丁酸盐改善肝脏缺血再灌注损伤的机制研究

赵含香; 李明伟; 罗明; 那淑芳; 叶啟发

doi:10.14188/j.1671-8852.2026.0914

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丁酸盐改善肝脏缺血再灌注损伤的机制研究

更新时间：2026-10-26

- 丁酸盐改善肝脏缺血再灌注损伤的机制研究
- Mechanistic study on the ameliorative effects of butyrate on hepatic ischemia⁃reperfusion injury
- 武汉大学学报（医学版） 2026年页码：1-10
- 作者机构：
  
  武汉大学中南医院/武汉大学肝胆疾病研究院/武汉大学移植医学中心/移植医学技术湖北省重点实验室湖北武汉 430071
- 作者简介：
  
  赵含香，女，1999—，医学硕士，主要从事肝脏缺血再灌注研究，E⁃mail:2326757946@qq.com。
  叶啟发，E⁃mail:yqf_china@163.com。
- 基金信息：
- DOI：10.14188/j.1671-8852.2026.0914
  中图分类号： R575
- 收稿：2026-06-02，
  
  网络首发：2026-10-26，
- 稿件说明：
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赵含香, 李明伟, 罗明, 等. 丁酸盐改善肝脏缺血再灌注损伤的机制研究[J/OL]. 武汉大学学报（医学版）, 2026,1-10.

ZHAO Hanxiang, LI Mingwei, LUO Ming, et al. Mechanistic study on the ameliorative effects of butyrate on hepatic ischemia⁃reperfusion injury[J/OL]. Medical Journal of Wuhan University, 2026, 1-10.
赵含香, 李明伟, 罗明, 等. 丁酸盐改善肝脏缺血再灌注损伤的机制研究[J/OL]. 武汉大学学报（医学版）, 2026,1-10. DOI： 10.14188/j.1671-8852.2026.0914.

ZHAO Hanxiang, LI Mingwei, LUO Ming, et al. Mechanistic study on the ameliorative effects of butyrate on hepatic ischemia⁃reperfusion injury[J/OL]. Medical Journal of Wuhan University, 2026, 1-10. DOI： 10.14188/j.1671-8852.2026.0914.

摘要

目的

探讨肠道丁酸代谢对肝脏缺血再灌注损伤（IRI）的作用及其分子机制。

方法

通过70%肝脏缺血建立小鼠IRI模型，利用链霉素建立的产丁酸菌缺失模型，外源性给予丁酸盐补充干预，检测不同模型下血清转氨酶、病理、凋亡、炎症及线粒体超微结构，结合转录组测序、Western Blot等验证组蛋白去乙酰化酶3(HDAC3)/NF⁃κB通路的变化。

结果

链霉素处理加重了小鼠IRI，转氨酶ALT和AST水平显著升高，肝脏呈现更为广泛的融合性坏死、肝索断裂及剧烈的炎症细胞浸润，细胞凋亡增多，线粒体嵴的崩解与空泡化加重。外源性补充丁酸盐显著逆转了上述病理表型。机制上，丁酸盐抑制HDAC3活性，稳定IκBα，阻断NF⁃κB p65核转位及下游炎症因子释放。

结论

肠道产丁酸菌的缺失会增加IRI易感性。丁酸盐通过抑制HDAC3/NF⁃κB通路发挥抗炎和保护线粒体作用，围手术期恢复肠道产丁酸菌生态位或补充丁酸盐有望成为减轻肝脏IRI的新策略。

Abstract

Objective

To explore the role of intestinal butyrate metabolism in liver ischemia⁃reperfusion injury (IRI) and its molecular mechanism.

Methods

A mouse model of IRI was established by 70% liver ischemia. A butyrate⁃producing bacteria⁃deficient model was established by streptomycin treatment. Exogenous butyrate supplementation was used for intervention. Serum enzymes

pathology

apoptosis

inflammation and mitochondrial ultrastructure were detected in different models. The changes of histone deacetylase 3 （HDAC3)/NF⁃κB pathway were verified by transcriptome sequencing and Western Blot.

Results

Streptomycin treatment aggravated IRI in mice

with significantly increased ALT and AST levels

more extensive confluent necrosis

disrupted hepatic cords and severe inflammatory cell infiltration in the liver

increased apoptosis

and aggravated mitochondrial cristae disintegration and vacuolization. Exogenous butyrate supplementation significantly reversed the above pathological phenotypes. Mechanistically

butyrate inhibited HDAC3 activity

stabilized IκBα

blocked NF⁃κB p65 nuclear translocation and the release of downstream inflammatory factors.

Conclusion

The absence of intestinal butyrate⁃producing bacteria increases the susceptibility to IRI. Butyrate exerts anti⁃inflammatory and mitochondrial protective effects by inhibiting the HDAC3/NF⁃κB pathway. Restoring the intestinal butyrate⁃producing bacteria niche or supplementing butyrate during the perioperative period may become a new strategy to alleviate liver IRI.

关键词

Keywords

references

HU X H , CHEN L , WU H , et al . Cell therapy in end‑stage liver disease: Replace and remodel [J ] . Stem Cell Res Ther , 2023 , 14 ( 1 ): 141 .

DE OLIVEIRA T H C , GONÇALVES G K N . Liver ischemia reperfusion injury: Mechanisms, cellular pathways, and therapeutic approaches [J ] . Int Immunopharmacol , 2025 , 150 : 114299 .

中华医学会器官移植学分会 , 中国医师协会器官移植医师分会 , 中国医师协会器官移植医师分会移植病理学组 , 等 . 肝移植常见并发症病理诊断指南(2024版) [J ] . 中华消化外科杂志 , 2024 , 23 ( 8 ): 1001 ‑ 1021 .

Chinese Society of Organ Transplantation of Chinese Medical Association , Chinese College of Organ Transplant Physicians of Chinese Medical Doctor Association , Transplant Pathology Group of Chinese College of Organ Transplant Physicians of Chinese Medical Doctor Association , et al . Guidelines for Pathological Diagnosis of Common Complications of Liver Transplantation (2024 Edition) [J ] . Chinese Journal of Digestive Surgery , 2024 , 23 ( 8 ): 1001 ⁃ 1021 .

DAR W A , SULLIVAN E , BYNON J S , et al . Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms [J ] . Liver Int , 2019 , 39 ( 5 ): 788 ‑ 801 .

ZHAI Y , PETROWSKY H , HONG J C , et al . Ischaemia‑reperfusion injury in liver transplantation: from bench to bedside [J ] . Nat Rev Gastroenterol Hepatol , 2013 , 10 ( 2 ): 79 ‑ 89 .

ITO T , NAINI B V , MARKOVIC D , et al . Ischemia‑reperfusion injury and its relationship with early allograft dysfunction in liver transplant patients [J ] . Am J Transplant , 2021 , 21 ( 2 ): 614 ‑ 625 .

CHEN G R , HU X , HUANG Y C , et al . Role of the immune system in liver transplantation and its implications for therapeutic interventions [J ] . MedComm , 2023 , 4 ( 6 ): e444 .

PENG Y M , YIN Q , YUAN M X , et al . Role of hepatic stellate cells in liver ischemia‑reperfusion injury [J ] . Front Immunol , 2022 , 13 : 891868 .

GAO Y N , YAO Q Q , MENG L , et al . Double‑side role of short chain fatty acids on host health via the gut‑organ axes [J ] . Anim Nutr , 2024 , 18 : 322 ‑ 339 .

MUKHOPADHYA I , LOUIS P . Gut microbiota‑derived short‑chain fatty acids and their role in human health and disease [J ] . Nat Rev Microbiol , 2025 , 23 ( 10 ): 635 ‑ 651 .

LOUIS P , FLINT H J . Diversity, metabolism and microbial ecology of butyrate‑producing bacteria from the human large intestine [J ] . FEMS Microbiol Lett , 2009 , 294 ( 1 ): 1 ‑ 8 .

COPPOLA S , AVAGLIANO C , CALIGNANO A , et al . The protective role of butyrate against obesity and obesity‑related diseases [J ] . Molecules , 2021 , 26 ( 3 ): 682 .

ZHOU D , PAN Q , XIN F Z , et al . Sodium butyrate attenuates high‑fat diet‑induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier [J ] . World J Gastroenterol , 2017 , 23 ( 1 ): 60 ‑ 75 .

KALKAN A E , BINMOWYNA M N , RAPOSO A , et al . Beyond the gut: Unveiling butyrate's global health impact through gut health and dysbiosis‑related conditions: A narrative review [J ] . Nutrients , 2025 , 17 ( 8 ): 1305 .

LA ROSA S L , LETH M L , MICHALAK L , et al . The human gut Firmicute Roseburia intestinalis is a primary degrader of dietary β‑mannans [J ] . Nat Commun , 2019 , 10 ( 1 ): 905 .

DE VUYST L , LEROY F . Cross‑feeding between bifidobacteria and butyrate‑producing colon bacteria explains bifdobacterial competitiveness, butyrate production, and gas production [J ] . Int J Food Microbiol , 2011 , 149 ( 1 ): 73 ‑ 80 .

GUO C , CHE X Y , BRIESE T , et al . Deficient butyrate‑producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS [J ] . Cell Host Microbe , 2023 , 31 ( 2 ): 288 ‑ 304.e8 .

SNODGRASS J L , VELAYUDHAN B T . Butyrate‑producing bacteria as a keystone species of the gut microbiome: A systemic review of dietary impact on gut‑brain and host health [J ] . Int J Mol Sci , 2026 , 27 ( 3 ): 1289 .

CHANG L Y , LIU Y , LI H P , et al . Gut microbiome and its metabolites in liver cirrhosis: Mechanisms and clinical implications [J ] . Front Cell Infect Microbiol , 2025 , 15 : 1717696 .

ODENWALD M A , RAMASWAMY R , LIN H Y , et al . Fecal butyrate and deoxycholic acid concentrations correlate with mortality in patients with liver disease [J ] . Gastro Hep Adv , 2025 , 4 ( 8 ): 100695 .

JIN C J , SELLMANN C , ENGSTLER A J , et al . Supplementation of sodium butyrate protects mice from the development of non‑alcoholic steatohepatitis (NASH) [J ] . Br J Nutr , 2015 , 114 ( 11 ): 1745 ‑ 1755 .

BYNDLOSS M X , OLSAN E E , RIVERA‑CHÁVEZ F , et al . Microbiota‑activated PPAR‑γ signaling inhibits dysbiotic Enterobacteriaceae expansion [J ] . Science , 2017 , 357 ( 6351 ): 570 ‑ 575 .

LEUS N G , ZWINDERMAN M R , DEKKER F J . Histone deacetylase 3 (HDAC 3) as emerging drug target in NF‑κB‑mediated inflammation [J ] . Curr Opin Chem Biol , 2016 , 33 : 160 ‑ 168 .

AKHTAR M , CHEN Y , MA Z Y , et al . Gut microbiota‑derived short chain fatty acids are potential mediators in gut inflammation [J ] . Anim Nutr , 2022 , 8 : 350 ‑ 360 .

PANT K , VENUGOPAL S K , LORENZO PISARELLO M J , et al . The role of gut microbiome‑derived short‑chain fatty acid butyrate in hepatobiliary diseases [J ] . Am J Pathol , 2023 , 193 ( 10 ): 1455 ‑ 1467 .

QIAO Y L , QIAN J M , WANG F R , et al . Butyrate protects liver against ischemia reperfusion injury by inhibiting nuclear factor kappa B activation in Kupffer cells [J ] . J Surg Res , 2014 , 187 ( 2 ): 653 ‑ 659 .

HADEM J , KIELSTEIN J T , MANNS M P , et al . Outcomes of renal dysfunction in patients with acute liver failure [J ] . U Eur Gastroenterol J , 2019 , 7 ( 3 ): 388 ‑ 396 .

LOUIS P , FLINT H J . Formation of propionate and butyrate by the human colonic microbiota [J ] . Environ Microbiol , 2017 , 19 ( 1 ): 29 ‑ 41 .

CHEN J Z , VITETTA L . Gut microbiota metabolites in NAFLD pathogenesis and therapeutic implications [J ] . Int J Mol Sci , 2020 , 21 ( 15 ): 5214 .

CANFORA E E , JOCKEN J W , BLAAK E E . Short‑chain fatty acids in control of body weight and insulin sensitivity [J ] . Nat Rev Endocrinol , 2015 , 11 ( 10 ): 577 ‑ 591 .

ARPAIA N , CAMPBELL C , FAN X Y , et al . Metabolites produced by commensal bacteria promote peripheral regulatory T‑cell generation [J ] . Nature , 2013 , 504 ( 7480 ): 451 ‑ 455 .

DE OLIVEIRA T H C , MARQUES P E , PROOST P , et al . Neutrophils: A cornerstone of liver ischemia and reperfusion injury [J ] . Lab Investig , 2018 , 98 ( 1 ): 51 ‑ 62 .

PERALTA C , JIMÉNEZ‑CASTRO M B , GRACIA‑SANCHO J . Hepatic ischemia and reperfusion injury: Effects on the liver sinusoidal milieu [J ] . J Hepatol , 2013 , 59 ( 5 ): 1094 ‑ 1106 .

XU J , YANG Z , ZENG J H . Role of NF‑kappaB in liver ischemia reperfusion injury of rats [J ] . Curr Med Sci , 2003 , 23 ( 2 ): 158 ‑ 160 .

ELTZSCHIG H K , ECKLE T . Ischemia and reperfusion: From mechanism to translation [J ] . Nat Med , 2011 , 17 ( 11 ): 1391 ‑ 1401 .

TRIPATHI A , DEBELIUS J , BRENNER D A , et al . The gut‑liver axis and the intersection with the microbiome [J ] . Nat Rev Gastroenterol Hepatol , 2018 , 15 ( 7 ): 397 ‑ 411 .

ASSIMAKOPOULOS S F , BHAGANI S , AGGELETOPOULOU I , et al . The role of gut barrier dysfunction in postoperative complications in liver transplantation: Pathophysiological and therapeutic considerations [J ] . Infection , 2024 , 52 ( 3 ): 723 ‑ 736 .

KATO K , NAGAO M , MIYAMOTO K , et al . Longitudinal analysis of the intestinal microbiota in liver transplantation [J ] . Transplant Direct , 2017 , 3 ( 4 ): e144 .

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