# Qing-Chang-Hua-Shi granule ameliorates experimental colitis by modulating Lactobacillus gasseri-mediated ferroptosis metabolic pathway

## TL;DR

This study shows that Qing-Chang-Hua-Shi granule helps treat colitis by reducing cell death and supporting a gut bacteria called Lactobacillus gasseri.

## Contribution

The study reveals Lactobacillus gasseri as a novel ferroptosis inhibitor in ulcerative colitis.

## Key findings

- QCHS reduced ferroptosis in colonic tissues of a UC mouse model.
- L. gasseri suppressed RSL3-induced ferroptosis via the GSH/GPX4 pathway in NCM-460 cells.
- QCHS modulated the microbiota-metabolome axis to alleviate UC symptoms.

## Abstract

Ulcerative colitis (UC) is a chronic inflammatory disorder marked by epithelial barrier disruption and persistent intestinal inflammation. Despite extensive research, its complex etiology continues to pose therapeutic challenges. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently been implicated in UC pathogenesis. Additionally, the gut microbiota and its metabolites play a pivotal role in maintaining intestinal homeostasis and barrier integrity.

This study aimed to investigate the therapeutic potential of a phytotherapeutic agent QCHS to alleviate UC by modulating ferroptosis and the microbiota-metabolome axis, with a particular focus on the role of Lactobacillus gasseri (L. gasseri).

A DSS-induced UC mouse model was used to evaluate QCHS efficacy. Gut microbial composition and metabolomic alterations were analyzed via 16S rDNA sequencing and UHPLC-MS/MS. L. gasseri was cultured in vitro to assess the impact of QCHS on its growth. RSL3-induced cell death was modeled in NCM-460 cells and ferroptosis-related changes were examined using transmission electron microscopy, immunohistochemistry, quantitative PCR, and Western blotting.

QCHS significantly mitigated DSS-induced ferroptosis in colonic tissues, with L. gasseri identified as a key mediator. Notably, L. gasseri was found to act as a novel ferroptosis inhibitor. In vitro studies confirmed that L. gasseri suppressed RSL3-induced ferroptosis in NCM-460 cells via activation of the GSH/GPX4 pathway.

This study provides compelling evidence for the regulatory role of QCHS on the microbiota-metabolome axis and ferroptosis in UC. It also uncovers a novel function of L. gasseri as a ferroptosis inhibitor, offering promising insights into microbiota-targeted and ferroptosis-modulating therapeutic strategies for UC.