Gut-liver axis dysregulation in colitis underlies structure-dependent pharmacokinetics of a traditional Chinese medicine.

Ulcerative colitis induced structure-dependent pharmacokinetic shifts in a multi-component herbal formula compared to healthy mice.

• Iridoids and flavonoids exhibited reduced systemic exposure, with a 0.8-fold change in AUC for loganin as an example.
• Alkaloids showed delayed systemic elimination, with a 5.8-fold change in T1/2 for berberine as an example.
• Saponins and polyphenols demonstrated altered colonic availability.
• Comparative analysis was performed between healthy and colitis mice.

Multi-omics profiling revealed disruptions along the gut-liver axis in colitis mice, including downregulation of hepatic metabolic enzymes.

• Hepatic enzymes including CYPs and UGTs were downregulated in colitis mice.
• Microbial glycoside hydrolases (GHs) were increased by 125% in colitis mice.
• Disruptions were identified across both hepatic metabolism and gut microbial metabolism.

Specific compounds were differentially influenced by hepatic versus microbial metabolism in the context of colitis.

• Berberine, liquiritin, and glycyrrhizic acid were influenced by both hepatic and microbial metabolism.
• Loganin and curcumin were primarily affected by gut processes rather than hepatic metabolism.
• This compound-specific pattern demonstrates structure-dependent susceptibility to gut-liver axis dysregulation.

Dysfunction of microbial glycoside hydrolases, particularly β-glucosidase and β-glucuronidase, was linked to pharmacokinetic variability and disease activity.

• Dysfunction of β-glucosidase and β-glucuronidase was specifically identified as relevant.
• Findings were confirmed using human microbiome datasets and clinical samples.
• The dysfunction of these enzymes was linked to disease activity in ulcerative colitis.
• These enzymes were proposed as potential biomarkers for PK variability.

Ulcerative colitis, characterized by immune dysregulation, gut microbiota dysbiosis, and hepatic inflammation, was used as a model to study gut-liver axis contributions to pharmacokinetic variability.

• UC was selected as a relevant disease model because it involves immune dysregulation, gut microbiota dysbiosis, and hepatic inflammation.
• The study investigated how UC-induced alterations in both liver metabolism and gut microbiota affect PK profiles.
• The model allowed simultaneous assessment of hepatic and microbial contributions to PK variability.
• Clinical data comparing PK in healthy individuals and patients is described as limited but evidence suggests disease-induced variability is common and clinically significant.

The study established a baseline of colitis-induced pharmacokinetic variability across various natural compound classes and proposed hypotheses for biomarker development.

• Compound classes examined included iridoids, flavonoids, saponins, polyphenols, and alkaloids.
• Key determinants of PK variability were identified including hepatic CYPs/UGTs and microbial GHs.
• The findings propose a basis for biomarker development linking gut-liver axis dysfunction to PK variability.
• The study used a multi-component herbal formula as the test medicine.