symptom with no differences between sexes. Nausea was the most reported GI symptom (63.3%), followed by vomiting (33.3%). I-FABP and L/R ratio did not exhibit differential responses between conditions. However, L/R ratio AUC was greater in males after RE than male CON ( P = 0.002) and both conditions for females ( P < 0.05). Furthermore, I-FABP AUC in the male RE condition was greater than both female conditions ( P < 0.05). Resistance-trained individuals experience GI distress after RE, with males incurring the greatest increases in markers of GI damage and permeability.

Update on Food Protein-Induced Enterocolitis Syndrome (FPIES).

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by delayed, and potentially severe, gastrointestinal symptoms. Since the advent of a specific diagnostic code and establishment of diagnostic guidelines, our understanding of this condition has grown. FPIES affects patients from early infancy into adulthood. Any food can be a trigger, and common culprit foods vary geographically and by age. An understanding of the complex underlying immune mechanisms remains elusive, although studies show pan-leukocyte activation, cytokine release, and increased gastrointestinal permeability. Management involves trigger avoidance, and patients may benefit from the support of a dietitian to ensure adequate nutrient intake. Tolerance develops over time for most children, but due to the risk of severe symptoms, re-introduction of a suspected FPIES trigger is recommended only under supervision at an oral food challenge. Studies continue to evaluate the optimal challenge protocol. Caregivers of children with FPIES report high levels of anxiety and stress, which is attributed to the dramatic symptomatology, dietary restrictions, nutritional concerns, lack of confirmatory diagnostic tests, and limited tools for management of reactions. Our understanding of the FPIES diagnosis has improved over the last few decades, but there remain opportunities, particularly regarding discerning the pathophysiology and best management practices.

A systematic review: Role of dietary supplements on markers of exercise-associated gut damage and permeability.

Nutrition strategies and supplements may have a role to play in diminishing exercise associated gastrointestinal cell damage and permeability. The aim of this systematic review was to determine the influence of dietary supplements on markers of exercise-induced gut endothelial cell damage and/or permeability. Five databases were searched through to February 2021. Studies were selected that evaluated indirect markers of gut endothelial cell damage and permeability in response to exercise with and without a specified supplement, including with and without water. Acute and chronic supplementation protocols were included. Twenty-seven studies were included. The studies investigated a wide range of supplements including bovine colostrum, glutamine, probiotics, supplemental carbohydrate and protein, nitrate or nitrate precursors and water across a variety of endurance exercise protocols. The majority of studies using bovine colostrum and glutamine demonstrated a reduction in selected markers of gut cell damage and permeability compared to placebo conditions. Carbohydrate intake before and during exercise and maintaining euhydration may partially mitigate gut damage and permeability but coincide with other performance nutrition strategies. Single strain probiotic strains showed some positive findings, but the results are likely strain, dosage and duration specific. Bovine colostrum, glutamine, carbohydrate supplementation and maintaining euhydration may reduce exercise-associated endothelial damage and improve gut permeability. In spite of a large heterogeneity across the selected studies, appropriate inclusion of different nutrition strategies could mitigate the initial phases of gastrointestinal cell disturbances in athletes associated with exercise. However, research is needed to clarify if this will contribute to improved athlete gastrointestinal and performance outcomes.

Preterm Delivery: Microbial Dysbiosis, Gut Inflammation and Hyperpermeability

Preterm birth is one of the main health problems encountered in the neonatal period, especially because it is also the first cause of death in the critical 1st month of life and the second in children under 5 years of age. Not only preterm birth entails short term health risks due to low weight and underdeveloped organs, but also increases the risk of suffering from non-transmissible diseases in the long term. To date, it is known that medical conditions and lifestyle factors could increase the risk of preterm birth, but the molecular mechanisms that control this process remain unclear. Luteolysis, increased inflammation or oxidative stress have been described as possible triggers for preterm birth and, in some cases, the cause of dysbiosis in preterm neonates. Several murine models have been developed to shed light into the mechanistic of preterm birth but, for the most part, are inflammation-based labor induction models and the offspring health readouts are mainly limited to survival and weight. Using a set of SWISS-CD1 mice born prematurely we analyzed inflammation and gut permeability parameters compared with term pups at weaning age. Overall, preterm mice presented higher systemic inflammation and gastrointestinal tract permeability. In this perspective article, we discuss the recent discoveries on preterm birth and the necessity of non-inflammatory murine models to really understand these phenotypes and be able to design strategies to prevent the sequels of this traumatic event in neonates.

Effects of oral cystine and glutamine on exercise-induced changes in gastrointestinal permeability and damage markers in young men

PurposeAlthough acute prolonged strenuous exercise has been shown to increase markers of gastrointestinal permeability and damage, little is known regarding the efficacy of nutritional supplement interventions on the attenuation of exercise-induced gastrointestinal syndrome. This study addressed the effects of oral amino acid supplementation on markers of gastrointestinal permeability and damage in response to exercise.MethodsSixteen active men aged 22.7 ± 2.6 years (mean ± standard deviation) completed placebo or cystine and glutamine supplementation trials in random order. Participants received either a placebo or cystine and glutamine supplements, three times a day for 5 days, separated by a 2-week washout period. On day 6, participants took their designated supplements 30 min before running at a speed corresponding to 75% of maximal oxygen uptake for 1 h, followed by a 4-h rest period. Blood samples were collected pre-exercise, immediately post-exercise, 30 min post-exercise, and 1, 2 and 4 h post-exercise on day 6. The plasma lactulose to mannitol ratio (L:M) and plasma intestinal fatty acid-binding protein (I-FABP) were used as markers of gastrointestinal permeability and damage, respectively.ResultsPlasma L:M (linear mixed model, coefficient ± standard error: − 0.011 ± 0.004, P = 0.0090) and changes (i.e., from pre-exercise) in plasma I-FABP (linear mixed model, − 195.3 ± 65.7 coefficient ± standard error (pg/mL), P = 0.0035) were lower in the cystine and glutamine supplementation trial than in the placebo trial.ConclusionOral cystine and glutamine supplementation attenuated the markers of gastrointestinal permeability and damage after 1 h of strenuous running in young men.Trial registration numberUMIN000026008.Date of registration13 December 2018.