Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling

Schneider, Kai Markus; Candels, Lena Susanna; Hov, Johannes R.; Myllys, Maiju; Hassan, Reham; Schneider, Carolin V.; Wahlström, Annika; Mohs, Antje; Zühlke, Sebastian; Liao, Lijun; Elfers, Carsten; Kilic, Konrad; Henricsson, Marcus; Molinaro, Antonio; Hatting, Maximilian; Zaza, Ayham; Drasdo, Dirk; Frissen, Mick; Devlin, A. Sloan; Galvez, Eric; Strowig, Till; Karlsen, Tom H.; Hengstler, Jan G.; Marschall, Hanns‐Ulrich; Ghallab, Ahmed; Trautwein, Christian

doi:10.1038/s42255-021-00452-1

Cited by 79 publications

(64 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notable hepatic lesions (figure 2A, E and G, arrows) range from hepatocytes with vacuolar and cystic degeneration to coagulation necrosis rimmed by inflammation. The cause of these lesions is not apparent, but a similar lesion has been reported in biliary ligation21 and antibiotic-induced cholestatic14 studies to be the result of bile salt leakage and described as bile infarcts. in GF mdr2 −/− mice.…”

Section: Resultsmentioning

confidence: 75%

“…GF conditions lead to extensive reuptake of intestinal BAs,12 emphasising the importance of microbial mediation of BA homeostasis. Microbial depletion expands hepatic non-micellar BA concentrations contributing to cholangiocyte inflammation, ductal disruption and parenchymal disease in mdr2 −/− mice 13–15. Dysbiosis in PSC patients results in altered BA pools that potentially contribute to PSC pathophysiology 3 14.…”

Section: Introductionmentioning

confidence: 99%

“…Microbial depletion expands hepatic non-micellar BA concentrations contributing to cholangiocyte inflammation, ductal disruption and parenchymal disease in mdr2 −/− mice 13–15. Dysbiosis in PSC patients results in altered BA pools that potentially contribute to PSC pathophysiology 3 14. Furthermore, increased microbial bile salt hydrolase (BSH) activity was found in PSC patients’ bile,3 possibly related to the high BSH activity of E. faecalis , abundant in the faeces and bile of PSC patients 3 4 16 17.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC

Awoniyi

Wang

Ngo

et al. 2022

Gut

View full text Add to dashboard Cite

ObjectiveConflicting 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.DesignWe 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.ResultsGF 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.ConclusionsWe 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.

show abstract

Section: Resultsmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC

Awoniyi

Wang

Ngo

et al. 2022

Gut

View full text Add to dashboard Cite

show abstract

“…These observations suggest that the proliferating cholangiocytes may play a causal role in fibrogenesis and may recapitulate features of the process by which they induce the embryonic development of periportal fields [51]. As a further mechanism, bile ducts may become leaky in inflamed hepatic tissue and the released bile acids may cause cytotoxicity to adjacent hepatocytes, further enhancing the inflammatory, pro-fibrotic microenvironment [52]. Although evidence has been presented it remains to be systematically studied if DR really is an initial event that induces all further processes in the formation of fibrotic streets.…”

Section: Ductular Reaction In Fibrogenesismentioning

confidence: 75%

Liver specific, systemic and genetic contributors to alcohol-related liver disease progression

et al. 2022

Self Cite

View full text Add to dashboard Cite

Alcohol-related liver disease (ALD) impacts millions of patients worldwide each year and the numbers are increasing. Disease stages range from steatosis via steatohepatitis and fibrosis to cirrhosis, severe alcohol-associated hepatitis and liver cancer. ALD is usually diagnosed at an advanced stage of progression with no effective therapies. A major research goal is to improve diagnosis, prognosis and also treatments for early ALD. This however needs prioritization of this disease for financial investment in basic and clinical research to more deeply investigate mechanisms and identify biomarkers and therapeutic targets for early detection and intervention. Topics of interest are communication of the liver with other organs of the body, especially the gut microbiome, the individual genetic constitution, systemic and liver innate inflammation, including bacterial infections, as well as fate and number of hepatic stellate cells and the composition of the extracellular matrix in the liver. Additionally, mechanical forces and damaging stresses towards the sophisticated vessel system of the liver, including the especially equipped sinusoidal endothelium and the biliary tract, work together to mediate hepatocytic import and export of nutritional and toxic substances, adapting to chronic liver disease by morphological and functional changes. All the aforementioned parameters contribute to the outcome of alcohol use disorder and the risk to develop advanced disease stages including cirrhosis, severe alcoholic hepatitis and liver cancer. In the present collection, we summarize current knowledge on these alcohol-related liver disease parameters, excluding the aspect of inflammation, which is presented in the accompanying review article by Lotersztajn and colleagues.

show abstract

“…The latter modulates the rate-limiting step of bile acid synthesis via the enzyme cholesterol 7 alpha-hydroxylase (CYP7A1), indicating that loss of microbiota-mediated negative feedback is a critical driver of cholestasis. This is alongside the loss of bile duct barrier function seen following downregulation of FXR activation [25]. Through an integrative biology approach, with analysis of mucosally adherent gut microbiota, our group have demonstrated that mechanisms associated with gut inflammation appear distinct to those of IBD alone, and linked to disturbances in bile acid metabolism [18].…”

Section: Key Pointsmentioning

confidence: 99%

Mucosal immunity in primary sclerosing cholangitis: from the bowel to bile ducts and back again

Liaskou

Quraishi

Trivedi

2022

Current Opinion in Gastroenterology

View full text Add to dashboard Cite

Purpose of reviewIn this article, we provide a contemporary overview on PSC pathogenesis, with a specific focus on the role of mucosal immunity. Recent findingsThe extent of enteric dysbiosis in PSC has been extensively quantified, with evidence of reduced bacterial diversity and enrichment of species capable of driving lymphocyte recruitment from the gut to the liver. Integrative pathway-based analysis and metagenomic sequencing indicate a reduction in butyrateproducing species, near absence of bacteria that activate the nuclear bile acid receptor FXR, and depletion of species that regulate the synthesis of vitamin B6 and branched-chain amino acids. Immunotyping of the cellular inflammatory infiltrate has identified a population of intrahepatic naive T cells, with tendency to acquire a Th17 polarisation state, paralleled by heightened responses to pathogen stimulation. Moreover, the search for antigen specificity has revealed the presence of overlapping nucleotide clonotypes across the gut and liver, highlighting the ability to recognize a common pool of epitopes bearing structural similarities across afflicted sites.

show abstract

Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling

Cited by 79 publications

References 48 publications

Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC

Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC

Liver specific, systemic and genetic contributors to alcohol-related liver disease progression

Mucosal immunity in primary sclerosing cholangitis: from the bowel to bile ducts and back again

Contact Info

Product

Resources

About