Background and Aims In inflammatory bowel disease, protein misfolding in the endoplasmic reticulum (ER) potentiates epithelial barrier dysfunction and impairs mucosal healing. Tauroursodeoxycholic acid (TUDCA), a naturally occurring bile acid, acts as a chemical chaperone to reduce protein aggregation and colitis severity in preclinical models. We conducted an open label trial evaluating oral TUDCA as therapy in patients with active ulcerative colitis (UC).

Methods Patients with moderate-to-severely active UC (Mayo score ≥6, endoscopic subscore ≥1) received oral TUDCA at 1.75 or 2 g/day for 6 weeks. Exclusion criteria included known hepatic disorders or change in UC therapy within 60 days. Clinical disease activity questionnaires, endoscopy with biopsy, blood, and stool were collected at enrollment and after 6 weeks. The primary outcome measure was change in ER stress markers while safety, tolerability and change in UC disease activity were secondary outcomes.

Results Thirteen participants completed the study with eleven evaluable for clinical response. TUDCA was well-tolerated with transient dyspepsia being the most common side effect. Mucosal biopsies revealed significant reductions in ER stress and inflammation as well as an increase in markers of epithelial restitution. Clinical, endoscopic, and histologic disease activity were significantly improved at week 6 (mean total Mayo Score: 9 to 4.5, p<0.001).

Conclusions Six weeks of oral TUDCA treatment was well-tolerated in patients with active ulcerative colitis and promoted mucosal healing, lessened ER stress, and reduced clinical disease activity. A randomized controlled trial of adjunctive TUDCA therapy in patients with UC is warranted.

Disclosures / COI: MAC: Consultant or advisory board for Janssen, Pfizer, AbbVie, and Geneoscopy. He has also received funding under a sponsored research agreement unrelated to the data in the paper from Incyte, Janssen, and Pfizer. PD: Consultant or on an advisory board for Janssen, Pfizer, Prometheus Biosciences, Boehringer Ingelheim, AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, CorEvitas LLC and Scipher Medicine Corporation. He has also received funding under a sponsored research agreement unrelated to the data in the paper from Takeda Pharmaceutical, Arena Pharmaceuticals, Bristol Myers Squibb-Celgene, and Boehringer Ingelheim. RJK: Consultant for Metagenomi Therapeutics. VL: Has equity interest and serves as a consultant to Edulis Therapeutics. All other authors have nothing to disclose as a potential conflict relevant to the manuscript.

NCT04114292

This trial was supported by a Litwin IBD Pioneers Award from the Crohn's and Colitis Foundation (RJK and MAC). This work was in part supported by grants NIH P30 CA030199, DK103185, UL1TR002345, T32 DK007130 P30 DK052574. Philanthropic support and other funding included Givin it all for Guts Foundation, the Lawrence C. Pakula IBD Education and Innovation Fund at Washington University in St. Louis (SC, MAC), a Doris Duke Fund to Retain Clinical Scientists Award (SC), and a American College of Gastroenterology Junior Faculty Development Award (PD).

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Ethics committee/IRB of WashU Medicine gave ethical approval for this work

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Disclosures / COI: MAC: Consultant or advisory board for Janssen, Pfizer, AbbVie, and Geneoscopy. He has also received funding under a sponsored research agreement unrelated to the data in the paper from Incyte, Janssen, and Pfizer. PD: Consultant or on an advisory board for Janssen, Pfizer, Prometheus Biosciences, Boehringer Ingelheim, AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, CorEvitas LLC and Scipher Medicine Corporation. He has also received funding under a sponsored research agreement unrelated to the data in the paper from Takeda Pharmaceutical, Arena Pharmaceuticals, Bristol Myers Squibb-Celgene, and Boehringer Ingelheim. RJK: Consultant for Metagenomi Therapeutics. VL: Has equity interest and serves as a consultant to Edulis Therapeutics. All other authors have nothing to disclose as a potential conflict relevant to the manuscript.

Transcript Profiling: ENA accession number for microbiome data is PRJEB73763. https://www.ebi.ac.uk/ena/browser/view/PRJEB73763, GEO accession number for RNA-Seq data is GSE266963. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi access code: ytmtqoeipxwrjwp

Trial registration ClinicalTrials.gov (NCT04114292).

Grant Support: Funding: This trial was supported by a Litwin IBD Pioneers Award from the Crohn’s and Colitis Foundation (RJK and MAC). This work was in part supported by grants NIH P30 CA030199, DK103185, UL1TR002345, T32 DK007130, P30 DK052574. Philanthropic support and other funding included Givin’ it all for Guts Foundation, the Lawrence C. Pakula IBD Education and Innovation Fund at Washington University in St. Louis (SC, MAC), a Doris Duke Fund to Retain Clinical Scientists Award (SC), and a American College of Gastroenterology Junior Faculty Development Award (PD).

All data produced in the present work are contained in the manuscript