Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tract eventually leading to bile duct destruction, liver failure, cholangiocellular adenocarcinoma and/or death. No disease modifying treatments are available. Especially cytotoxicity of bile acids, are discussed as potential driver of disease progression. Cholangiocytes are protected by a bicarbonate umbrella formed by the glycocalyx, a dense layer of membrane bound polyglycans extending into the extracellular space. Bile of PSC patients harbors a unique microbiome. Here we identified a new factor in the pathogenesis of PSC. The bacterial degradation of sialic acid and galactose are associated with a poor event free survival of PSC patients and could identify bacterial liberation of sialic acid as crucial element in cholangiocyte damage using cell culture experiments, individualized organoid models and liver biopsies. With this study the view on bacteria-host interactions in bile duct associated diseases is widened. Functional patterns of the bacterial community are crucial for bile duct destruction in PSC patients. This opens a new field of diagnostic tools, disease modifying treatment options and identification of patients at risk.

The authors have declared no competing interest.

The study was funded by the Deutsche Forschungsgemeinschaft (DFG German Research Foundation) under Germany Excellence Strategy EXC 2155 RESIST Project ID 390874280 and by the German Centre for Infection Research (DZIF e.V.). This work was supported by a grant from the German Federal Ministry of Education and Research (reference number: 01EO1302) and by the Helmholtz Association Initiative on Aging and Metabolic Programming.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study had been approved by the ethics committee of the Hannover Medical School (approval no. 220- 2007, approval no. 3241- 2016, approval no. 9660_BO_K_2021 and approval no. 10183_BO_K_2022).

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Raw data from 16S amplicon sequencing, metagenomic sequence data, bacterial genome data and data from mass spectrometry will be available upon publication after peer-review. All additional data in the present study are available upon reasonable request to the authors.