RÉSUMÉ
Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.
Sujet(s)
Microbiome gastro-intestinal , Lipopolysaccharides , Facteur de transcription NF-kappa B , Prevotella , Transduction du signal , Calcification vasculaire , Animaux , Humains , Mâle , Rats , Fèces/microbiologie , Inflammasomes/métabolisme , Lipopolysaccharides/métabolisme , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Myocytes du muscle lisse/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/génétique , Ostéogenèse/effets des médicaments et des substances chimiques , Prevotella/métabolisme , Rat Sprague-Dawley , Insuffisance rénale chronique/complications , Insuffisance rénale chronique/microbiologie , Insuffisance rénale chronique/anatomopathologie , Récepteur de type Toll-4/métabolisme , Récepteur de type Toll-4/génétique , Calcification vasculaire/métabolisme , Calcification vasculaire/microbiologie , Calcification vasculaire/anatomopathologieRÉSUMÉ
T-2 toxin is a worldwide problem for feed and food safety, leading to livestock and human health risks. The objective of this study was to explore the mechanism of T-2 toxin-induced small intestine injury in broilers by integrating the advanced microbiomic, metabolomic and transcriptomic technologies. Four groups of 1-day-old male broilers (n = 4 cages/group, 6 birds/cage) were fed a control diet and control diet supplemented with T-2 toxin at 1.0, 3.0, and 6.0 mg/kg, respectively, for 2 weeks. Compared with the control, dietary T-2 toxin reduced feed intake, body weight gain, feed conversion ratio, and the apparent metabolic rates and induced histopathological lesions in the small intestine to varying degrees by different doses. Furthermore, the T-2 toxin decreased the activities of glutathione peroxidase, thioredoxin reductase and total antioxidant capacity but increased the concentrations of protein carbonyl and malondialdehyde in the duodenum in a dose-dependent manner. Moreover, the integrated microbiomic, metabolomic and transcriptomic analysis results revealed that the microbes, metabolites, and transcripts were primarily involved in the regulation of nucleotide and glycerophospholipid metabolism, redox homeostasis, inflammation, and apoptosis were related to the T-2 toxin-induced intestinal damage. In summary, the present study systematically elucidated the intestinal toxic mechanisms of T-2 toxin, which provides novel ideas to develop a detoxification strategy for T-2 toxin in animals.
Sujet(s)
Poulets , Toxine T-2 , Humains , Animaux , Mâle , Poulets/métabolisme , Toxine T-2/toxicité , Compléments alimentaires , Régime alimentaire , Antioxydants/métabolisme , Oxydoréduction , Apoptose , Inflammation , Homéostasie , Aliment pour animaux/analyseRÉSUMÉ
This study was conducted to determine the effect of T-2 toxin on the transcriptome of the glandular stomach in chicks using RNA-sequencing (RNA-Seq). Four groups of 1-day-old Cobb male broilers (nâ¯=â¯4 cages/group, 6 chicks/cage) were fed a corn-soybean-based diet (control) and control supplemented with T-2 toxin at 1.0, 3.0, and 6.0â¯mg/kg, respectively, for 2 weeks. The histological results showed that dietary supplementation of T-2 toxin at 3.0 and 6.0â¯mg/kg induced glandular gastric injury including serious inflammation, increased inflammatory cells, mucosal edema, and necrosis and desquamation of the epithelial cells in the glandular stomach of chicks. RNA-Seq analysis revealed that there were 671, 1393, and 1394 genes displayed ≥2 (Pâ¯<â¯0.05) differential expression in the dietary supplemental T-2 toxin at 1.0, 3.0, and 6.0â¯mg/kg, respectively, compared with the control group. Notably, 204 differently expressed genes had shared similar changes among these three doses of T-2 toxin. GO and KEGG pathway analysis results showed that many genes involved in oxidation-reduction process, inflammation, wound healing/bleeding, and apoptosis/carcinogenesis were affected by T-2 toxin exposure. In conclusion, this study systematically elucidated toxic mechanisms of T-2 toxin on the glandular stomach, which might provide novel ideas to prevent adverse effects of T-2 toxin in chicks.
Sujet(s)
Muqueuse gastrique/effets des médicaments et des substances chimiques , Toxine T-2/toxicité , Transcriptome/effets des médicaments et des substances chimiques , Administration par voie orale , Animaux , Poulets , Oedème/induit chimiquement , Muqueuse gastrique/anatomopathologie , Inflammation/induit chimiquement , Mâle , Nécrose/induit chimiquement , ARN messager/métabolisme , Toxine T-2/administration et posologie , Cicatrisation de plaie/effets des médicaments et des substances chimiquesRÉSUMÉ
The objective of this study was to evaluate the ability of a modified hydrated sodium calcium aluminosilicate (HSCAS) adsorbent to reduce the toxicity of T-2 toxin in broilers. Ninety-six one-day-old male broilers were randomly allocated into four experimental groups with four replicates of six birds each. The four groups, 1-4, received a basal diet (BD), a BD plus 6.0 mg/kg T-2 toxin, a BD plus 6.0 mg/kg T-2 toxin with 0.05% modified HSCAS adsorbent, and a BD plus 0.05% modified HSCAS adsorbent, respectively, for two weeks. Growth performance, nutrient digestibility, serum biochemistry, and small intestinal histopathology were analyzed. Compared to the control group, dietary supplementation of T-2 toxin decreased (p < 0.05) body weight gain, feed intake, and the feed conversion ratio by 11.4%-31.8% during the whole experiment. It also decreased (p < 0.05) the apparent metabolic rates of crude protein, calcium, and total phosphorus by 14.9%-16.1%. The alterations induced by T-2 toxin were mitigated (p < 0.05) by the supplementation of the modified HSCAS adsorbent. Meanwhile, dietary modified HSCAS adsorbent supplementation prevented (p < 0.05) increased serum aspartate aminotransferase by T-2 toxin at d 14. It also prevented (p < 0.05) T-2 toxin-induced morphological changes and damage in the duodenum, jejunum, and ileum of broilers. However, dietary supplementation of the modified HSCAS adsorbent alone did not affect (p > 0.05) any of these variables. In conclusion, these findings indicate that the modified HSCAS adsorbent could be used against T-2 toxin-induced toxicity in growth performance, nutrient digestibility, and hepatic and small intestinal injuries in chicks.
Sujet(s)
Silicates d'aluminium/composition chimique , Poulets/physiologie , Toxine T-2/composition chimique , Toxine T-2/toxicité , Adsorption , Alanine transaminase/sang , Animaux , Aspartate aminotransferases/sang , Protéines du sang/analyse , Compléments alimentaires , Digestion/effets des médicaments et des substances chimiques , Consommation alimentaire/effets des médicaments et des substances chimiques , Intestin grêle/effets des médicaments et des substances chimiques , Intestin grêle/anatomopathologie , Foie/effets des médicaments et des substances chimiques , Mâle , NutrimentsRÉSUMÉ
Breast cancer in young women is typically with higher proportion of adverse pathological features. Breast cancer with BRCA1 mutation is often early-onset, and is usually associated with triple negative phenotpe. In this study, we aim to analyze the clinicopathological characteristics and prognosis in young breast cancer patients (≤35 years old) comparing to non-young patients (>35 years old). A total of 1913 cases of primary breast carcinoma with stage I-III were enrolled, with 283 cases diagnosed as young patients. No significant difference was observed in tumor size, TNM staging, lymph node metastasis, ER, HER-2 or histological grade between young and non-young patients. Multivariate analysis demonstrated that age was an independent prognostic factor for overall survival (OS). In 70 samples of young patients available, BRCA1 was immunohistochemically positive 85.7% in cytoplasm and 41.4% in nuclear. BRCA1 nuclear expression is not significantly associated with clinicopathological characteristics in young breast cancer patients.