Fidaxomicin and Crohn's Disease

Fidaxomicin has emerged as a promising therapeutic candidate for intestinal fibrosis in Crohn’s disease, a condition where up to 50% of patients develop strictures due to excessive collagen deposition and tissue scarring. Currently, no antifibrotic drugs are available for this complication. A study employing advanced multi-omics analysis and high-throughput drug screening identified platelet-derived growth factor receptor beta (PDGFRβ) and glycogen synthase kinase-3 beta (GSK3β) as key molecular regulators of collagen production in intestinal fibroblasts. Fidaxomicin, an FDA-approved antibiotic, was discovered to potently inhibit PDGFRβ activity.

Mechanistic studies revealed that fidaxomicin binds strongly to PDGFRβ (binding score: −8.5 kcal/mol), reducing its phosphorylation and mRNA expression. This inhibition led to decreased collagen I and II (COL1A1/COL1A2) expression in patient-derived fibroblasts and tissues. Additionally, fidaxomicin maintained GSK3β in its active, antifibrogenic state by preventing its phosphorylation. The antifibrotic effects were confirmed to depend on the PDGFRβ–GSK3β signaling pathway, as external stimulation with PDGF-BB or IGF-1 reversed its beneficial impact.

In vivo validation using a Crohn’s-like fibrosis mouse model demonstrated that oral fidaxomicin significantly reduced ileal fibrosis, inflammation, and disease activity scores. Importantly, fidaxomicin’s antifibrotic effects were localized to the gut, avoiding systemic toxicity and preserving gut microbiota diversity. Moreover, fidaxomicin exhibited anti-inflammatory benefits by reducing IL8 and TNFα secretion in immune cells.

With its gut-restricted action and minimal adverse effects compared to cytotoxic PDGFR inhibitors, fidaxomicin holds potential for repurposing as a targeted antifibrotic therapy for Crohn’s disease strictures.