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Research Article | Open Access

Gut microbiota metabolite butyric acid alleviated Klebsiella Pneumoniae induced lung injury by regulating CX3CR1+NK via PI3K/AKT pathway

Sucheng Mu1,‡, Meijia Chang1,2,‡ , Yongqi Shen1,‡, Xingyue Wu1, Yi Han1, Hao Xiang1, Yue Luo1, Yao Chen1, Huajun Zheng3( ), Zhenju Song1,2,4,5( ), Chaoyang Tong1( )
Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
Shanghai Institute of Infectious Disease and Biosecurity, Zhongshan Hospital, Fudan University, 38 Yixueyuan Road, Shanghai 200032, China
Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, National Health Commission Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, 2140 Xietu Road, Shanghai 200237, China
Shanghai Key Laboratory of Lung Inflammation and Injury, 180 Fenglin Road, Shanghai 200032, China
Institute of Emergency Rescue and Critical Care, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China

‡Sucheng Mu, Meijia Chang, and Yongqi Shen are the first co-authors.

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Highlights

• Gut microbiota-depleted mice exhibit increased mortality after Klebsiella pneumoniae infection, which is rescued by fecal microbiota transplantation through the restoration of CX3CR1+ NK cells, highlighting the essential role of the gut microbiota in sepsis defense.

• Butyric acid, a key microbial metabolite, increases the expression of CX3CR1 on NK cells through the PI3K/AKT pathway, improving bacterial clearance, IFN-γ secretion and survival in infected mice.

• Targeted butyric acid supplementation reduces lung injury and mortality in gut microbiota-depleted mice, suggesting a potential therapeutic strategy for sepsis by that involves modulation of the gut–lung NK cell axis.

Abstract

Background

The expression of CX3CR1 is regulated by the gut microbiota and is correlated with the prognosis of sepsis in patients. However, the underlying mechanism has remained uncertain. This study aims to explore the role of gut microbiota components in regulating CX3CR1 expression and its impact on pneumonia-induced lung injury during sepsis.

Methods

Mice were fed a mixture of antibiotics to establish a pseudogerm-free mouse model and then infected with Klebsiella pneumoniae. Fecal microbiota transplantation (FMT) was performed on microbiota-depleted mice, and 16S rRNA gene sequencing and targeted metabolomics were used to identify the key metabolites. Flow cytometry was employed to analyze the phenotypes of natural killer (NK) cells. Butyric acid was added as a supplement for rescue. Next, NK92 cells were pretreated with butyric acid to explore the potential signaling pathways involved.

Results

In the animal study, we revealed that the expression of CX3CR1 on NK cells depended on the intestinal microbiota and its metabolites, which were related to the survival rates of gut microbiota-depleted mice after K. pneumoniae infection. FMT increased the percentage of CX3CR1+ NK cells in the lungs of these mice, restored the disordered microbiota and metabolites, and alleviated the lung injury induced by infection. Among the metabolites, butyric acid was identified as the key metabolite and was shown to increase the proportion of CX3CR1+ NK cells and interferon (IFN)-γ secretion, reduce bacterial loads, increase lung tissue damage, and increase survival rates. In vitro, butyric acid activated the PI3K/AKT pathway in NK92 cells, promoted CX3CR1 expression, and enhanced NK cell activity and migration ability.

Conclusions

We concluded that butyric acid alleviated K. pneumoniae-induced lung injury by regulating CX3CR1+ NK cells via the PI3K/AKT pathway.

Keywords

Klebsiella pneumoniaeAcute lung injuryGut microbiotaButyric acidNatural killer cells

References

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Burns & Trauma
Volume 14 Issue 1,
May 2026
Article number: tkaf069
DOI: 10.1093/burnst/tkaf069

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Cite this article:
Mu S, Chang M, Shen Y, et al. Gut microbiota metabolite butyric acid alleviated Klebsiella Pneumoniae induced lung injury by regulating CX3CR1+NK via PI3K/AKT pathway. Burns & Trauma, 2026, 14(1): tkaf069. https://doi.org/10.1093/burnst/tkaf069

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Received: 22 September 2024
Revised: 15 September 2025
Accepted: 19 October 2025
Published: 29 October 2025
© The Author(s) 2025. Published by Oxford University Press.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.