Cxcr2 signaling and the microbiome suppress inflammation, bile duct injury, and the phenotype of experimental biliary atresia

• Published in: PloS one 2017-08, Vol.12 (8), p.e0182089-e0182089
• Main Authors: Jee, Junbae, Mourya, Reena, Shivakumar, Pranavkumar, Fei, Lin, Wagner, Michael, Bezerra, Jorge A
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics; Bacteria; Bile; Bile ducts; Bile Ducts - injuries; Biliary atresia; Biliary Atresia - metabolism; Biliary Atresia - microbiology; Biology and Life Sciences; Cellular signal transduction; Cholestasis; Colon; Colonization; Complications and side effects; CXCR2 protein; Deactivation; Development and progression; Disease Models, Animal; Female; Gastroenterology; Gene expression; Gene Expression Profiling; Genetic aspects; Hepatology; Immune system; Inactivation; Inflammation; Inflammation - metabolism; Inflammatory bowel disease; Injuries; Interleukin 8; Intestinal microflora; Intestine; Jaundice; Lactation; Leukocytes (neutrophilic); Linear Models; Lymphocytes; Macaca mulatta; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Microbiota; Microbiota (Symbiotic organisms); Mortality; Neonates; Neutrophils; Nutrition; Pathogenesis; Pathogens; Phenotype; Physical Sciences; Physiological aspects; Polymerase Chain Reaction; Pregnancy; Pregnancy, Animal; Prevention; Receptors, Interleukin-8B - genetics; Receptors, Interleukin-8B - metabolism; Research and Analysis Methods; Risk factors; RNA, Ribosomal, 16S - genetics; Rotavirus; rRNA 16S; Signal Transduction; Sulfamethoxazole; Sulfamethoxazole - administration & dosage; Survivability; Trimethoprim; Trimethoprim - administration & dosage; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0182089

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.