Cxcr2 signaling and the microbiome suppress inflammation, bile duct injury, and the phenotype of experimental biliary atresia
نویسندگان
چکیده
Biliary atresia is progressive fibro-inflammatory cholangiopathy of young children. Central to pathogenic mechanisms of injury is the tissue targeting by the innate and adaptive immune cells. Among these cells, neutrophils and the IL-8/Cxcl-8 signaling via its Cxcr2 receptor have been linked to bile duct injury. Here, we aimed to investigate whether the intestinal microbiome modulates Cxcr2-dependent bile duct injury and obstruction. Adult wild-type (WT) and Cxcr2-/- mice were fed a diet supplemented with sulfamethoxazole/trimethoprim (SMZ/TMP) during pregnancy and lactation, and their pups were injected intraperitoneally with rhesus rotavirus (RRV) within 24 hours of life to induce experimental biliary atresia. The maternal exposure to SMZ/TMP significantly lowered the incidence of jaundice and bile duct obstruction and resulted in improved survival, especially in Cxcr2-/- mice. Analyses of the microbiome by deep sequencing of 16S rRNA of the neonatal colon showed a delay in bacterial colonization of WT mice induced by SMZ/TMP, with a notable switch from Proteobacteria to Firmicutes. Interestingly, the genetic inactivation of Cxcr2 alone produced a similar bacterial shift. When treated with SMZ/TMP, Cxcr2-/- mice infected with RRV to induce experimental biliary atresia showed further enrichment of Corynebacterium, Anaerococcus and Streptococcus. Among these, Anaerococcus lactolyticus was significantly associated with a suppression of biliary injury, cholestasis, and survivability. These results suggest that the postnatal development of the intestinal microbiota is an important susceptibility factor for experimental biliary atresia.
منابع مشابه
Preferential TNFα signaling via TNFR2 regulates epithelial injury and duct obstruction in experimental biliary atresia.
Biliary atresia is an obstructive cholangiopathy of infancy that progresses to end-stage cirrhosis. Although the pathogenesis of the disease is not completely understood, previous reports link TNFα to apoptosis of the bile duct epithelium in the presence of IFNγ. Here, we investigate if TNFα signaling regulates pathogenic mechanisms of biliary atresia. First, we quantified the expression of TNF...
متن کاملNatural Killer Cells Promote Long-Term Hepatobiliary Inflammation in a Low-Dose Rotavirus Model of Experimental Biliary Atresia
UNLABELLED Biliary atresia is a rapidly progressive obstructive cholangiopathy of infants. Mechanistic studies in the mouse model of Rhesus rotavirus (RRV)-induced biliary atresia have linked the importance of effector lymphocytes to the pathogenesis of extrahepatic bile duct (EHBD) injury and obstruction in experimental biliary atresia; however, studies of the progressive liver injury have bee...
متن کاملNeonatal NK cells target the mouse duct epithelium via Nkg2d and drive tissue-specific injury in experimental biliary atresia.
Biliary atresia is a neonatal obstructive cholangiopathy that progresses to end-stage liver disease. Although the etiology is unknown, a neonatal adaptive immune signature has been mechanistically linked to obstruction of the extrahepatic bile ducts. Here, we investigated the role of the innate immune response in the pathogenesis of biliary atresia. Analysis of livers of infants at diagnosis re...
متن کاملToll-Like Receptors in Secondary Obstructive Cholangiopathy
Secondary obstructive cholangiopathy is characterized by intra- or extrahepatic bile tract obstruction. Liver inflammation and structural alterations develop due to progressive bile stagnation. Most frequent etiologies are biliary atresia in children, and hepatolithiasis, postcholecystectomy bile duct injury, and biliary primary cirrhosis in adults, which causes chronic biliary cholangitis. Bil...
متن کاملObstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia.
The etiology and pathogenesis of bile duct obstruction in children with biliary atresia are largely unknown. We have previously reported that, despite phenotypic heterogeneity, genomic signatures of livers from patients display a proinflammatory phenotype. Here, we address the hypothesis that production of IFN-gamma is a key pathogenic mechanism of disease using a mouse model of rotavirus-induc...
متن کامل