# Fidaxomicin Reduces Collagen Expression in Intestinal Fibroblasts Via Platelet-Derived Growth Factor Receptor Beta and Glycogen Synthase Kinase-3 Beta Inhibition

## TL;DR

Fidaxomicin, a drug approved for C. difficile infection, reduces intestinal fibrosis by inhibiting key proteins involved in collagen production in intestinal fibroblasts.

## Contribution

Fidaxomicin is shown to inhibit intestinal fibrosis via PDGFRβ and GSK3β pathways in human and mouse models.

## Key findings

- Fidaxomicin reduced collagen and PDGFRB mRNA expression in CD patient-derived intestinal fibroblasts.
- Fidaxomicin inhibited PDGFRβ and GSK3β phosphorylation in fibrotic intestinal tissues.
- Oral fidaxomicin treatment reduced ileal fibrosis in a mouse model of intestinal fibrosis.

## Abstract

About 30%–50% of patients with Crohn’s disease (CD) eventually develop intestinal strictures, with intestinal fibrosis being a major component of them. There is currently no approved medication to treat fibrotic strictures.

10X Genomics Visium spatial RNA sequencing and high-throughput screening were used to discover the molecular targets of intestinal fibrosis. Stricturing Crohn’s disease (CDS) patient-derived primary human intestinal fibroblasts (CD-HIFs), stricturing Crohn’s disease patient-derived serum exosomes (CDSE), fresh surgically resected whole-thickness ileal tissues, and mouse models of intestinal fibrosis were used.

Spatial RNA sequencing found overexpression of platelet-derived growth factor receptor beta (PDGFRB) in the fibrotic ileal tissues of CDS patients. PDGFRB small interfering RNA inhibited collagen expression in the CDSE-treated CD-HIFs. High-throughput screening identified PDGFRB inhibitors that suppressed collagen promoter activity in CDSE-treated CD-HIFs. A machine learning algorithm and molecular docking predicted PDGFR as a target for fidaxomicin. Fidaxomicin, a Food and Drug Administration–approved drug for Clostridioides difficile infection, inhibited collagen and PDGFRB messenger RNA (mRNA) expression in CDSE-treated CD-HIFs and CDS patient-derived ileal tissues. CDSE-treated CD-HIFs had increased PDGFRβ and glycogen synthase kinase-3 alpha/beta (GSK3ɑ/β) phosphorylation. Fidaxomicin inhibited PDGFRβ phosphorylation, PDGFRB mRNA expression, and GSK3β phosphorylation in CDSE-treated CD-HIFs. The anti-fibrogenic effect of fidaxomicin was attenuated by platelet-derived growth factor-BB (PDGF-BB) and insulin-like growth factor 1, which are a PDGFRβ ligand and a GSK3ɑ/β phosphorylation activator, respectively. In the SAMP1/YitFc mice, oral fidaxomicin treatment inhibited ileal fibrosis and ileal PDGFRB mRNA expression and PDGFRβ and GSK3β phosphorylation, which were abolished by Pdgfrb and Gsk3b overexpression.

Fidaxomicin inhibits intestinal fibrosis by reducing PDGFRb phosphorylation and expression, GSK3b phosphorylation, and collagen expression in intestinal fibroblasts.