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Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis
- Source :
- Nature Microbiology. 4:492-503
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper 17 (TH17) cell responses in the liver and increased susceptibility to hepatobiliary injuries. Bacterial culture of mesenteric lymph nodes in these mice isolated K. pneumoniae, Proteus mirabilis and Enterococcus gallinarum, which were prevalently detected in patients with PSC. A bacterial-organoid co-culture system visualized the epithelial-damaging effect of PSC-derived K. pneumoniae that was associated with bacterial translocation and susceptibility to TH17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the TH17 immune response induced by PSC-derived microbiota. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC. Klebsiella pneumoniae from the gut microbiota of patients with primary sclerosing cholangitis (PSC) can damage the intestinal epithelial barrier, resulting in bacterial translocation and T helper 17 cell responses in the liver, indicating a role in PSC pathogenesis.
- Subjects :
- Male
endocrine system diseases
Gut flora
Applied Microbiology and Biotechnology
Pathogenesis
Mice
Liver disease
Mesenteric lymph nodes
0303 health sciences
biology
digestive, oral, and skin physiology
Middle Aged
Ulcerative colitis
Intestines
Organoids
Klebsiella pneumoniae
medicine.anatomical_structure
Liver
Female
Adult
Microbiology (medical)
Cholangitis, Sclerosing
Immunology
digestive system
Microbiology
Primary sclerosing cholangitis
03 medical and health sciences
Immune system
Genetics
medicine
Animals
Germ-Free Life
Humans
T helper 17 cell
Proteus mirabilis
Aged
030304 developmental biology
030306 microbiology
business.industry
Epithelial Cells
Cell Biology
medicine.disease
biology.organism_classification
digestive system diseases
Gastrointestinal Microbiome
Mice, Inbred C57BL
Bacterial Translocation
Th17 Cells
Colitis, Ulcerative
Lymph Nodes
business
Enterococcus
Subjects
Details
- ISSN :
- 20585276
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- Nature Microbiology
- Accession number :
- edsair.doi.dedup.....c74f223f3ddc451c5c17fafaadbb6926