Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC
Standard
Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC. / Awoniyi, Muyiwa; Wang, Jeremy; Ngo, Billy; Meadows, Vik; Tam, Jason; Viswanathan, Amba; Lai, Yunjia; Montgomery, Stephanie; Farmer, Morgan; Kummen, Martin; Thingholm, Louise; Schramm, Christoph; Bang, Corinna; Franke, Andre; Lu, Kun; Zhou, Huiping; Bajaj, Jasmohan S; Hylemon, Phillip B; Ting, Jenny; Popov, Yury V; Hov, Johannes Roksund; Francis, Heather L; Sartor, Ryan Balfour.
In: GUT, Vol. 72, No. 4, 04.2023, p. 671-685.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC
AU - Awoniyi, Muyiwa
AU - Wang, Jeremy
AU - Ngo, Billy
AU - Meadows, Vik
AU - Tam, Jason
AU - Viswanathan, Amba
AU - Lai, Yunjia
AU - Montgomery, Stephanie
AU - Farmer, Morgan
AU - Kummen, Martin
AU - Thingholm, Louise
AU - Schramm, Christoph
AU - Bang, Corinna
AU - Franke, Andre
AU - Lu, Kun
AU - Zhou, Huiping
AU - Bajaj, Jasmohan S
AU - Hylemon, Phillip B
AU - Ting, Jenny
AU - Popov, Yury V
AU - Hov, Johannes Roksund
AU - Francis, Heather L
AU - Sartor, Ryan Balfour
N1 - © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2023/4
Y1 - 2023/4
N2 - OBJECTIVE: Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models.GOAL: define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient (mdr2-/- ) mice and microbial profiles in PSC patient cohorts.DESIGN: We measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients.RESULTS: GF mdr2-/- mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients' clinical severity by Mayo risk scores.CONCLUSIONS: We identified novel functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.
AB - OBJECTIVE: Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models.GOAL: define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient (mdr2-/- ) mice and microbial profiles in PSC patient cohorts.DESIGN: We measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients.RESULTS: GF mdr2-/- mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients' clinical severity by Mayo risk scores.CONCLUSIONS: We identified novel functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.
U2 - 10.1136/gutjnl-2021-326500
DO - 10.1136/gutjnl-2021-326500
M3 - SCORING: Journal article
C2 - 35705368
VL - 72
SP - 671
EP - 685
JO - GUT
JF - GUT
SN - 0017-5749
IS - 4
ER -
