Neutrophil elastase inhibition improves intestinal mucosal damage and
gut microbiota in a mouse model of 5-fluorouracil--induced intestinal
mucositis
Abstract
Background and Purpose: 5-Fluorouracil (5-FU)-based chemotherapy is the
first-line chemotherapeutic agent for colorectal cancer. However,
5-FU–induced intestinal mucositis (FUIIM) is a common adverse effect
that severely impairs drug tolerance and results in poor patient health.
Experimental Approach: Neutrophil elastase (NE) overexpression
contributes to FUIIM via abnormal inflammatory responses, microbiota
imbalance, and tissue damage. Therefore, restoring NE homeostasis could
prevent or improve FUIIM. Key Results: This study shows that treatment
with the specific NE inhibitor MPH966 (7.5 mg/kg; p.o.) significantly
reversed 5-FU–induced losses in body weight; reversed villus atrophy;
significantly suppressed myeloperoxidase, NE, and proteinase 3 activity;
and reduced pro-inflammatory cytokine levels in a mouse model of FUIIM.
In addition, MPH966 prevented 5-FU–induced intestinal barrier
dysfunction, as was indicated by modulated expression of the tight
junction proteins zonula occludin-1 and occludin. MPH966 also reversed
5-FU–induced changes in gut microbiota diversity and abundances,
specifically the Firmicutes-to-Bacteroidetes ratio; Muribaculaceae,
Ruminococcaceae, and Eggerthellaceae abundances at the family level; and
Candidatus Arthromitus abundance at the genus level. Conclusion and
Implications: These data indicate that NE inhibitors are a potential
treatment candidate to alleviate FUIIM by regulating abnormal
inflammatory responses, intestinal barrier dysfunction, and gut
microbiota imbalance.