# Caspase 6 deficiency exacerbates inflammatory bowel disease via enterocyte necroptosis and bacterial translocation

## TL;DR

Caspase 6 deficiency worsens inflammatory bowel disease by causing gut cell death and poor bacterial control.

## Contribution

This study reveals a novel role for caspase 6 in preventing intestinal necroptosis and bacterial translocation in IBD.

## Key findings

- Caspase 6 deficiency increases necroptosis in intestinal epithelial cells.
- Caspase 6 loss impairs macrophage bacterial clearance via a CTSL-dependent mechanism.
- Reduced caspase 6 activity correlates with intestinal stem cell damage and fewer endocrine cells.

## Abstract

Caspase 6 is a pivotal executioner caspase involved in cell death; however, its role in inflammatory bowel disease (IBD) remains incompletely understood. Levels of cleaved caspase 6 were quantified in colonic tissues from IBD patients, and an IBD mouse model was established via DSS induction, incorporating both systemic (Casp6 KO) and IEC-specific knockout (Casp6 cKO) strategies. Single-cell RNA sequencing (scRNA-seq) revealed that Casp6 KO enhanced necroptosis in IECs, reducing intestinal endocrine cells and damaging intestinal stem cells. Both in vivo and in vitro studies confirmed that caspase 6 deficiency activates the necroptosis pathway by upregulating RIPK1 in IECs and impairs macrophage bacterial clearance. Importantly, Casp6 KO reduces bactericidal activity in a cathepsin L (CTSL)-dependent manner. These findings demonstrate that preserving caspase 6 activity is essential for necroptosis prevention and effective bacterial clearance, providing new insights for future IBD therapies.