Unraveling the Mechanisms Underlying Primary Sclerosing Cholangitis Through a Multidisciplinary, Integrative Research Approach

Study Description:

We hypothesize that primary sclerosing cholangitis (PSC) develops as a consequence of a genetically driven aberrant immune response to commensal or pathogenic bacteria, and that unique genetic-immunemicrobial associations may underlie development of distinct disease patterns. We intend to conduct a thorough radiologic, endoscopic, histologic and microbiological investigation of patients with PSC in order to determine potential associations.

Objectives:

Primary Objective:

The ultimate goal of this study is to generate understanding of how factors driving pathogenesis in PSC interact by capturing and integrating collated datasets from across relevant biologic systems and interpreting those in the context of phenotypic presentation in one exceptionally well-characterized set of patients.

Secondary Objectives:

• To collect comprehensive data on distinct patterns of disease expression, through single cell sequencing and microRNA and transcriptome profiling.
• To conduct extensive phenotypic characterization of cellular and humoral immune responses as well as microbiome signatures at multiple anatomic sites.
• To evaluate metabolic signatures or biomarkers for PSC diagnosis and prognostication.
• To generate a humanized mouse model of each subject s disease by obtaining bone marrow aspirate.

Endpoints:

Primary Endpoint:

• Identification of immune signatures at multiple levels and from different anatomical sites and tissues
• Characterization of microbiome signatures (taxonomic and functional), as well as identification of specific species.
• Identification of metabolomic signatures from different anatomical sites and tissues as well as identification of different biomarkers correlating with disease progression.
• MicroRNA profiling of portal and systemic blood.

• PSC SUBJECTS:

Inclusion criteria

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or nonpregnant female, greater than or equal to 18 years of age
• Evidence of PSC established by biochemical testing and either MRCP or ERCP. Participant must have evidence of large duct disease on imaging.
• Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Pregnant or lactating women or females of child-bearing age not taking measures to prevent pregnancy during the period of study.
• History of clinical, serologic, or histopathologic evidence supporting etiologies of chronic liver disease other than PSC
• History of liver transplantation
• Diagnosis consistent with secondary sclerosing cholangitis (cholelithiasis, bile duct strictures secondary to ischemia, HIV cholangiopathy, etc.).
• Current or past clinical evidence of decompensated liver disease (e.g. ascites, bleeding esophageal varices, spontaneous bacterial peritonitis, encephalopathy, etc.).
• History of liver or bile duct lesions concerning for malignancy.
• Ca-19-9 >130 U/microL
• Alpha-fetoprotein level greater than 200 ng/microL.
• Patients with active bacterial, viral, or fungal, systemic or localized infection.
• Unwillingness to refrain from ingesting probiotics during study.
• History of systemic disease not related to PSC that is poorly controlled or associated with declining functional status. Examples include but are not limited to: poorly controlled diabetes mellitus, chronic renal failure with eGFR is <60 microl/min/1.73m^2, chronic

symptomatic heart failure or severe COPD.

• Patients with history of any gastrointestinal malignancy in the last 3 years prior to enrollment will be excluded. Patients with history of any malignancy in the last 3 years prior to enrollment other than those individuals who had undergone curative surgical therapy and deemed as low risk for recurrence by her/his treating physician would be excluded.
• History of portal vein thrombosis
• Patients with severe allergic reactions to iodine or other contrast, which cannot be controlled by premedication with antihistamines or steroids.
• History of gastric and/or proximal small bowel surgery including bariatric surgery such as Roux-en-Y gastric bypass
• Contraindication to monitored anesthesia care and/or medications that are commonly used for conscious sedation during GI Endoscopy
• Use of anti-coagulant and anti-platelet agents excluding aspirin and NSAIDs
• Contraindications to completing MRCP or MRI
• Absolute neutrophil count below 1000/mm^3
• Hemoglobin level below 10.0 g/dl
• Platelet count lower than 50,000/mm^3.
• INR greater than or equal to 1.5, PTT greater thna or equal to 1.3 times control and/or any known history of disease associated with

increased bleeding diathesis.

• Inability to provide informed consent

CONTROLS:

Inclusion criteria

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Male or female greater than or equal to 18 years of age
• Any individual who is either a parent, sibling or child of a PSC patient enrolled to the study, or an unrelated person who has been living with the patient for at least 3 consecutive months before study enrollment

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• History suggestive of PSC
• History of chronic liver disease (except for steatosis)
• Patients with history of any malignancy in the 3 years prior to enrollment other than those individuals who had undergone curative surgical therapy and deemed as low risk for recurrence by her/his treating physician would be excluded.
• History of Inflammatory Bowel Disease
• Antibiotic use within the last 6 weeks
• Pregnancy
• Inability to provide informed consent