RESUMEN
Indole3propionic acid (IPA), a product of Clostridium sporogenes metabolism, has been shown to improve intestinal barrier function. In the present study, in vitro experiments using NCM460 human colonic epithelial cells were performed to investigate how IPA alleviates lipopolysaccharide (LPS)induced intestinal epithelial cell injury, with the aim of improving intestinal barrier function. In addition, the underlying mechanism was explored. NCM460 cell viability and apoptosis were measured using the Cell Counting Kit8 assay and flow cytometry, respectively. The integrity of the intestinal epithelial barrier was evaluated by measuring transepithelial electrical resistance (TEER). The underlying molecular mechanism was explored using western blotting, immunofluorescence staining, a dual luciferase reporter gene assay and quantitative PCR. The results showed that 10 µg/ml LPS induced the most prominent decrease in cell viability after 24 h of treatment. By contrast, IPA effectively inhibited LPSinduced apoptosis in the intestinal epithelial cells. Additionally, >0.5 mM IPA improved intestinal barrier function by increasing TEER and upregulating the expression of tight junction proteins (zonula occludens1, claudin1 and occludin). Furthermore, IPA inhibited the release of proinflammatory cytokines (IL1ß, IL6 and TNFα) in a dosedependent manner and this was achieved via regulation of the Tolllike receptor 4 (TLR4)/myeloid differentiation factor 88/NFκB and TLR4/TRIF/NFκB pathways. In conclusion, IPA may alleviate LPSinduced inflammatory injury in human colonic epithelial cells. Taken together, these results suggest that IPA may be a potential therapeutic approach for the management of diseases characterized by LPSinduced intestinal epithelial cell injury and intestinal barrier dysfunction.
Asunto(s)
Apoptosis , Células Epiteliales , Indoles , Mucosa Intestinal , Lipopolisacáridos , FN-kappa B , Transducción de Señal , Receptor Toll-Like 4 , Humanos , Receptor Toll-Like 4/metabolismo , FN-kappa B/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Lipopolisacáridos/efectos adversos , Indoles/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Funcion de la Barrera IntestinalRESUMEN
This single blind placebo-controlled study has as its main objectives to investigate the influence of dark sweet cherries (DSC) consumption on obesity-related dysbiosis, metabolic endotoxemia, and intestinal permeability. Participants (>18 years old, BMI: 30-40 kg m-2) consumed 200 mL of DSC juice with 3 g of DSC powder (n = 19) or a placebo drink (n = 21) twice per day for 30 days. The gut microbiota abundance was investigated using 16S ribosomal RNA sequencing on fecal DNA. Metabolic endotoxemia was evaluated by measuring lipopolysaccharide-binding protein (LBP) in fasting plasma samples. Intestinal permeability was assessed using the lactulose/mannitol (L/M) test and by measuring regeneration islet-derived protein 4 (REG4), and interleukin-22 (IL-22) mRNA levels in stool samples. Results showed that DSC supplementation decreased the abundance of Anaerostipes hadrus (p = 0.02) and Blautia (p = 0.04), whose changes were significant in BMI ≥ 35 participants (p = 0.004 and p = 0.006, respectively). Additionally, DSC prevented the increase of Alistipes shahii (p = 0.005) and Bilophila (p = 0.01) compared to placebo. Notably, DSC intervention favored the abundance of bacteria supporting a healthy gut ecosystem such as Roseburia intestinalis (p = 0.01), Turicibacter (p = 0.01), and Bacteroides vulgatus (p = 0.003) throughout the intervention, along with Clostridium leptum (p = 0.03) compared to placebo. The LBP, L/M ratio, REG-4 and IL-22 mRNA levels remained unchanged in placebo and cherry groups, implying that participants did not experience alterations in intestinal permeability. These findings highlight the potential gut-health benefits of DSC and encourage future research among individuals with BMI ≥ 35 and increased intestinal permeability.
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Suplementos Dietéticos , Endotoxemia , Heces , Microbioma Gastrointestinal , Obesidad , Permeabilidad , Prunus avium , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Heces/microbiología , Obesidad/microbiología , Obesidad/metabolismo , Obesidad/dietoterapia , Adulto , Femenino , Persona de Mediana Edad , Método Simple Ciego , Interleucina-22 , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Mucosa Intestinal/metabolismo , Adulto Joven , Funcion de la Barrera IntestinalRESUMEN
Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D in-vitro Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.
Asunto(s)
Tamaño de la Partícula , Permeabilidad , Solubilidad , Telmisartán , Telmisartán/administración & dosificación , Telmisartán/farmacocinética , Telmisartán/química , Humanos , Células CACO-2 , Composición de Medicamentos/métodos , Absorción Intestinal/efectos de los fármacos , Polvos/química , Concentración de Iones de Hidrógeno , Nanopartículas/química , Química Farmacéutica/métodos , Liberación de Fármacos , Funcion de la Barrera IntestinalRESUMEN
Obesity is often associated with sex-dependent metabolic complications, in which altered intestinal barrier function and gut microbiota contribute. We aimed to characterize in mice the sex-dependent effects of a high fat diet on these parameters. Male and female C57BL/6 mice received a standard (SD) or high fat diet (HFD; 60% kcal from fat) during 14 weeks (W14). Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic expression of 44 genes encoding factors involved in inflammatory response and gut barrier function, cecal microbiota, plasma adipokines and white adipose tissue response have been assessed. Both male and female HFD mice exhibited an increase of body weight and fat mass gain and glucose intolerance compared to SD mice. However, only male HFD mice tended to develop insulin resistance associated to increased Tnfα and Ccl2 mRNA expression in perigonadal adipose tissue. By contrast, only female HFD mice showed significant intestinal hyperpermeability that was associated with more markedly altered colonic inflammatory response. Cecal microbiota richness was markedly reduced in both sexes (Observed species) with sex-dependent modifications at the phyla or family level, e.g. decreased relative abundance of Bacillota and Lachnospiraceae in females, increased of Bacteroidaceae in males. Interestingly, some of these microbiota alterations were correlated with peripheral metabolic and inflammatory markers. In conclusions, male and female mice exhibit different responses to a high fat diet with specific changes of gut microbiota, intestinal barrier function, colonic and white adipose tissue inflammation, metabolic markers and body weight gain. The underlying mechanisms should be deciphered in further investigations.
Asunto(s)
Dieta Alta en Grasa , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Masculino , Ratones , Resistencia a la Insulina , Enfermedades Metabólicas/microbiología , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/metabolismo , Obesidad/microbiología , Obesidad/metabolismo , Factores Sexuales , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Permeabilidad , Tejido Adiposo Blanco/metabolismo , Peso Corporal , Funcion de la Barrera IntestinalRESUMEN
BACKGROUND: Older subjects are at risk of elevated intestinal permeability (IP) which can lead to immune system activation and low-grade systemic inflammation. Dietary changes are a potential strategy to reduce IP. The MaPLE project evaluated the hypothesis that increasing (poly)phenol intake would beneficially impact on several important markers and pathways related to IP. The objective of the present study was to assess the effects of the MaPLE (poly)phenol-rich diet (PR-diet) on additional IP-related biomarkers and any relationships between biomarker responses. METHODS: A randomised, controlled, crossover study was performed involving 51 participants (≥ 60 y) with increased IP, as determined by serum zonulin levels. Participants were randomly assigned to one of two intervention groups: a control diet (C-diet) or a PR-diet. Each intervention lasted 8 weeks and was separated by an 8-week washout period. For the present study, serum and faecal samples were used to measure zonula occludens-1 (ZO-1), occludin, adiponectin, calprotectin, faecal calprotectin, soluble cluster of differentiation 14 (sCD14), interleukin-6 receptor (IL-6R), and vascular endothelial-cadherin (VEC) levels using quantitative ELISA assays. Data were analysed using ANOVA, and Spearman and network correlation analysis were performed to identify the relationship among biomarkers at baseline. RESULTS: Among the different markers analysed, a significant reduction was observed for faecal and serum calprotectin (p = 0.0378 and p = 0.0186, respectively) following the PR-diet, while a significant increase in ZO-1 was found (p = 0.001) after both the intervention periods (PR-diet and C-diet). In addition, a time effect was observed for VEC levels showing a reduction (p = 0.038) following the PR-diet. Based on network correlation analysis, two clusters of correlations were identified: one cluster with high levels of serum calprotectin, faecal calprotectin, sCD14, interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP) and bacterial DNAemia (16 S rRNA gene copies), with potential inflammatory-induced intestinal permeability. Differently, the other cluster had high levels of serum occludin, IL-6R, soluble intercellular adhesion molecule-1 (sICAM-1) and VEC, with potential inflammatory-induced endothelial dysfunction. CONCLUSIONS: Overall, this study provides further support to the hypothesis that a (poly)phenol-rich diet may help to ameliorate intestinal permeability-associated conditions. In this regard, calprotectin might represent a promising biomarker since it is a protein that typically increases with age and it is considered indicative of intestinal and systemic inflammation. Further research is needed to develop targeted (poly)phenol-rich diets against age-related gut dysfunction and inflammation. TRIAL REGISTRATION: 28/04/2017; ISRCTN10214981; https://doi.org/10.1186/ISRCTN10214981 .
Asunto(s)
Estudios Cruzados , Heces , Complejo de Antígeno L1 de Leucocito , Permeabilidad , Polifenoles , Humanos , Masculino , Femenino , Anciano , Complejo de Antígeno L1 de Leucocito/análisis , Complejo de Antígeno L1 de Leucocito/sangre , Heces/química , Polifenoles/farmacología , Polifenoles/administración & dosificación , Persona de Mediana Edad , Biomarcadores/sangre , Mucosa Intestinal/metabolismo , Dieta/métodos , Anciano de 80 o más Años , Funcion de la Barrera IntestinalRESUMEN
Diacylglycerol O-acyltransferase 1 (DGAT1) is a key enzyme for fat absorption step in the enterocytes. We previously reported that DGAT1 inhibition increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in corn oil-loaded rats via protein kinase C (PKC) activation. In the present study, we investigated the mechanism with respect to the morphology and permeability of the small intestine, focusing on PKC function, and found that shortening of the intestinal villi and a decrease in the number of tdT-mediated dUTP-biotin nick-end labeling-positive cells in the tips of the villi were observed in the jejunum of DGAT1 inhibitor-treated rats loaded with corn oil. These results suggested that the tips of the villi were shed into the intestinal lumen. Next, fluorescein isothiocyanate-dextran, 110â¯kDa (FD-110) was administered intraduodenally to DGAT1 inhibitor-treated rats loaded with corn oil and we found that plasma FD-110 concentrations increased, indicating that the intestinal permeability to molecules with a molecular weight of approximately 110,000 (e.g., ALT and AST) increased. Taken together, the present results suggested that DGAT1 inhibitor-treatment in combination with corn oil causes ALT and AST to leak from the enterocytes into the blood by shedding the tips of the intestinal villi and increasing intestinal permeability.
Asunto(s)
Alanina Transaminasa , Aspartato Aminotransferasas , Aceite de Maíz , Diacilglicerol O-Acetiltransferasa , Mucosa Intestinal , Permeabilidad , Animales , Alanina Transaminasa/sangre , Masculino , Aspartato Aminotransferasas/sangre , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diacilglicerol O-Acetiltransferasa/metabolismo , Permeabilidad/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Ratas , Dextranos , Proteína Quinasa C/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Fluoresceína-5-Isotiocianato/análogos & derivados , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Absorción Intestinal/efectos de los fármacos , Ratas Sprague-Dawley , Ratas Wistar , Funcion de la Barrera IntestinalRESUMEN
Cerebral palsy (CP) results in non-progressive damage to the central nervous system, leading to functional disorders of the gastrointestinal tract and requiring enteral nutrition via gastrostomy in some patients. The aim of the study was to assess the impact of enteral nutrition on intestinal inflammation expressed by stool calprotectin and intestinal permeability determined by fecal zonulin and IFABP, and to determine whether CP affects these parameters. The study group consisted of 30 children with CP, fed enterally (Cerebral Palsy Enteral Nutrition-CPEN), and two reference groups: 24 children with CP, fed orally with a standard diet (CPC-Cerebral Palsy Controls) and 24 healthy children (HC-healthy controls). The differences between these groups and between the combined CP groups (CPG and CPEN + CPC) and HC were analyzed. Fecal zonulin, calprotectin, and intestinal fatty acid-binding protein 2 (IFABP2) levels were determined by ELISA. The concentrations of fecal calprotectin and zonulin were significantly higher in the CPEN group than in the CPC group (p = 0.012, p = 0.025). When comparing the CPG (n = 53) with the HC group (n = 24), statistically significant differences were observed for calprotectin (p = 0.000018, higher in the CPG) and IFABP (p = 0.021, higher in HC). Enteral nutrition was associated in our cohort with increased fecal calprotectin and zonulin. Children with cerebral palsy presented with increased fecal calprotectin but not increased intestinal permeability expressed by stool zonulin.
Asunto(s)
Biomarcadores , Parálisis Cerebral , Toxina del Cólera , Nutrición Enteral , Heces , Haptoglobinas , Funcion de la Barrera Intestinal , Complejo de Antígeno L1 de Leucocito , Precursores de Proteínas , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios de Casos y Controles , Parálisis Cerebral/metabolismo , Nutrición Enteral/métodos , Proteínas de Unión a Ácidos Grasos/metabolismo , Heces/química , Haptoglobinas/metabolismo , Inflamación , Mucosa Intestinal/metabolismo , Intestinos , Complejo de Antígeno L1 de Leucocito/análisis , Complejo de Antígeno L1 de Leucocito/metabolismo , Precursores de Proteínas/metabolismoRESUMEN
This study investigated the effect of Lacticaseibacillus rhamnosus LRa05 on alcoholic fatty liver disease (ALD) and its mechanism for liver protection. Mice were randomly divided into three groups: a control (CLT) group, an ALD group, and a LRa05 intervention group. The ALD mouse model was established by Lieber-DeCarli chronic alcohol feeding. Tissues staining, enzyme-linked immunosorbent assay (ELISA) was performed to detect changes in histopathology and inflammatory cytokines, respectively. Moreover, intestinal permeability was evaluated by the level of dextran-fluorescein isothiocyanate (Dx-FITC) in serum and tight junction protein in the colon. Changes in the composition of the gut microbiota were assessed by 16S rRNA sequencing. Alcohol consumption induced liver damage in mice with significantly increased levels of triglycerides (TG), aspartate aminotransferase (AST), alanine transaminase (ALT), and inflammatory cytokines. Moreover, alcohol further induced the increase of intestinal permeability and disruption of gut microbiota in mice, with an increase in the relative abundance of potentially pathogenic bacteria Enterococcus, Parabacteroides, and Alistipes. LRa05 intervention significantly attenuated alcohol-induced liver injury by reducing the contents of TG, ALT, and AST, and suppressing the inflammatory responses. Meanwhile, by stimulating the expression of ZO-1, Occludin, and Claudin in the colon tissue, LRa05 additionally strengthened the intestine barrier function. Furthermore, gut microbiota analysis suggested that LRa05 partially ameliorated gut microbiota disorders in ALD mice and up-regulated the abundance of Desulfovibrio and Akkermansia, which were negatively correlated with the indicators of ALD progression. The reconstructive effects of LRa05 on the gut microbiota might be related to the efficacy of LRa05 in improving gut permeability and further protecting against ALD.
Asunto(s)
Modelos Animales de Enfermedad , Hígado Graso Alcohólico , Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Permeabilidad , Probióticos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Permeabilidad/efectos de los fármacos , Probióticos/administración & dosificación , Probióticos/farmacología , Probióticos/uso terapéutico , Hígado Graso Alcohólico/tratamiento farmacológico , Lacticaseibacillus rhamnosus/fisiología , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/metabolismo , Citocinas/metabolismo , Ratones Endogámicos C57BL , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Triglicéridos/sangre , Triglicéridos/metabolismo , Colon/microbiología , Colon/patología , Colon/efectos de los fármacos , Funcion de la Barrera IntestinalRESUMEN
BACKGROUND: The invasion of luminal antigens and an aberrant immune response resulting from a disrupted physical epithelial barrier are the key characteristics of ulcerative colitis (UC). The restoration of damaged epithelial function is crucial for maintaining mucosal homeostasis and disease quiescence. Current therapies for UC primarily focus on suppressing inflammation. However, most patients fail to respond to therapy or develop secondary resistance over time, emphasizing the need to develop novel therapeutic targets for UC. Our study aimed to identify the potential targets of a novel modified herbal formula from the Zhen Wu Decoction, namely CDD-2103, which has demonstrated promising efficacy in treating chronic colitis. METHODS: The effect of CDD-2103 on epithelial barrier function was examined using in vitro and ex vivo models of tissue injury, as well as a chronic colitis C57BL/6 mouse model. Transcriptomic analysis was employed to profile gene expression changes in colonic tissues following treatment with CDD-2103. RESULTS: Our in vivo experiments demonstrated that CDD-2103 dose-dependently reduced disease severity in mice with chronic colitis. The efficacy of CDD-2103 was mediated by a reduction in goblet cell loss and the enhancement of tight junction protein integrity. Mechanistically, CDD-2103 suppressed epithelial cell apoptosis and tight junction protein breakdown by activating the soluble guanynyl cyclase (sGC)-mediated cyclic guanosine monophosphate (cGMP)/PKG signaling cascade. Molecular docking analysis revealed strong sGC ligand recognition by the CDD-2103-derived molecules, warranting further investigation. CONCLUSION: Our study revealed a novel formulation CDD-2103 that restores intestinal barrier function through the activation of sGC-regulated cGMP/PKG signaling. Furthermore, our findings suggest that targeting sGC can be an effective approach for promoting mucosal healing in the management of UC.
Asunto(s)
Proteínas Quinasas Dependientes de GMP Cíclico , GMP Cíclico , Medicamentos Herbarios Chinos , Mucosa Intestinal , Ratones Endogámicos C57BL , Transducción de Señal , Animales , Medicamentos Herbarios Chinos/farmacología , GMP Cíclico/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Humanos , Modelos Animales de Enfermedad , Guanilil Ciclasa Soluble/metabolismo , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Funcion de la Barrera IntestinalRESUMEN
The therapeutic effect of 5-amino salicylic acid (5-ASA), a first-line therapeutic agent for the treatment of ulcerative colitis (UC), is limited by the modest bioavailability afforded by its oral administration. In this study, a 5-ASA oral delivery system was developed using Eudragit S100-coated iron oxide-chitosan nanocomposites (ES-IOCS/5-ASA) to address this issue. According to drug release studies in vitro, ES-IOCS/5-ASA only released a small amount of drug in simulated gastric fluid with a pH of 1.2. However, in a medium with a pH of 7.5, a relatively rapid and complete release was noted. 5-ASA-loaded iron oxide-chitosan nanocomposites (IOCS/5-ASA) could be effectively taken up by NCM460 cells and performed better anti-inflammatory effects than free 5-ASA. At the same time, IOCS/5-ASA improved barrier damage in DSS-induced NCM460 cells. In vivo models of dextran sulphate sodium (DSS)-induced colitis were used to assess the therapeutic efficacy of oral administration of ES-IOCS/5-ASA. ES-IOCS/5-ASA significantly relieved DSS-induced colitis and enhanced the integrity of the intestinal epithelial barrier. ES-IOCS/5-ASA also reduced the expression of NLRP3, ASC and IL-1ß. Additionally, iron oxide nanoparticles used as nanozymes could alleviate inflammation. In summary, this study indicates that ES-IOCS/5-ASA exert anti-inflammatory effects on DSS-induced colitis by improving intestinal barrier function and inhibiting NLRP3 inflammasome expression, presenting a viable therapeutic choice for the treatment of UC.
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Quitosano , Colitis Ulcerosa , Colon , Inflamasomas , Mesalamina , Proteína con Dominio Pirina 3 de la Familia NLR , Nanocompuestos , Ácidos Polimetacrílicos , Quitosano/química , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Mesalamina/uso terapéutico , Mesalamina/farmacología , Mesalamina/administración & dosificación , Mesalamina/química , Colitis Ulcerosa/tratamiento farmacológico , Inflamasomas/metabolismo , Nanocompuestos/química , Humanos , Ácidos Polimetacrílicos/química , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Ratones , Compuestos Férricos/química , Sulfato de Dextran , Línea Celular , Ratones Endogámicos C57BL , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Funcion de la Barrera IntestinalRESUMEN
BACKGROUND: The intestinal-liver axis is associated with various liver diseases. Here, we verified the role of the gut microbiota and macrophage activation in the progression of pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome (PA-HSOS), and explored the possible mechanisms and new treatment options. METHODS: The HSOS murine model was induced by gavage of monocrotaline (MCT). An analysis of 16S ribosomal DNA (16S rDNA) of the feces was conducted to determine the composition of the fecal microbiota. Macrophage clearance, fecal microbiota transplantation (FMT), and butyrate supplementation experiments were used to assess the role of intestinal flora, gut barrier, and macrophage activation and to explore the relationships among these three variables. RESULTS: Activated macrophages and low microflora diversity were observed in HSOS patients and murine models. Depletion of macrophages attenuated inflammatory reactions and apoptosis in the mouse liver. Moreover, compared with control-FMT mice, the exacerbation of severe liver injury was detected in HSOS-FMT mice. Specifically, butyrate fecal concentrations were significantly reduced in HSOS mice, and administration of butyrate could partially alleviated liver damage and improved the intestinal barrier in vitro and in vivo. Furthermore, elevated lipopolysaccharides in the portal vein and high proportions of M1 macrophages in the liver were also detected in HSOS-FMT mice and mice without butyrate treatment, which resulted in severe inflammatory responses and further accelerated HSOS progression. CONCLUSIONS: These results suggested that the gut microbiota exacerbated HSOS progression by regulating macrophage M1 polarization via altered intestinal barrier function mediated by butyrate. Our study has identified new strategies for the clinical treatment of HSOS.
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Butiratos , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Enfermedad Veno-Oclusiva Hepática , Hígado , Macrófagos , Animales , Ratones , Butiratos/metabolismo , Macrófagos/inmunología , Masculino , Humanos , Enfermedad Veno-Oclusiva Hepática/microbiología , Hígado/metabolismo , Activación de Macrófagos , Ratones Endogámicos C57BL , Mucosa Intestinal/microbiología , Femenino , Heces/microbiología , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Funcion de la Barrera IntestinalRESUMEN
BACKGROUND: Obesity is associated with low-grade inflammation and increased intestinal permeability (IP). The Brazil nut (BN) (Bertholletia excelsa H.B.K.) appears to be a promising dietary intervention to control inflammation by enhancing antioxidant defenses. OBJECTIVES: We aimed to assess the effect of daily BN consumption on inflammatory biomarkers and IP in the context of an energy-restricted intervention. Furthermore, we evaluated the correlation between the changes in these inflammatory markers and the changes in serum selenium and IP. METHODS: In this 8-wk nonrandomized controlled trial, 56 women with overweight or obesity were allocated into 2 groups, both following an energy-restricted diet (-500 kcal/d). The control group (CO) consumed a nut-free diet, while the BN group consumed 8 g BN/d, providing 347.2 µg selenium (Se). Inflammatory cytokines were analyzed in plasma and Se in serum. IP was assessed using the lactulose/mannitol test (LM ratio). RESULTS: Forty-six women completed the intervention. Both groups achieved similar energy restriction (CO Δ= -253.7 ± 169.4 kcal/d; BN Δ= -265.8 ± 141.8 kcal/d) and weight loss (CO Δ= -2.5 ± 0.5 kg; BN Δ= -3.5 ± 0.5 kg). The BN group showed lower values of C-reactive protein, tumor necrosis factor, interleukin (IL)1-ß, IL-8, percentage lactulose excretion, and LM ratio than the CO group. Additionally, changes in serum Se concentration were predictive of changes in IL-8 concentration (ß: -0.054; adjusted R2: 0.100; 95% confidence interval [CI]: -0.100; -0.007; P = 0.025), and changes in IL-8 were predictive of changes in the LM ratio (ß: 0.006; adjusted R2: 0.101; 95% CI: 0.001, 0.011; P = 0.024). CONCLUSIONS: Regular intake of BNs can be a promising complementary dietary strategy for controlling low-grade inflammation and improving IP in women with overweight/obesity undergoing energy-restricted treatment. However, the effects of BNs seem to be Se status-dependent. This trial was registered at the Brazilian Registry of Clinical Trials (ReBEC: https://ensaiosclinicos.gov.br/rg/RBR-3ntxrm/.
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Bertholletia , Biomarcadores , Obesidad , Sobrepeso , Selenio , Humanos , Femenino , Bertholletia/química , Adulto , Obesidad/dietoterapia , Obesidad/sangre , Biomarcadores/sangre , Sobrepeso/dietoterapia , Sobrepeso/sangre , Persona de Mediana Edad , Selenio/sangre , Inflamación/sangre , Restricción Calórica , Permeabilidad , Brasil , Nueces , Citocinas/sangre , Funcion de la Barrera IntestinalRESUMEN
Miao sour soup (MSS), a daily fermented food in Guizhou, China, is rich in microorganisms with various beneficial activities, including anti-inflammatory and antioxidant activities. However, the therapeutic effects of MSS on IBD remain unexplored. This study aimed to investigate the protective effect of MSS against colitis in mice. In this study, we examined the microbial community structure of MSS by metagenomic sequencing and also explored the protective effect of MSS on DSS-induced colitis in mice. We investigated the effects of MSS on intestinal inflammatory response and intestinal barrier function in mice. Finally, the changes in intestinal flora were analyzed based on the 16S rRNA gene sequencing results. Significantly, the experiment result shows that MSS ameliorated the severity of DSS-induced disease in mice by mitigating colitis-associated weight loss, reducing the disease activity index of IBD, alleviating colonic hemorrhagic lesions, increasing colon length, and improving colonic tissue damage. Moreover, MSS preserved intestinal barrier integrity and restored intestinal epithelial function in mice. Additionally, MSS modulated the structure and composition of the intestinal flora. Furthermore, MSS downregulated pro-inflammatory factors and attenuated the NF-κB p65 expression, thereby mitigating the inflammatory response. These findings highlight the protective effect of MSS against DSS-induced colitis, providing substantial scientific support for potential applications of MSS as a functional food.
Asunto(s)
Colitis , Sulfato de Dextran , Microbioma Gastrointestinal , Mucosa Intestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Colitis/inducido químicamente , Sulfato de Dextran/efectos adversos , Masculino , Mucosa Intestinal/microbiología , Ratones Endogámicos C57BL , Alimentos Fermentados , Modelos Animales de Enfermedad , Colon/microbiología , Colon/metabolismo , ARN Ribosómico 16S/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Funcion de la Barrera IntestinalRESUMEN
A new polysaccharide fraction (ATP) was obtained from Armillariella tabescens mycelium. Structural analysis suggested that the backbone of ATP was â4)-α-D-Glcp(1 â 2)-α-D-Galp(1 â 2)-α-D-Glcp(1 â 4)-α-D-Glcp(1â, which branched at O-3 of â2)-α-D-Glcp(1 â and terminated with T-α-D-Glcp or T-α-D-Manp. Besides, ATP significantly alleviated ulcerative colitis (UC) symptoms and inhibited the production of pro-inflammation cytokines (IL-1ß, IL-6). Meanwhile, ATP could improve colon tissue damage by elevating the expression of MUC2 and tight junction proteins (ZO-1, occludin and claudin-1) levels and enhance intestinal barrier function through inhibiting the activation of MMP12/MLCK/p-MLC2 signaling pathway. Further studies exhibited that ATP could increase the relative abundance of beneficial bacteria such as f. Muribaculacese, g. Muribaculaceae, and g. Alistips, and decrease the relative abundance of g. Desulfovibrio, g. Colidextribacter, g. Ruminococcaceae and g.Oscillibacter, and regulate the level of short-chain fatty acids. Importantly, FMT intervention with ATP-derived microbiome certified that gut microbiota was involved in the protective effects of ATP on UC. The results indicated that ATP was potential to be further developed into promising therapeutic agent for UC.
Asunto(s)
Colitis , Microbioma Gastrointestinal , Polisacáridos , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Ratones , Polisacáridos/farmacología , Polisacáridos/química , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Armillaria/química , Citocinas/metabolismo , Modelos Animales de Enfermedad , Funcion de la Barrera IntestinalRESUMEN
In this study, we investigated the effect of monobutyrin (MB) on the gut microbiota and intestinal health of weaned mice. MB was administered via gavage to 21-day-old weaned mice. Samples of small intestinal and ileal contents were collected on day 1, day 7, and day 21 post-administration. Seven days of MB administration enhanced the mucin layer and morphological structure of the intestine and the integrity of the intestinal brush border. Both MB and sodium butyrate (SB) accelerated tight junction development. Compared to SB, MB modulated intestinal T cells in a distinct manner. MB increased the ratio of Treg cells in the small intestine upon the cessation of weaning. After 21 days of MB administration, enhancement of the villus structure of the ileum was observed. MB increased the proportion of Th17 cells in the ileum. MB facilitated the transition of the small intestinal microbiota toward an adult microbial community structure and enhanced the complexity of the microbial community structure. An increase in Th17 cells enhanced intestinal barrier function. The regulatory effect of MB on Th17 cells may occur through the intestinal microbiota. Therefore, MB can potentially be used to promote intestinal barrier function, especially for weaning animals, with promising application prospects.
Asunto(s)
Microbioma Gastrointestinal , Mucosa Intestinal , Células Th17 , Destete , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Masculino , Ratones Endogámicos C57BL , Íleon/microbiología , Intestino Delgado/microbiología , Intestino Delgado/efectos de los fármacos , Ácido Butírico/farmacología , Ácido Butírico/metabolismo , Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Linfocitos T Reguladores , Funcion de la Barrera IntestinalRESUMEN
ß-glucans found in cereal grains have been previously demonstrated to improve blood glucose control; however, current understanding points to their high viscosity as the primary mechanism of action. In this work, we present a novel, highly soluble, low-viscosity ß-glucan fiber (HS-BG fiber) and a preclinical dataset that demonstrates its impact on two mechanisms related to the prevention of hyperglycemia. Our results show that HS-BG inhibits the activity of two key proteins involved in glucose metabolism, the α-glucosidase enzyme and the SGLT1 transporter, thereby having the potential to slow starch digestion and subsequent glucose uptake. Furthermore, we demonstrate in a multi-donor fecal fermentation model that HS-BG is metabolized by several different members of the gut microbiome, producing high amounts of short-chain fatty acids (SCFAs), known agonists of GPR43 receptors in the gut related to GLP-1 secretion. The production of SCFAs was verified in the translational gut model, SHIME®. Moreover, HS-BG fiber fermentation produces compounds that restored permeability in disrupted epithelial cells, decreased inflammatory chemokines (CXCL10, MCP-1, and IL-8), and increased anti-inflammatory marker (IL-10), which could improve insulin resistance. Together, these data suggest that the novel HS-BG fiber is a promising new functional ingredient that can be used to modulate postprandial glycemic responses while the high solubility and low viscosity enable easy formulation in both beverage and solid food matrices.
Asunto(s)
Glucemia , Fibras de la Dieta , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Permeabilidad , Transportador 1 de Sodio-Glucosa , beta-Glucanos , Fibras de la Dieta/farmacología , beta-Glucanos/farmacología , Glucemia/metabolismo , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Ácidos Grasos Volátiles/metabolismo , Transportador 1 de Sodio-Glucosa/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Fermentación , Solubilidad , Heces/química , Heces/microbiología , Viscosidad , Inhibidores de Glicósido Hidrolasas/farmacología , Hiperglucemia/prevención & control , Funcion de la Barrera IntestinalRESUMEN
Irinotecan use is linked to the development of gastrointestinal toxicity and inflammation, or gastrointestinal mucositis. Selected phytocannabinoids have been ascribed anti-inflammatory effects in models of gastrointestinal inflammation, associated with maintaining epithelial barrier function. We characterised the mucoprotective capacity of the phytocannabinoids: cannabidiol, cannabigerol, cannabichromene and cannabidivarin in a cell-based model of intestinal epithelial stress occurring in mucositis. Transepithelial electrical resistance (TEER) was measured to determine changes in epithelial permeability in the presence of SN-38 (5 µM) or the pro-inflammatory cytokines TNFα and IL-1ß (each at 100 ng/mL), alone or with concomitant treatment with each of the phytocannabinoids (1 µM). The DCFDA assay was used to determine the ROS-scavenging ability of each phytocannabinoid following treatment with the lipid peroxidant tbhp (200 µM). Each phytocannabinoid provided significant protection against cytokine-evoked increases in epithelial permeability. Cannabidiol, cannabidivarin and cannabigerol were also able to significantly inhibit SN-38-evoked increases in permeability. None of the tested phytocannabinoids inhibited tbhp-induced ROS generation. These results highlight a novel role for cannabidiol, cannabidivarin and cannabigerol as inhibitors of SN-38-evoked increases in epithelial permeability and support the rationale for the further development of novel phytocannabinoids as supportive therapeutics in the management of irinotecan-associated mucositis.
Asunto(s)
Cannabidiol , Cannabinoides , Mucosa Intestinal , Irinotecán , Especies Reactivas de Oxígeno , Humanos , Células CACO-2 , Cannabidiol/farmacología , Cannabinoides/farmacología , Citocinas/metabolismo , Interleucina-1beta/metabolismo , Funcion de la Barrera Intestinal , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Irinotecán/farmacología , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Maintaining the mucus layer is crucial for the innate immune system. Urolithin A (Uro A) is a gut microbiota-derived metabolite; however, its effect on mucin production as a physical barrier remains unclear. This study aimed to elucidate the protective effects of Uro A on mucin production in the colon. In vivo experiments employing wild-type mice, NF-E2-related factor 2 (Nrf2)-deficient mice, and wild-type mice treated with an aryl hydrocarbon receptor (AhR) antagonist were conducted to investigate the physiological role of Uro A. Additionally, in vitro assays using mucin-producing cells (LS174T) were conducted to assess mucus production following Uro A treatment. We found that Uro A thickened murine colonic mucus via enhanced mucin 2 expression facilitated by Nrf2 and AhR signaling without altering tight junctions. Uro A reduced mucosal permeability in fluorescein isothiocyanate-dextran experiments and alleviated dextran sulfate sodium-induced colitis. Uro A treatment increased short-chain fatty acid-producing bacteria and propionic acid concentration. LS174T cell studies confirmed that Uro A promotes mucus production through the AhR and Nrf2 pathways. In conclusion, the enhanced intestinal mucus secretion induced by Uro A is mediated through the actions of Nrf-2 and AhR, which help maintain intestinal barrier function.
Asunto(s)
Colitis , Cumarinas , Mucosa Intestinal , Factor 2 Relacionado con NF-E2 , Receptores de Hidrocarburo de Aril , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Ratones , Mucosa Intestinal/metabolismo , Cumarinas/farmacología , Colitis/metabolismo , Colitis/inducido químicamente , Mucina 2/metabolismo , Mucina 2/genética , Humanos , Colon/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Masculino , Microbioma Gastrointestinal , Ratones Noqueados , Sulfato de Dextran , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Funcion de la Barrera IntestinalRESUMEN
Intestinal dysbiosis is believed to play a role in the development of necrotizing enterocolitis (NEC). The efficacy of JNK-inhibitory peptide (CPJIP) in treating NEC was assessed. Treatment with CPJIP led to a notable reduction in p-JNK expression in IEC-6 cells and NEC mice. Following LPS stimulation, the expression of RNA and protein of claudin-1, claudin-3, claudin-4 and occludin was significantly decreased, with this decrease being reversed by CPJIP administration, except for claudin-3, which remained consistent in NEC mice. Moreover, the expression levels of the inflammatory factors TNF-α, IL-1ß and IL-6 were markedly elevated, a phenomenon that was effectively mitigated by the addition of CPJIP in both IEC-6 cells and NEC mice. CPJIP administration resulted in improved survival rates, ameliorated microscopic intestinal mucosal injury, and increased the total length of the intestines and colon in NEC mice. Additionally, CPJIP treatment led to a reduction in serum concentrations of FD-4, D-lactate and DAO. Furthermore, our results revealed that CPJIP effectively inhibited intestinal cell apoptosis and promoted cell proliferation in the intestine. This study represents the first documentation of CPJIP's ability to enhance the expression of tight junction components, suppress inflammatory responses, and rescue intestinal cell fate by inhibiting JNK activation, ultimately mitigating intestinal severity. These findings suggest that CPJIP has the potential to serve as a promising candidate for the treatment of NEC.