Gut microbiota-mediated C-sulfonate metabolism impairs the bioavailability and anti-cholestatic efficacy of andrographolide

Cholestatic liver injury results from the accumulation of toxic bile acids in the liver, and to date, effective therapeutic strategies for this condition remain elusive. Andrographolide (AP) has exhibited potential as a treatment for cholestatic liver disease. However, its limited oral bioavailability poses a significant obstacle to harnessing its potent therapeutic properties and restricts its clinical utility. This disparity is potentially attributed to the involvement of gut microbiota in drug metabolism. In our study, employing pseudo and germ-free animal models, we have uncovered the pivotal role played by gut microbiota in the C-sulfonate metabolism of AP, a process that profoundly impacts its bioavailability and anti-cholestatic effect. To verify that the pseudo sterile mouse model was successfully established, we explored the effect of antibiotic treatment on the intestinal flora of mice by 16S rRNA sequencing analysis for further subsequent studies.