Macrophage-Derived IL-23 Drives Intestinal and Hepatobiliary Inflammation Along the Gut-Liver Axis in Primary Sclerosing Cholangitis_Feces

Objective and design: Primary sclerosing cholangitis (PSC) is a gut–liver disease in which intestinal and hepatobiliary inflammation remain therapeutically uncoupled. Although IL-23-directed antibodies improve intestinal inflammation, hepatobiliary benefit is limited. We investigated whether IL-23 belongs to a broader inflammatory circuit and whether dual GPBAR1 agonism/RORγt inverse agonism can interrupt it. Material or subjects: Colonic biopsies from PSC-UC patients and controls, human liver cohorts, immune cells and Abcb4−/− mice were studied. Treatment: BAR501, ML209 and PBT002 were tested in vitro; PBT002 was evaluated in spontaneous and IL-23-driven disease. Methods: Transcriptomics, quantitative PCR, histology, immune deconvolution, microbiota and bile-acid profiling were integrated. Results: PSC-associated colonic mucosa displayed myeloid, interferon and IL-17 activation with loss of epithelial barrier and differentiation programs, while hepatic RORC was increased. Abcb4−/− mice reproduced epithelial dysfunction, myeloid expansion and Il23a induction. PBT002 restrained macrophage and Th17 responses, improved intestinal and hepatobiliary injury, partially corrected dysbiosis and restored bile-acid homeostasis. Conversely, exogenous IL-23 amplified systemic inflammation, colonic damage and enterohepatic bile-acid disruption, all attenuated by PBT002. Conclusions: IL-23 is embedded in a gut-liver inflammatory network. Dual GPBAR1/RORγt modulation broadens control of its immune and metabolic consequences.