Time-restricted feeding protects against septic liver injury by reshaping gut microbiota and metabolite 3-hydroxybutyrate.

Apr 14, 2025

Experts: Jing-Juan Hu,Fan Deng,Qi-Shun Sun,Qing-Ming Xiong,Yue Min,Si-Yuan Feng,Ze-Bin Lin,Peng-Han Chen,Zhen Hu,Ling Wu,Xiao-Feng Chen,Sun Xie,Wei-Feng Liu,Cai Li,Ke-Xuan Liu

Liver injury is an independent risk factor for multiple organ dysfunction and high mortality in patients with sepsis. However, the pathological mechanisms and therapeutic strategies for sepsis-associated liver injury have not been fully elucidated. Time-restricted feeding (TRF) is a promising dietary regime, but its role in septic liver injury remains unknown. Using 16S rRNA gene sequencing, Q200 targeted metabolomics, transcriptomics, germ-free mice, Hmgcs2/Lpin1 gene knockout mice, and Aml12 cells experiments, we revealed that TRF can mitigate septic liver injury by modulating the gut microbiota, particularly by increasing () abundance, which was significantly reduced in septic mice. Further study revealed that live could markedly elevate serum levels of metabolite 3-hydroxybutyrate (3-HB) and alleviate sepsis-related injury, while the knockout of the key enzyme for 3-HB synthesis (3-hydroxy-3-methylglutaryl-CoA synthase 2, Hmgcs2) in the liver negated this protective effect. Additionally, serum 3-HB levels were significantly positively correlated with abundance and negatively correlated with liver injury indicators in septic patients, demonstrating a strong predictive value for septic liver injury (AUC = 0.8429). Mechanistically, 3-HB significantly inhibited hepatocyte ferroptosis by activating the PI3K/AKT/mTOR/LPIN1 pathway, reducing ACSL4, MDA, LPO, and Fe levels. This study demonstrates that TRF reduces septic liver injury by modulating gut microbiota to increase , which elevates 3-HB to activate PI3K/AKT/mTOR/LPIN1 and inhibit hepatocyte ferroptosis. Overall, this study elucidates the protective mechanism of TRF against septic liver injury and identifies 3-HB as a potential therapeutic target and predictive biomarker, thereby providing new insights into the clinical management and diagnosis of septic liver injury.

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ABOUT THE EXPERTS

Jing-Juan Hu,Fan Deng,Qi-Shun Sun,Qing-Ming Xiong,Yue Min,Si-Yuan Feng,Ze-Bin Lin,Peng-Han Chen,Zhen Hu,Ling Wu,Xiao-Feng Chen,Sun Xie,Wei-Feng Liu,Cai Li,Ke-Xuan Liu

Jing-Juan Hu

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Fan Deng

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Qi-Shun Sun

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Qing-Ming Xiong

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan, China.

Yue Min

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Si-Yuan Feng

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Ze-Bin Lin

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Peng-Han Chen

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Zhen Hu

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Ling Wu

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Xiao-Feng Chen

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Sun Xie

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Wei-Feng Liu

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Cai Li

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.

Ke-Xuan Liu

Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Precision Anesthesia and Perioperative Organ Protection, Guangzhou, Guangdong, China.