Journal of inflammation research · 2026
Pneumococcal Endopeptidase O Attenuates Colitis by Inhibiting the Macrophage-CCL2 Axis and Reshaping Gut Microbiota.
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Wang Hanyi, Shao Shuangmei, Peng Yuan, Xu Wenlong, Zhang Jia, Liu Xiao, Bian Xintong, Huang Kun, Zhang Xuemei
Аннотация
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease characterized by persistent immune activation and gut microbiota dysbiosis, for which current therapies remain limited by incomplete efficacy and substantial adverse effects. This study aimed to investigate the protective effects of pneumococcal endopeptidase O (PepO) on UC and its potential mechanisms of action.
METHODS: The efficacy of PepO was evaluated in a dextran sulfate sodium (DSS)-induced acute colitis mouse model. Clinical phenotypes were assessed using the disease activity index (DAI), colon length, histopathological analysis, and inflammatory cytokine levels. Macrophage infiltration and key inflammatory mediators were analyzed via immunofluorescence, flow cytometry, ELISA, and qPCR. Mechanisms were further validated by macrophage depletion using clodronate liposomes and recombinant CCL2 supplementation. In addition, gut microbiota composition was analyzed via 16S rRNA sequencing, and causality was confirmed through antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) experiments.
RESULTS: PepO administration significantly improved disease activity, colon length, and ameliorated histopathological damage in the mice. Mechanistically, PepO directly inhibited macrophage CCL2 production, reducing macrophage infiltration and the release of pro-inflammatory cytokines in colitis. Additionally, PepO remodelled the gut microbiota and markedly increased the abundance of beneficial bacteria, such as Lactobacillus and Akkermansia. Antibiotic-induced microbiota depletion completely abolished PepO's protective effect, while FMT successfully replicated its protective actions, including suppression of CCL2 expression and macrophage infiltration.
CONCLUSION: This study shows that PepO exerts potent anti-colitic effects through a dual mechanism involving direct inhibition of the macrophage-CCL2 axis and microbiota-dependent enhancement of gut immune homeostasis.
METHODS: The efficacy of PepO was evaluated in a dextran sulfate sodium (DSS)-induced acute colitis mouse model. Clinical phenotypes were assessed using the disease activity index (DAI), colon length, histopathological analysis, and inflammatory cytokine levels. Macrophage infiltration and key inflammatory mediators were analyzed via immunofluorescence, flow cytometry, ELISA, and qPCR. Mechanisms were further validated by macrophage depletion using clodronate liposomes and recombinant CCL2 supplementation. In addition, gut microbiota composition was analyzed via 16S rRNA sequencing, and causality was confirmed through antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) experiments.
RESULTS: PepO administration significantly improved disease activity, colon length, and ameliorated histopathological damage in the mice. Mechanistically, PepO directly inhibited macrophage CCL2 production, reducing macrophage infiltration and the release of pro-inflammatory cytokines in colitis. Additionally, PepO remodelled the gut microbiota and markedly increased the abundance of beneficial bacteria, such as Lactobacillus and Akkermansia. Antibiotic-induced microbiota depletion completely abolished PepO's protective effect, while FMT successfully replicated its protective actions, including suppression of CCL2 expression and macrophage infiltration.
CONCLUSION: This study shows that PepO exerts potent anti-colitic effects through a dual mechanism involving direct inhibition of the macrophage-CCL2 axis and microbiota-dependent enhancement of gut immune homeostasis.