肠道菌群在脓毒症相关性肝损伤发病与治疗中的作用研究进展

doi:10.12114/j.issn.1007-9572.2023.0069

摘要/Abstract

摘要： 脓毒症的特点是对感染的免疫反应失调，导致威胁生命的器官功能障碍。脓毒症相关性肝损伤（SALI）被认为是重症监护室（ICU）中预测患者死亡的独立危险因素。随着近年来对肠-肝轴的研究越来越多，肠道菌群与肝脏疾病的密切联系逐步被揭开。肠道菌群失调被证明可以通过丝裂原活化蛋白激酶/核转录因子κB（MAPK/NF-κB）信号通路和损害肠道屏障诱发SALI。同时，粪便微生物移植（FMT）和益生菌的使用在SALI的治疗中具有很大的潜力。本文综述了近年来国内外相关研究进展，以期为SALI的发病和治疗提供新的见解。

关键词: 胃肠道微生物组, 肠道菌群, 脓毒症, 肝损伤, 粪便微生物移植, 益生菌, 综述

Abstract:

Sepsis is characterized by a dysregulation of immune response to infection, leading to life-threatening organ dysfunction. Sepsis-associated liver injury (SALI) is considered an independent risk factor for predicting death in the intensive care unit (ICU). With the increasing number of studies on the gut-liver axis in recent years, the close linkage of gut microbiota and liver diseases has been gradually revealed. Dysbiosis of gut microbiota has been shown to induce SALI through the mitogen-activated protein kinase/nuclear transcription factorκB (MAPK/NF-κB) signaling pathway and damage to the intestinal barrier. Meanwhile, fecal microbiota transplantation (FMT) and the application of probiotics have great potential in the treatment of SALI. This paper reviews the relevant research progress in recent years both at home and abroad, in order to provide new insights into the pathogenesis and treatment of SALI.

Key words: Gastrointestinal microbiome, Gut microbiota, Sepsis, Liver injury, FMT, Probiotics, Review

陈文胜,刘文明. 肠道菌群在脓毒症相关性肝损伤发病与治疗中的作用研究进展[J]. 中国全科医学, 2024, 27(21): 2665-2671. DOI: 10.12114/j.issn.1007-9572.2023.0069.
CHEN Wensheng,LIU Wenming. Research Progress on the Role of Gut Microbiota in the Pathogenesis and Treatment of Sepsis-associated Liver Injury[J]. Chinese General Practice, 2024, 27(21): 2665-2671. DOI: 10.12114/j.issn.1007-9572.2023.0069.

图/表 1

参考文献 61

[1]	MINASYAN H. Sepsis：mechanisms of bacterial injury to the patient[J]. Scand J Trauma Resusc Emerg Med，2019，27（1）：19. DOI：10.1186/s13049-019-0596-4.
[2]	SCHULER A，WULF D A，LU Y，et al. The impact of acute organ dysfunction on long-term survival in Sepsis[J]. Crit Care Med，2018，46（6）：843-849. DOI：10.1097/CCM.0000000000003023.
[3]	SUN J，ZHANG J X，WANG X F，et al. Gut-liver crosstalk in sepsis-induced liver injury[J]. Crit Care，2020，24（1）：614. DOI：10.1186/s13054-020-03327-1.
[4]	YEH A，ROGERS M B，FIREK B，et al. Dysbiosis across multiple body sites in critically ill adult surgical patients[J]. Shock，2016，46（6）：649-654. DOI：10.1097/SHK.0000000000000691.
[5]	HYOJU S K，ZABORIN A，KESKEY R，et al. Mice fed an obesogenic western diet，administered antibiotics，and subjected to a sterile surgical procedure develop lethal septicemia with multidrug-resistant pathobionts[J]. mBio，2019，10（4）：e00903-00919. DOI：10.1128/mBio.00903-19.
[6]	FAY K T，KLINGENSMITH N J，CHEN C W，et al. The gut microbiome alters immunophenotype and survival from sepsis[J]. FASEB J，2019，33（10）：11258-11269. DOI：10.1096/fj.201802188R.
[7]	MENG X，LI S，LI Y，et al. Gut microbiota's relationship with liver disease and role in hepatoprotection by dietary natural products and probiotics[J]. Nutrients，2018，10（10）：1457. DOI：10.3390/nu10101457.
[8]	STALEY C，WEINGARDEN A R，KHORUTS A，et al. Interaction of gut microbiota with bile acid metabolism and its influence on disease states[J]. Appl Microbiol Biotechnol，2017，101（1）：47-64. DOI：10.1007/s00253-016-8006-6.
[9]	MA C，HAN M J，HEINRICH B，et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells[J]. Science，2018，360（6391）：eaan5931. DOI：10.1126/science.aan5931.
[10]	JUANOLA O，HASSAN M，KUMAR P，et al. Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns[J]. Gut Microbes，2021，13（1）：1-20. DOI：10.1080/19490976.2021.1911534.
[11]	URDANETA V，CASADESÚS J. Interactions between bacteria and bile salts in the gastrointestinal and hepatobiliary tracts[J]. Front Med （Lausanne），2017，4：163. DOI：10.3389/fmed.2017.00163.
[12]	YUAN Y Q，LIU Q B，ZHAO F Q，et al. Holothuria leucospilota polysaccharides ameliorate hyperlipidemia in high-fat diet-induced rats via short-chain fatty acids production and lipid metabolism regulation[J]. Int J Mol Sci，2019，20（19）：4738.
[13]	WANG G，PAN R L，LIANG X，et al. Perfluorooctanoic acid-induced liver injury is potentially associated with gut microbiota dysbiosis[J]. Chemosphere，2021，266：129004. DOI：10.1016/j.chemosphere.2020.129004.
[14]	MA S M，SUN Y Y，ZHENG X T，et al. Gastrodin attenuates perfluorooctanoic acid-induced liver injury by regulating gut microbiota composition in mice[J]. Bioengineered，2021，12（2）：11546-11556. DOI：10.1080/21655979.2021.2009966.
[15]	LI X L，LIU Y，GUO X F，et al. Effect of Lactobacillus casei on lipid metabolism and intestinal microflora in patients with alcoholic liver injury[J]. Eur J Clin Nutr，2021，75（8）：1227-1236. DOI：10.1038/s41430-020-00852-8.
[16]	XU B C，HAO K Y，CHEN X G，et al. Broussonetia papyrifera polysaccharide alleviated acetaminophen-induced liver injury by regulating the intestinal flora[J]. Nutrients，2022，14（13）：2636. DOI：10.3390/nu14132636.
[17]	XIA J F，LV L X，LIU B Q，et al. Akkermansia muciniphila ameliorates acetaminophen-induced liver injury by regulating gut microbial composition and metabolism[J]. Microbiol Spectr，2022，10（1）：e0159621. DOI：10.1128/spectrum.01596-21.
[18]	SUN Y，CONG L，YANG S，et al. Moxifloxacin induced liver injury by causing Lachnospiraceae deficiency and interfering with butyric acid production through gut-liver axis[J]. Dis Markers，2022，2022：9302733. DOI：10.1155/2022/9302733.
[19]	周杰，刘文明，许峂嵘，等. 脓毒症相关胆汁淤积性肝功能障碍的回顾性研究[J]. 中国中西医结合急救杂志，2018，25（4）：346-350. DOI：10.3969/j.issn.1008-9691.2018.04.003.
[20]	LIANG H Y，SONG H，ZHANG X J，et al. Metformin attenuated sepsis-related liver injury by modulating gut microbiota[J]. Emerg Microbes Infect，2022，11（1）：815-828. DOI：10.1080/22221751.2022.2045876.
[21]	MA Y，LIU G，TANG M Y，et al. Epigallocatechin gallate can protect mice from acute stress induced by LPS while stabilizing gut microbes and serum metabolites levels[J]. Front Immunol，2021，12：640305. DOI：10.3389/fimmu.2021.640305.
[22]	LIU Z G，LI N，FANG H，et al. Enteric dysbiosis is associated with sepsis in patients[J]. FASEB J，2019，33（11）：12299-12310. DOI：10.1096/fj.201900398RR.
[23]	WULLAERT A，BONNET M C，PASPARAKIS M. NF-κB in the regulation of epithelial homeostasis and inflammation[J]. Cell Res，2011，21（1）：146-158. DOI：10.1038/cr.2010.175.
[24]	XU D Q，LIAO S T，LV Y，et al. NMR-based metabolomics approach reveals effects of antioxidant nutrients in sepsis-induced changes in rat liver injury[J]. J Nutr Biochem，2020，85：108440. DOI：10.1016/j.jnutbio.2020.108440.
[25]	DKHIL M A，AL-QURAISHY S，MONEIM A E A. Ziziphus spina-christi leaf extract pretreatment inhibits liver and spleen injury in a mouse model of sepsis via anti-oxidant and anti-inflammatory effects[J]. Inflammopharmacology，2018，26（3）：779-791. DOI：10.1007/s10787-017-0439-8.
[26]	LI X L，LI M F，LIU L Y，et al. Protective effects of glucocorticoid on liver injury in a rat sepsis model[J]. Exp Ther Med，2019，18（4）：3153-3160. DOI：10.3892/etm.2019.7899.
[27]	GONG S H，YAN Z Z，LIU Z G，et al. Intestinal microbiota mediates the susceptibility to polymicrobial Sepsis-induced liver injury by granisetron generation in mice[J]. Hepatology，2019，69（4）：1751-1767. DOI：10.1002/hep.30361.
[28]	CHEN Y Y，GUAN W Y，ZHANG N，et al. Lactobacillus plantarum Lp2 improved LPS-induced liver injury through the TLR-4/MAPK/NFκB and Nrf2-HO-1/CYP2E1 pathways in mice[J]. Food Nutr Res，2022：66. DOI：10.29219/fnr.v66.5459.
[29]	LAU T Y，XIAO J，LIONG E C，et al. Hepatic response to chronic hypoxia in experimental rat model through HIF-1 alpha，activator protein-1 and NF-kappa B[J]. Histol Histopathol，2013，28（4）：463-471.
[30]	ZHAN C Y，CHEN D，LUO J L，et al. Protective role of down-regulated microRNA-31 on intestinal barrier dysfunction through inhibition of NF-κB/HIF-1α pathway by binding to HMOX1 in rats with sepsis[J]. Mol Med，2018，24（1）：55. DOI：10.1186/s10020-018-0053-2.
[31]	MA Z H，ZHANG Y M，LI Q C，et al. Resveratrol improves alcoholic fatty liver disease by downregulating HIF-1α expression and mitochondrial ROS production[J]. PLoS One，2017，12（8）：e0183426. DOI：10.1371/journal.pone.0183426.
[32]	DING L，GONG Y H，YANG Z F，et al. Lactobacillus rhamnosus GG ameliorates liver injury and hypoxic hepatitis in rat model of CLP-induced Sepsis[J]. Dig Dis Sci，2019，64（10）：2867-2877. DOI：10.1007/s10620-019-05628-0.
[33]	OTANI S，COOPERSMITH C M. Gut integrity in critical illness[J]. J Intensive Care，2019，7：17. DOI：10.1186/s40560-019-0372-6.
[34]	GUO X X，ZHANG Y D，WANG T C，et al. Ginger and 6-gingerol prevent lipopolysaccharide-induced intestinal barrier damage and liver injury in mice[J]. J Sci Food Agric，2022，102（3）：1066-1075. DOI：10.1002/jsfa.11442.
[35]	FU J H，LI G F，WU X M，et al. Sodium butyrate ameliorates intestinal injury and improves survival in a rat model of cecal ligation and puncture-induced Sepsis[J]. Inflammation，2019，42（4）：1276-1286. DOI：10.1007/s10753-019-00987-2.
[36]	LORENTZ C A，LIANG Z，MENG M，et al. Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis[J]. Mol Med，2017，23：155-165. DOI：10.2119/molmed.2016.00256.
[37]	BUFFIE C G，PAMER E G. Microbiota-mediated colonization resistance against intestinal pathogens[J]. Nat Rev Immunol，2013，13（11）：790-801. DOI：10.1038/nri3535.
[38]	WANG G，HUANG S，WANG Y M，et al. Bridging intestinal immunity and gut microbiota by metabolites[J]. Cell Mol Life Sci，2019，76（20）：3917-3937. DOI：10.1007/s00018-019-03190-6.
[39]	GARGIULLO L，DEL CHIERICO F，D'ARGENIO P，et al. Gut microbiota modulation for multidrug-resistant organism decolonization：present and future perspectives[J]. Front Microbiol，2019，10：1704. DOI：10.3389/fmicb.2019.01704.
[40]	KIM S M，DEFAZIO J R，HYOJU S K，et al. Fecal microbiota transplant rescues mice from human pathogen mediated sepsis by restoring systemic immunity[J]. Nat Commun，2020，11（1）：2354. DOI：10.1038/s41467-020-15545-w.
[41]	GAI X W，WANG H W，LI Y Q，et al. Fecal microbiota transplantation protects the intestinal mucosal barrier by reconstructing the gut microbiota in a murine model of Sepsis[J]. Front Cell Infect Microbiol，2021，11：736204. DOI：10.3389/fcimb.2021.736204.
[42]	LI Q R，WANG C Y，TANG C，et al. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation：a case report[J]. Crit Care，2015，19（1）：37. DOI：10.1186/s13054-015-0738-7.
[43]	ZHAO H Y，LYU Y J，ZHAI R Q，et al. Metformin mitigates Sepsis-related neuroinflammation via modulating gut microbiota and metabolites[J]. Front Immunol，2022，13：797312. DOI：10.3389/fimmu.2022.797312.
[44]	ZHANG H D，XU J，WU Q R，et al. Gut microbiota mediates the susceptibility of mice to Sepsis-associated encephalopathy by butyric acid[J]. J Inflamm Res，2022，15：2103-2119. DOI：10.2147/JIR.S350566.
[45]	GUNDACKER N D，TAMHANE A，WALKER J B，et al. Comparative effectiveness of faecal microbiota transplant by route of administration[J]. J Hosp Infect，2017，96（4）：349-352.
[46]	RAMAI D，ZAKHIA K，OFOSU A，et al. Fecal microbiota transplantation：donor relation，fresh or frozen，delivery methods，cost-effectiveness[J]. Ann Gastroenterol，2019，32（1）：30-38. DOI：10.20524/aog.2018.0328.
[47]	KAO D N，ROACH B，SILVA M，et al. Effect of oral capsule- vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection：a randomized clinical trial[J]. JAMA，2017，318（20）：1985-1993. DOI：10.1001/jama.2017.17077.
[48]	DEFILIPP Z，BLOOM P P，TORRES SOTO M，et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant[J]. N Engl J Med，2019，381（21）：2043-2050. DOI：10.1056/NEJMoa1910437.
[49]	BARBOSA R S D，VIEIRA-COELHO M A. Probiotics and prebiotics：focus on psychiatric disorders - a systematic review[J]. Nutr Rev，2020，78（6）：437-450. DOI：10.1093/nutrit/nuz080.
[50]	YIN J T，SUN W，YU X Q，et al. Lacticaseibacillus rhamnosus TR08 alleviated intestinal injury and modulated microbiota dysbiosis in septic mice[J]. BMC Microbiol，2021，21（1）：249. DOI：10.1186/s12866-021-02317-9.
[51]	ÁVILA P R M，MICHELS M，VUOLO F，et al. Protective effects of fecal microbiota transplantation in sepsis are independent of the modulation of the intestinal flora[J]. Nutrition，2020，73：110727. DOI：10.1016/j.nut.2020.110727.
[52]	TSUI K C，YEN T L，HUANG C J，et al. Lactobacillus rhamnosus GG as dietary supplement improved survival from lipopolysaccharides-induced sepsis in mice[J]. Food Sci Nutr，2021，9（12）：6786-6793. DOI：10.1002/fsn3.2630.
[53]	ABUOHASHISH H M，ZAGHLOUL E H，EL SHARKAWY A S，et al. Pharmacological effects of marine-derived Enterococcus faecium EA9 against acute lung injury and inflammation in cecal ligated and punctured septic rats[J]. Biomed Res Int，2021，2021：5801700. DOI：10.1155/2021/5801700.
[54]	TSILIKA M，THOMA G，AIDONI Z，et al. A four-probiotic preparation for ventilator-associated pneumonia in multi-trauma patients：results of a randomized clinical trial[J]. Int J Antimicrob Agents，2022，59（1）：106471. DOI：10.1016/j.ijantimicag.2021.106471.
[55]	CHU C，MURDOCK M H，JING D Q，et al. The microbiota regulate neuronal function and fear extinction learning[J]. Nature，2019，574（7779）：543-548. DOI：10.1038/s41586-019-1644-y.
[56]	LIU J M，JIN Y J，LI H J，et al. Probiotics exert protective effect against Sepsis-induced cognitive impairment by reversing gut microbiota abnormalities[J]. J Agric Food Chem，2020，68（50）：14874-14883. DOI：10.1021/acs.jafc.0c06332.
[57]	CHANG C M，TSAI M H，LIAO W C，et al. Effects of probiotics on gut microbiomes of extremely preterm infants in the neonatal intensive care unit：a prospective cohort study[J]. Nutrients，2022，14（15）：3239. DOI：10.3390/nu14153239.
[58]	GRANGER C，DERMYSHI E，ROBERTS E，et al. Necrotising enterocolitis，late-onset sepsis and mortality after routine probiotic introduction in the UK[J]. Arch Dis Child Fetal Neonatal Ed，2022，107（4）：352-358. DOI：10.1136/archdischild-2021-322252.
[59]	AYDOǦAN S，DILLI D，ÖZYAZICI A，et al. Lactobacillus rhamnosus Sepsis associated with probiotic therapy in a term infant with congenital heart disease[J]. Fetal Pediatr Pathol，2022，41（5）：823-827. DOI：10.1080/15513815.2021.1966144.
[60]	GÜN E，ÖZDEMIR H，ÇELIK D B，et al. Saccharomyces cerevisiae fungemia due to an unexpected source in the pediatric intensive care unit[J]. Turk J Pediatr，2022，64（1）：138-141. DOI：10.24953/turkjped.2020.1668.
[61]	SINHA A P，GUPTA S S，POLURU R，et al. Evaluating the efficacy of a multistrain probiotic supplementation for prevention of neonatal sepsis in 0-2-month-old low birth weight infants in India-the "ProSPoNS" Study protocol for a phaseⅢ，multicentric，randomized，double-blind，placebo-controlled trial[J]. Trials，2021，22（1）：242. DOI：10.1186/s13063-021-05193-w.

供体	受体	结果	参考文献
Sen小鼠与Res小鼠	无菌小鼠	Res小鼠粪便的受体小鼠在CLP后表现的肝损伤更轻（P<0.05）	GONG等^[27]
脓毒症患者与健康人	无菌小鼠	健康人粪便的受体小鼠在CLP后表现的肝损伤更轻（P<0.05），而其他器官损伤在两组之间无显著差异	LIU等^[22]
SALI小鼠与MET+SALI小鼠	无菌小鼠	MET+SALI小鼠粪便的受体小鼠在CLP后表现的肝损伤更轻（P<0.05）	LIANG等^[20]
CLP小鼠与MET+CLP小鼠	无菌小鼠	MET+CLP小鼠粪便的受体小鼠在CLP后表现出更轻的神经炎症（P>0.05）和神经元损伤（P<0.05）	ZHAO等^[43]
SSAE小鼠与LSAE小鼠	无菌小鼠	LSAE小鼠粪便的受体小鼠在CLP后表现出更轻的神经元损伤（P<0.05）	ZHANG等^[44]

供体	受体	结果	参考文献
Sen小鼠与Res小鼠	无菌小鼠	Res小鼠粪便的受体小鼠在CLP后表现的肝损伤更轻（P<0.05）	GONG等^[27]
脓毒症患者与健康人	无菌小鼠	健康人粪便的受体小鼠在CLP后表现的肝损伤更轻（P<0.05），而其他器官损伤在两组之间无显著差异	LIU等^[22]
SALI小鼠与MET+SALI小鼠	无菌小鼠	MET+SALI小鼠粪便的受体小鼠在CLP后表现的肝损伤更轻（P<0.05）	LIANG等^[20]
CLP小鼠与MET+CLP小鼠	无菌小鼠	MET+CLP小鼠粪便的受体小鼠在CLP后表现出更轻的神经炎症（P>0.05）和神经元损伤（P<0.05）	ZHAO等^[43]
SSAE小鼠与LSAE小鼠	无菌小鼠	LSAE小鼠粪便的受体小鼠在CLP后表现出更轻的神经元损伤（P<0.05）	ZHANG等^[44]