微生物学报

Drugs	Targets	Results	References
Sal	PPARα, TLR4, HO-1	Its crude extract can reduce ALT and TG levels, alleviate liver inflammation and ALD-related liver damage, activate PPARα to promote 4-HNE degradation, and down-regulate the mRNA expression of TLR4 and HO-1	[31-32]
SalA	Sirt1	SalA can regulate the Sirt1 expression, reduce the levels of ALT, AST, TG, and TC, enhance hepatocyte vitality, and alleviate ALD	[33-34]
SalB	Sirt1, CRP, TNF-α, IL-6	SalB can activate Sirt1, inhibit the expression of CRP, reduce the levels of pro-inflammatory factors such as TNF-α and IL-6, inhibit the increase of serum transaminase, and alleviate ALD	[35]
CTS	AMPK, Sirt1, Nrf2, CYP2E1	CTS can activate AMPK, Sirt1 pathways, and phosphorylate Nrf2, meanwhile, it can also inhibit CYP2E1 expression, suppress alcohol-induced hepatic steatosis, liver inflammatory response and oxidative stress injury, and alleviate ALD damage	[36-37]
Tan ⅡA	RXRα	Tan ⅡA can reverse abnormal RXRα expression, promote fatty acid oxidation, reduce hepatic lipid accumulation, and alleviate ALD-induced liver injury	[38]

Drugs	Targets	Results	References
Sal	PPARα, TLR4, HO-1	Its crude extract can reduce ALT and TG levels, alleviate liver inflammation and ALD-related liver damage, activate PPARα to promote 4-HNE degradation, and down-regulate the mRNA expression of TLR4 and HO-1	[31-32]
SalA	Sirt1	SalA can regulate the Sirt1 expression, reduce the levels of ALT, AST, TG, and TC, enhance hepatocyte vitality, and alleviate ALD	[33-34]
SalB	Sirt1, CRP, TNF-α, IL-6	SalB can activate Sirt1, inhibit the expression of CRP, reduce the levels of pro-inflammatory factors such as TNF-α and IL-6, inhibit the increase of serum transaminase, and alleviate ALD	[35]
CTS	AMPK, Sirt1, Nrf2, CYP2E1	CTS can activate AMPK, Sirt1 pathways, and phosphorylate Nrf2, meanwhile, it can also inhibit CYP2E1 expression, suppress alcohol-induced hepatic steatosis, liver inflammatory response and oxidative stress injury, and alleviate ALD damage	[36-37]
Tan ⅡA	RXRα	Tan ⅡA can reverse abnormal RXRα expression, promote fatty acid oxidation, reduce hepatic lipid accumulation, and alleviate ALD-induced liver injury	[38]

Types	Drugs	Total target subjects	Results	References
Natural products	CG	152 ALD patients	It significantly improved serum AST and ALT levels, thereby ameliorating liver function in ALD patients when combined with Sal	[40-41]
	SIL	112 ALD patients	It can improve serum TBIL and hepatic fibrosis markers, with no significant adverse reactions in ALD patients when combined with Sal	[44]
	PN, DPE	ALD model	They can increase the expression level of PPARα mRNA and inhibit alcohol-induced hepatic steatosis when combined with Sal	[45]
	SC, PUE, SIL	ALD model	They can inhibit the TGF-β/Smad signaling pathway, a key pathway involved in hepatic fibrosis, thereby alleviating liver fibrosis when combined with Sal	[46]
	GLPS, PUE, AM	ALD model	They can inhibit hepatic oxidative stress, lipid accumulation and apoptosis in mice with acute ALD when combined with Sal	[47]
	MA, CP, AO, PUE, AM	ALD model	They can restore alcohol-suppressed hepatic levels of PPARα and MTP, thereby alleviating ALD when combined with Sal	[48-49]
Antioxidant	GSH	270 ALD patients	It can reduce the levels of serum transaminase and liver fibrosis indicators in patients (60 cases), when combined with Sal, and has other clinical effective rate 90.48% (126 cases) and 95.24% (84 cases) with a significant synergistic effect	[51-53]
	PPC	118 ALD patients	It increases the abundance of intestinal Bifidobacterium bifidum, reduces the serum levels of LP and LPO when combined with Sal	[54]
Hepatoprotective drugs	Tiopronin	246 ALD patients	Its combined therapy was more effective than monotherapy when combined with Sal	[55-57]
	Magnesium sulfate	76 ALD patients	The combination of high-dose Sal and magnesium sulfate has a significant therapeutic effect on ALD cirrhosis, with mild toxic side effects	[59]
	Bicyclol	70 ALD patients	It downregulated TBIL and fibrosis markers, leading to significant improvement in ALD liver function, when combined with Sal	[60]

Types	Drugs	Total target subjects	Results	References
Natural products	CG	152 ALD patients	It significantly improved serum AST and ALT levels, thereby ameliorating liver function in ALD patients when combined with Sal	[40-41]
	SIL	112 ALD patients	It can improve serum TBIL and hepatic fibrosis markers, with no significant adverse reactions in ALD patients when combined with Sal	[44]
	PN, DPE	ALD model	They can increase the expression level of PPARα mRNA and inhibit alcohol-induced hepatic steatosis when combined with Sal	[45]
	SC, PUE, SIL	ALD model	They can inhibit the TGF-β/Smad signaling pathway, a key pathway involved in hepatic fibrosis, thereby alleviating liver fibrosis when combined with Sal	[46]
	GLPS, PUE, AM	ALD model	They can inhibit hepatic oxidative stress, lipid accumulation and apoptosis in mice with acute ALD when combined with Sal	[47]
	MA, CP, AO, PUE, AM	ALD model	They can restore alcohol-suppressed hepatic levels of PPARα and MTP, thereby alleviating ALD when combined with Sal	[48-49]
Antioxidant	GSH	270 ALD patients	It can reduce the levels of serum transaminase and liver fibrosis indicators in patients (60 cases), when combined with Sal, and has other clinical effective rate 90.48% (126 cases) and 95.24% (84 cases) with a significant synergistic effect	[51-53]
	PPC	118 ALD patients	It increases the abundance of intestinal Bifidobacterium bifidum, reduces the serum levels of LP and LPO when combined with Sal	[54]
Hepatoprotective drugs	Tiopronin	246 ALD patients	Its combined therapy was more effective than monotherapy when combined with Sal	[55-57]
	Magnesium sulfate	76 ALD patients	The combination of high-dose Sal and magnesium sulfate has a significant therapeutic effect on ALD cirrhosis, with mild toxic side effects	[59]
	Bicyclol	70 ALD patients	It downregulated TBIL and fibrosis markers, leading to significant improvement in ALD liver function, when combined with Sal	[60]

Ecological regulators	Types	Targets	Results	References
Akkermansia muciniphila	Probiotics	ALD model	It can regulate the intestinal functional barrier, inhibit bacterial endotoxins from entering the circulatory system, and alleviate ALD liver injury	[67-69]
Lactiplantibacillus plantarum	Probiotics	ALD model	It can regulate the EGFR-dependent mechanism prevents and alleviates alcohol-induced disruption of colonic epithelial tight junctions and liver injury	[71]
Lactiplantibacillus plantarum FB091	Probiotics	ALD model	It can reduce ballooning degeneration of liver cells and infiltration of inflammatory cells in ALD, alleviate the damage to the colonic tissue structure, promote alcohol metabolism, and relieve ALD liver injury	[72]
Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0052	Probiotics	89 ALD patients	They can reduce the levels of Proteus, Fusobacterium, and LPS, protect the intestinal barrier, and alleviate hepatitis	[73]
Lactobacillus rhamnosus CCFM1107	Probiotics	ALD model	It significantly inhibited the increase in the levels of serum aminotransferase, endotoxin, TG and TC, and ameliorated ALD liver injury	[74]
Lactobacillus rhamnosus NKU FL1-8	Probiotics	ALD model	It can decrease the levels of AST, ALT, MDA, SOD and GSH, relieve oxidative stress and decrease hepatic inflammation	[75]
Lactobacillus rhamnosus GG	Probiotics	ALD model	It ameliorates ALD liver injury through modulating antioxidant defenses	[76]
Bifidobacterium and PPC	Probiotics	ALD model	They can ameliorate liver function indicators in ALD rats, inhibit lipid accumulation and hepatic steatosis in ALD liver	[77]
Bifidobacterium and smectite powder	Probiotics	60 ALD patients	They can ameliorate ALD liver injury, without serious adverse reactions, and have the relatively safe therapeutic effect	[78]
Bifidobacterium pseudocatenulatum	Probiotics	ALD model	It can regulate the expression of Cd36, Fasn, Accα, Il-1β, CCL2 and TNF‑α, and ameliorate ALD liver injury	[79]
Bifidobacterium longum subsp. longum BL21	Probiotics	ALD model	It reduced the ethanol-induced abnormal elevation of serum AST and ALT levels in ALD mice	[80]
Bacillus subtilis and Enterococcus faecium	Probiotics	117 ALD patients	They can regulate the expression of TNF‑α, and alleviate ALD liver injury	[81]
Compound probiotic preparation	Probiotics	ALD model	It can alleviate hepatic inflammation, repair the intestinal barrier, reshape the intestinal flora, and alleviate ALD-induced injury	[82]
HRFP-Ⅱ-a, HRFP-Ⅱ-b, HRFP-Ⅱ-c	Prebiotics	ALD model	They can protect ALD mice via antioxidant, anti-inflammatory, lipid metabolism regulation and intestinal flora improvement	[83]
Chitosan oligosaccharide	Prebiotics	ALD model	It can reduce the expression of the liver metabolic enzyme CYP2E1 in ALD, activate the Keap1/Nrf2/HO-1 pathway, inhibit the NF-κB and MAPK pathways, alleviate ALD oxidative damage, hepatic steatosis and inflammation	[85]
Lactobacillus johnsonii HKLJ	Postbiotics	ALD model	It can activate the nucleotide-binding NOD2/IL-23/IL-22 signaling pathway, improve intestinal homeostasis, activate the hepatic STAT3 pathway, and alleviate ALD	[86]
CPS and SLP	Postbiotics	ALD model	It can promote short-chain fatty acid production, improve the intestinal functional barrier, and alleviate ALD injury	[87]
Bacillus coagulans and pectin	Synbiotics	ALD model	It can enhance intestinal barrier function and alleviate ALD liver injury	[88]
Bacteroides fragilis ATCC25285 and pectin	Synbiotics	ALD model	It can promote tryptophan metabolism, enhance intestinal immune function and alleviate ALD liver injury	[89]
Lactiplantibacillus plantarum and EGCG	Synbiotics	ALD model	They can inhibit the level of NF-κB, TNF-α, IL-12, TLR4, CD14, MD2, MyD88, COX-2, and alleviate ALD	[90]

Ecological regulators	Types	Targets	Results	References
Akkermansia muciniphila	Probiotics	ALD model	It can regulate the intestinal functional barrier, inhibit bacterial endotoxins from entering the circulatory system, and alleviate ALD liver injury	[67-69]
Lactiplantibacillus plantarum	Probiotics	ALD model	It can regulate the EGFR-dependent mechanism prevents and alleviates alcohol-induced disruption of colonic epithelial tight junctions and liver injury	[71]
Lactiplantibacillus plantarum FB091	Probiotics	ALD model	It can reduce ballooning degeneration of liver cells and infiltration of inflammatory cells in ALD, alleviate the damage to the colonic tissue structure, promote alcohol metabolism, and relieve ALD liver injury	[72]
Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0052	Probiotics	89 ALD patients	They can reduce the levels of Proteus, Fusobacterium, and LPS, protect the intestinal barrier, and alleviate hepatitis	[73]
Lactobacillus rhamnosus CCFM1107	Probiotics	ALD model	It significantly inhibited the increase in the levels of serum aminotransferase, endotoxin, TG and TC, and ameliorated ALD liver injury	[74]
Lactobacillus rhamnosus NKU FL1-8	Probiotics	ALD model	It can decrease the levels of AST, ALT, MDA, SOD and GSH, relieve oxidative stress and decrease hepatic inflammation	[75]
Lactobacillus rhamnosus GG	Probiotics	ALD model	It ameliorates ALD liver injury through modulating antioxidant defenses	[76]
Bifidobacterium and PPC	Probiotics	ALD model	They can ameliorate liver function indicators in ALD rats, inhibit lipid accumulation and hepatic steatosis in ALD liver	[77]
Bifidobacterium and smectite powder	Probiotics	60 ALD patients	They can ameliorate ALD liver injury, without serious adverse reactions, and have the relatively safe therapeutic effect	[78]
Bifidobacterium pseudocatenulatum	Probiotics	ALD model	It can regulate the expression of Cd36, Fasn, Accα, Il-1β, CCL2 and TNF‑α, and ameliorate ALD liver injury	[79]
Bifidobacterium longum subsp. longum BL21	Probiotics	ALD model	It reduced the ethanol-induced abnormal elevation of serum AST and ALT levels in ALD mice	[80]
Bacillus subtilis and Enterococcus faecium	Probiotics	117 ALD patients	They can regulate the expression of TNF‑α, and alleviate ALD liver injury	[81]
Compound probiotic preparation	Probiotics	ALD model	It can alleviate hepatic inflammation, repair the intestinal barrier, reshape the intestinal flora, and alleviate ALD-induced injury	[82]
HRFP-Ⅱ-a, HRFP-Ⅱ-b, HRFP-Ⅱ-c	Prebiotics	ALD model	They can protect ALD mice via antioxidant, anti-inflammatory, lipid metabolism regulation and intestinal flora improvement	[83]
Chitosan oligosaccharide	Prebiotics	ALD model	It can reduce the expression of the liver metabolic enzyme CYP2E1 in ALD, activate the Keap1/Nrf2/HO-1 pathway, inhibit the NF-κB and MAPK pathways, alleviate ALD oxidative damage, hepatic steatosis and inflammation	[85]
Lactobacillus johnsonii HKLJ	Postbiotics	ALD model	It can activate the nucleotide-binding NOD2/IL-23/IL-22 signaling pathway, improve intestinal homeostasis, activate the hepatic STAT3 pathway, and alleviate ALD	[86]
CPS and SLP	Postbiotics	ALD model	It can promote short-chain fatty acid production, improve the intestinal functional barrier, and alleviate ALD injury	[87]
Bacillus coagulans and pectin	Synbiotics	ALD model	It can enhance intestinal barrier function and alleviate ALD liver injury	[88]
Bacteroides fragilis ATCC25285 and pectin	Synbiotics	ALD model	It can promote tryptophan metabolism, enhance intestinal immune function and alleviate ALD liver injury	[89]
Lactiplantibacillus plantarum and EGCG	Synbiotics	ALD model	They can inhibit the level of NF-κB, TNF-α, IL-12, TLR4, CD14, MD2, MyD88, COX-2, and alleviate ALD	[90]

丹参与微生态调节剂：临床干预酒精性肝病的研究前景

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叶晨 ¹^,² , 沈秀芸 ² , 朱勍 ¹^,^* , 孙立涛 ²^,^*

微生物学报 | 综述 2026,66(10): 4808-4824

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微生物学报 |综述 2026 , 66 (10) : 4808 -4824

丹参与微生态调节剂：临床干预酒精性肝病的研究前景

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叶晨¹^,², 沈秀芸², 朱勍¹^,^*, 孙立涛²^,^*

作者信息

^1.浙江工业大学生物工程学院，浙江省生物有机合成重点实验室，浙江杭州

^2.杭州医学院附属人民医院(浙江省人民医院)，超声医学科肿瘤中心，浙江杭州

通讯作者:

朱勍, 孙立涛

作者简介:

作者贡献声明

叶晨：初稿写作，收集整理表格；沈秀芸：稿件修改和润色，绘制图片；朱勍：指导写作逻辑；孙立涛：指导写作思路。

Salvia miltiorrhiza and microecological regulators: research prospects for clinical intervention in alcoholic liver disease

Chen YE¹^,², Xiuyun SHEN², Qing ZHU¹^,^*, Litao SUN²^,^*

Affiliations

^1.Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, Zhejiang, China

^2.Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China

Corresponding Author:

^*E-mail: SUN Litao, sunlitao@hmc.edu.cn

ZHU Qing, zhuq@zjut.edu.cn

出版时间: 2026-10-04 doi: 10.13343/j.cnki.wsxb.20260233

文章导航

摘要

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酒精性肝病(alcoholic liver disease, ALD)是全球最常见的慢性肝病之一，也是肝硬化和肝癌的重要诱因。当前ALD诊疗面临诊断延迟、戒酒依从性差、特效药物匮乏等挑战，开发新的干预策略意义重大。近年来，药用植物丹参(Salvia miltiorrhiza, Sal)对ALD的干预作用受到广泛关注。其粗提物及活性单体可通过抗炎、调节脂质代谢等途径缓解ALD病理进程，但单药疗效存在局限性，因此联合用药成为ALD治疗的重要策略。本文综述Sal联合天然产物、抗氧化剂、保肝药物、微生态调节剂等联合策略干预ALD的研究进展。发现Sal联合用药可调控肠道菌群丰度，经肠道菌群介导发挥协同保肝作用。相关研究证实，益生菌、益生元、后生元及合生元等微生态调节剂也可通过“肠-肝轴”调控机制改善ALD，是Sal干预ALD的潜在临床联合策略，具有良好的临床前景。靶向ALD肠道菌群稳态调控，开发ALD微生态调节剂不仅可为开发高效低毒的生物活性制剂提供全新思路，还对改善ALD疗效缓解ALD预后具有潜在的临床价值，是未来Sal联合干预ALD新策略的重要研发方向。

关键词

酒精性肝病 / 微生态调节剂 / 肠道菌群稳态 / 丹参 / 联合用药

Abstract

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Alcoholic liver disease (ALD) is one of the most common types of chronic liver diseases globally and an important cause of liver cirrhosis and liver cancer. Currently, the diagnosis and treatment of ALD face challenges such as delayed diagnosis, poor compliance with alcohol abstinence, and a lack of specific drugs. Therefore, it is of great significance to develop new intervention strategies. In recent years, the intervention effect of the medicinal herb Salvia miltiorrhiza (Sal) on ALD has received extensive attention. The crude extracts and active components of Sal can alleviate the pathological process of ALD through anti-inflammatory and lipid metabolism regulation, while the efficacy of single Sal treatment has limitations. Thus, combination medication has become an important strategy for ALD treatment. This article reviews the research progress in the combination strategies of Sal with natural products, antioxidants, liver-protecting drugs, and microecological regulators in the intervention of ALD. It is found that the combination medication with Sal can regulate the abundance of the gut microbiota and play a synergistic liver-protecting role through the mediation of gut microbiota. Relevant studies have confirmed that microecological regulators such as probiotics, prebiotics, postbiotics, and synbiotics can also ameliorate ALD by regulating the “gut-liver axis”, and they can be combined with Sal to intervene in ALD, demonstrating good clinical prospects. Developing microecological regulators targeting the gut microbiota homeostasis in ALD can not only provide new ideas for the development of bioactive preparations with high efficiency and low toxicity, but also have potential clinical value in improving the therapeutic efficacy and prognosis for ALD. It is an important research and development direction for new combination intervention strategies with Sal for ALD in the future.

Key words

alcoholic liver disease / microecological regulator / gut microbiota homeostasis / Salvia miltiorrhiza / combination medication

引用本文

叶晨, 沈秀芸, 朱勍, 孙立涛. 丹参与微生态调节剂：临床干预酒精性肝病的研究前景. 微生物学报, 2026 , 66 (10) : 4808 -4824 . DOI: 10.13343/j.cnki.wsxb.20260233

Chen YE, Xiuyun SHEN, Qing ZHU, Litao SUN. Salvia miltiorrhiza and microecological regulators: research prospects for clinical intervention in alcoholic liver disease[J]. Acta Microbiologica Sinica, 2026 , 66 (10) : 4808 -4824 . DOI: 10.13343/j.cnki.wsxb.20260233

正文

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酒精性肝病(alcoholic liver disease, ALD)已成为全球重大公共卫生难题，全球疾病、伤害和风险因素负担研究(global burden of diseases, injuries, and risk factors study, GBD)数据库2023年明确将酒精使用(alcohol use)纳入健康危险因素评估^[1]。根据世界卫生组织2022年的数据统计，全球癌症新发案例近2 000万例，肝癌位列第六(占4.3%)；新增死亡病例970万例，肝癌位列第三(占7.8%)^[2]。酒精过度使用给个人健康与社会医疗体系带来沉重负担，当前临床针对ALD的治疗手段存在明显局限性，难以满足临床需求^[3-4]。因此，开发ALD新药对于缓解ALD临床局限性、改善患者预后具有重要的临床意义。药用植物丹参(Salvia miltiorrhiza, Sal)是唇形科(Labiatae)鼠尾草属(Salvia)直立草本植物，具有活血化瘀的药理功效，临床上常用于治疗心血管系统疾病^[5]。研究发现，Sal对多种肝脏疾病也具有良好的效果^[6-7]，本文系统性综述了Sal粗提物、其活性单体，以及它们联合天然产物(natural products)、抗氧化剂(antioxidant)等药物缓解ALD的机制研究，同时梳理了微生态调节剂(microecological regulator)及其联合Sal治疗ALD的相关研究，以期为开发Sal缓解ALD的联合用药新策略提供新思路。

1 ALD的临床简介和研究进展

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ALD是长期过量饮酒导致的肝脏疾病，可诱导肝脂肪变性，严重时可诱发肝硬化甚至肝癌^[8]。有数据预测表明：2019-2039年肝硬化的数量和发病率将持续上升^[9]。目前临床筛查ALD主要依赖饮酒史、肝功能指标及影像学检查，干预策略常包括酒精戒断、感染监测、抗生素治疗、营养补充和肝移植等^[10]，然而，晚期ALD硬化及重症肝炎预后较差，死亡风险高^[11]。糖皮质激素是目前唯一被证实对重症ALD有效的药物，但死亡率仍有10%^[12-13]，并且，ALD发病机制复杂，酒精可诱导肝脏多种病理改变，例如氧化应激^[14]、脂质代谢异常和脂质积累^[15]、内质网应激^[16]、细胞自噬^[17]、细胞焦亡^[18]、细胞铁死亡^[19]、细胞坏死^[20]和细胞凋亡^[21]等，还可诱导肠道微生物群失调^[22-23]，共同介导肝细胞损伤、肝脂肪变性、肝纤维化甚至肝癌的发生发展^[24-27]。因此，开发ALD新的干预策略是缓解其临床局限性的重要研究方向。

2 Sal治疗ALD的作用机制研究进展

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2.1 Sal 粗提物治疗ALD的研究进展

Sal为临床常用活血化瘀中药^[28]，其主要活性成分包括水溶性酚酸类[丹酚酸A (salvianolic acid A, SalA)、丹酚酸B (salvianolic acid B, SalB)、迷迭香酸(rosmarinic acid, RA)等]与脂溶性酮类[丹参酮ⅡA (tanshinone ⅡA, Tan ⅡA)、隐丹参酮(cryptotanshinone, CTS)、丹参酮Ⅰ (tanshinone Ⅰ, Tan Ⅰ)等]。近年来，Sal在ALD防治中展现出多靶点、多通路的保护作用，已成为ALD新药研发的重要方向。其粗提物能够降低丙氨酸氨基转移酶(alanine aminotransferase, ALT)、天门冬氨酸氨基转移酶(aspartate aminotransferase, AST)水平，减少肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)、白细胞介素-1 (interleukin-1, IL-1)等炎症因子释放，减轻肝脏炎症^[29-30]。同时，Sal可通过激活过氧化物酶体增殖物激活受体α (peroxisome proliferator activated receptor α, PPARα)，促进4-羟基壬烯醛(4-hydroxynonenal, 4‑HNE)降解，并下调Toll样受体4 (Toll-like receptor 4, TLR4)和血红素氧化酶-1 (heme oxygenase-1, HO-1) mRNA的表达，缓解ALD肝脂肪变性^[31-32]。

2.2 Sal 活性单体治疗ALD的研究进展

相较于粗提物，Sal水溶性活性单体作用明确、机制清晰，在ALD精准治疗研究中更受关注。丹酚酸A是Sal一种水溶性活性成分，可调控沉默信息调节因子1 (silent information regulator 1, Sirt1)介导的细胞自噬，降低ALT、AST、甘油三酯(triglyceride, TG)和胆固醇(total cholesterol, TC)水平，增强肝细胞活力、减轻肝细胞凋亡与脂肪变性^[33-34]。丹酚酸B是Sal的另一种水溶性活性成分，其通过激活Sirt1，介导C反应蛋白(C-reactive protein, CRP)表达，降低TNF-α、白细胞介素-6 (interleukin-6, IL-6)等促炎因子表达，减少血清及肝脏脂质积累，抑制血清转氨酶升高，缓解ALD肝损伤^[35]。

除水溶性酚酸外，Sal的脂溶性活性单体同样对干预ALD发挥关键作用。隐丹参酮是Sal中的脂溶性单体，可激活腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase, AMPK)、Sirt1通路及核因子E2相关因子2 (nuclear factor erythroid 2-related factor 2, Nrf2)磷酸化，同时抑制细胞色素P450 2E1 (cytochrome P450 2E1, CYP2E1)的表达，抑制酒精诱导的肝脂肪变性、炎症反应及氧化应激损伤^[36-37]。丹参酮ⅡA是Sal的另一种脂溶性单体，可通过逆转乙醇诱导的视黄醇X受体α (retinoid X receptor-alpha, RXRα)的异常表达，抑制脂肪酸合成并促进其氧化分解，减少酒精介导的肝脏脂质积累^[38]。

综上所述，Sal的粗提物和多种活性单体对ALD具有良好的生物学活性，可缓解ALD诱导的肝脂肪变性、炎症反应、氧化应激损伤、细胞自噬等病理改变。Sal及其活性单体治疗ALD的作用机制总结如表1所示，与单一用药相比，Sal与多种天然产物、抗氧化剂及其他药物联合应用在改善ALD患者肝功能、减轻肝脏病理损伤等方面更具优势，是临床干预ALD的重要手段。

3 Sal联合用药缓解ALD的临床应用

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3.1 Sal 联合天然产物缓解ALD的临床应用

复方甘草甜素(compound glycyrrhizin, CG)，又称复方甘草酸苷，是从甘草中提取的复方制剂，其主要成分为2%甘氨酸、0.2%甘草酸苷及0.1%盐酸半胱氨酸，目前已纳入医保目录，为临床治疗肝脏疾病的常用药物，临床研究发现，其可与还原型谷胱甘肽(glutathione, GSH)联用用于治疗儿童急性肝损伤，且CG联合用药组疗效明显优于对照组^[39]。一项调查报告(2014-2016年)显示，给予60例ALD患者复方甘草酸苷和Sal注射液联合治疗，可明显改善ALD患者血清AST和ALT水平^[40]。另一项临床研究发现，92例ALD患者在严格戒酒基础上联合Sal治疗可明显改善患者肝功能指标^[41]。

水飞蓟(Silybum marianum, SIL)是菊科水飞蓟属的草本植物，原产地在南欧或北非地区，其制剂可成为一种护肝类膳食补充剂，主要用于改善肝损伤等病症。研究表明，水飞蓟和葛根(Pueraria lobata, PUE)联用可激活肝激酶B1 (liver kinase B1, LKB1)/AMPK/乙酰辅酶A羧化酶(acetyl-CoA carboxylase, ACC)信号通路，减轻酒精诱导的肝脂肪变性，同时抑制TLR4介导的核因子κB (nuclear factor-κB, NF-κB)信号通路缓解ALD肝损伤^[42]。一项121例非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)患者的临床试验结果显示，水飞蓟、葛根素和Sal联合给药的患者乙醛脱氢酶活性显著升高，治疗效果更优良，有助于促进酒精在肝脏的代谢，该方案已在美国临床试验注册平台上注册(NCT05076058)^[43]。另一项临床研究发现，112例ALD患者中56例水飞蓟宾胶囊和复方Sal滴丸联合治疗组总胆红素(total bilirubin, TBIL)及肝纤维化指标明显低于单独给药组，治疗期间未见明显不良反应，安全性较高^[44]。

中草药三七(Panax notoginseng, PN)、芳香二苯醚(diphenyl ether, DPE)和Sal是用于治疗冠状动脉和脑梗死等心血管疾病的中药复方，可升高PPARα mRNA表达水平，抑制酒精诱导的肝脂肪变性，缓解ALD肝损伤^[45]。

五味子(Schisandra chinensis, SC)、葛根、水飞蓟宾和Sal联用可降低血清透明质酸(hyaluronan, HA)、层粘连蛋白(laminin, LN)和羟脯氨酸(hydroxyproline, Hyp)水平，抑制肝脏金属蛋白酶-1抑制剂(tissue inhibitor of metalloproteinase-1, TIMP-1)的表达，增加肝脏基质金属蛋白酶抑制剂-13 (matrix metalloproteinase-13, MMP-13)的表达，抑制肝脏转化生长因子-β (transforming growth factor-β, TGF-β)信号通路，减轻肝脏纤维化，缓解ALD^[46]。

肝舒诺丹(Ganshu Nuodan, GN)是一种由灵芝孢子粉(Ganoderma lucidum spore powder, GLSP)、葛根、黄芪(Astragalus membranaceus, AM)和Sal组成的护肝膳食补充剂，其中含有21种醌类、18种黄酮类、11种有机酸、7种萜类、5种酮类、4种甾醇类、3种香豆素类和7种其他化学成分，研究发现GN可降低急性ALD小鼠模型AST、ALT和丙二醛(malondialdehyde, MDA)水平，升高肝脏GSH含量和超氧化物歧化酶(superoxide dismutase, SOD)活力，调控环氧化物水解酶2 (epoxide hydrolase 2, Ephx2)、白三烯A4水解酶(leukotriene a4 hydrolase, Lta4h)、丝裂原活化蛋白激酶激酶1 (mitogen-activated protein kinase kinase 1, Map2k1)、信号转导与转录激活因子3 (signal transducer and activator of transcription 3, STAT3)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR和二酰甘油酰基转移酶1 (diacylglycerol O-acyltransferase 1, Dgat1)表达，抑制急性肝脏氧化应激、脂质积累和细胞凋亡，缓解急性ALD肝损伤^[47]。

白桑(Morus alba, MA)、山楂(Crataegus pinnatifida, CP)、泽泻(Alisma orientale, AO)、黄芪、葛根和Sal联合用药为传统中药治疗组，可改善ALD大鼠AST、ALT、TG和TC血清含量，减少肝脏脂质积累，缓解ALD肝损伤^[48]。另有研究证明，中药(白桑、山楂、泽泻、黄芪、葛根与Sal)治疗可恢复酒精抑制的肝脏PPARα和微粒体甘油三酯转移蛋白(microsomal triglyceride transfer protein, MTP)水平，缓解ALD^[49]。综上所述，Sal可联合多种天然产物协同干预ALD进程，具有良好的临床潜力。

3.2 Sal 联合抗氧化剂治疗ALD的临床应用

还原型GSH是一种内源性抗氧化剂，临床研究发现，多烯磷脂酰胆碱联合还原型GSH治疗可有效改善ALD患者AST、ALT、TBIL和γ-谷氨酰转移酶(γ-glutamyl transferase, GGT)水平^[50]，多项临床研究显示，Sal联合还原型GSH治疗ALD可发挥协同保肝作用，一项60例ALD患者的临床研究显示，给予Sal联合GSH干预可有效降低患者血清转氨酶及肝纤维化指标水平，疗效显著优于单一治疗^[51]，临床试验(84例ALD患者)结果显示，Sal联合还原型GSH组有效率高达95.24%^[52]。另一项126例ALD患者的临床研究显示，Sal联合GSH治疗有效率高达90.48%，明显高于GSH单独给药组(76.19%)，可缓解失代偿期肝硬化患者的肝纤维化程度，具有协同疗效^[53]。上述临床研究结果进一步肯定了还原型GSH和Sal联用在ALD治疗中的临床价值。

多烯磷脂酰胆碱(polyene phosphatidylcholine, PPC)是一种肝胆疾病辅助治疗药物，从大豆中提取的粗制磷脂物质精制而成的抗氧化药物可促进肝细胞再生，调节脂质代谢。一项118例ALD患者的临床报告发现，Sal川芎嗪注射液联合多烯磷脂酰胆碱可降低酒精升高的肝脏ALT、AST、TBIL和GGT水平，提高ALD患者肠道有益菌两歧双歧杆菌(Bifidobacterium bifidum)水平，降低有害菌大肠埃希氏菌(Escherichia coli)、肠球菌(Enterococcus)丰度，以及血清脂蛋白(lipoprotein, LP)、脂质过氧化物(lipid peroxide, LPO)水平，缓解ALD^[54]。

3.3 Sal 联合其他药物缓解ALD的临床应用

硫普罗宁(tiopronin)是一种含巯基的保肝药物，具有抗氧化、抗炎和解毒等药理作用，可促进肝细胞代谢和修复再生，一项86例ALD患者的临床研究发现，其联合Sal注射液治疗效果优于Sal单药组，且未出现明显不良反应^[55]。另一项临床报告显示，将80例ALD患者分为单药治疗组和联合治疗组，联合用药治疗组肝功能明显优于单独给药组^[56]。一项86例ALD患者的临床报告发现，硫普罗宁联合Sal可改善ALD患者肝功能，降低肝脏纤维化水平，未出现明显不良反应，用药安全性较高^[57]。

异甘草酸镁(magnesium isoglycyrrhizinate, MgIG)具有抗炎、抗氧化的保肝活性，有研究发现，其可改善酗酒引起的肝细胞氧化应激，调控中性粒细胞活性，缓解ALD肝损伤^[58]。镁离子是多种酶的辅助因子，可抑制自由基生成酶的活性，减少自由基形成，降低线粒体内钙离子浓度，保护肝细胞膜的完整性，一项76例酒精性肝硬化患者的临床报告显示(2011-2013年)，大剂量Sal联合硫酸镁(magnesium sulfate, MgSO₄)治疗ALD肝硬化的疗效明显，存在轻微毒副反应，少数患者出现轻微头疼，面色潮红等，可未经处理自行缓解，安全性较高^[59]。

双环醇(bicyclol)是一类肝脏保护药物，可缓解药物、酒精等诱导的肝脏转氨酶水平升高，缓解肝脏炎症。临床上双环醇主要用于治疗慢性肝炎、药物性肝损伤等，一项临床研究发现，复方丹参滴丸与双环醇联合用药可抑制70例ALD患者ALT、AST、GGT与ALP异常升高，下调TBIL和肝纤维化指标，明显改善患者肝功能^[60]。Sal联合用药在ALD治疗中普遍呈现协同效应，但现有的Sal临床用药策略仍具有不同程度的临床不良反应，且作用机制尚未完全阐明。因此开发新的Sal联合用药新策略对改善ALD患者预后，提高疗效具有重要的临床意义。Sal联合用药干预ALD的作用机制总结如表2所示。

4 微生态调节剂治疗ALD的研究进展

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肠道菌群稳态参与调控ALD的发展进程，研究发现酒精暴露可显著抑制小鼠肠道微生物乙酰辅酶A (acetyl coenzyme A, CoA)依赖的丁酸合成途径，降低产丁酸菌丰度，进而加剧肝脏脂肪变性、炎症反应及肝损伤，而丁酸前体药物三丁酸甘油酯(tributyrin, Tb)可逆转酒精所致的产丁酸菌丰度下降，改善肝脏病理损伤^[61]。此外，核黄素也可通过调节小鼠肠道菌群结构，提升有益菌丰度，减轻肝脏炎症反应，进而改善ALD的病理进程^[62]。虾青素是一种类胡萝卜素，可恢复有益菌嗜黏蛋白阿克曼氏菌(Akkermansia muciniphila)丰度，改善肠道菌群结构失衡，逆转酒精诱导的小鼠肝脏比重升高以及脂质代谢紊乱^[63]。靶向肠道菌群是干预ALD的潜在调控靶点，也是Sal联合用药新策略研发的重要思路。

微生态调节剂是基于微生态学原理，通过调节宿主微生态平衡以改善健康状态的制剂，主要包含益生菌(probiotics)、益生元(prebiotics)、后生元(postbiotics)和合生元(synbiotics)等制剂，研究发现其可改善肠道功能屏障，调控肠-肝循环，对缓解ALD具有良好的生物学活性^[64-66]。因此，益生菌、益生元、后生元和合生元等微生态调节剂是Sal联合用药治疗ALD的潜在干预策略。

4.1 改善ALD的益生菌

益生菌是一类通过摄入足够数量对宿主健康产生有益作用的活性微生物，研究发现存在众多益生菌菌株可改善肠道功能屏障，通过调控“肠-肝轴”循环系统改善ALD肝损伤，例如嗜黏蛋白阿克曼氏菌、植物乳植杆菌(Lactiplantibacillus plantarum)、鼠李糖乳酪杆菌(Lacticaseibacillus rhamnosus)、双歧杆菌属(Bifidobacterium)、枯草芽孢杆菌(Bacillus subtilis)及屎肠球菌(Enterococcus faecium)、复合细菌制剂等益生菌及其制剂，对ALD肠道功能稳态均具有重要的生物调控活性。

嗜黏蛋白阿克曼氏菌是一种肠道有益菌，研究发现ALD患者粪便阿克曼菌丰度数量减少与ALD疾病严重程度间接相关，而乙醇可抑制ALD小鼠肠道阿克曼菌相对丰度，口服阿克曼菌补充剂可缓解ALD小鼠肝脏中性粒细胞浸润、氧化应激损伤和肝脂肪变性，调控肠道1型常规树突状细胞(conventional type 1 dendritic cells, cDC1s)功能，改善肠道屏障功能，抑制细菌内毒素进入循环系统，缓解ALD^[67-69]。研究发现，在患有肝性脑病和认知功能障碍的人群粪便样本中阿克曼氏菌的丰度显著下调^[70]。

植物乳植杆菌是一类属于乳酸菌家族中乳植杆菌属(Lactiplantibacillus)的常见益生菌。据报道，其可阻断ALD诱导的炎症相关因子TNF-α、白细胞介素-1β (interleukin-1β, IL-1β)、IL-6、单核细胞趋化蛋白1 (monocyte chemotactic protein 1, MCP1)、C-X-C基序趋化因子配体1 (C-X-C motif chemokine ligand 1, CXCL1)和C-X-C基序趋化因子配体2 (C-X-C motif chemokine ligand 2, CXCL2)在结肠中的表达，通过表皮生长因子受体(epidermal growth factor receptor, EGFR)依赖性机制预防和减轻酒精引起的结肠上皮紧密连接破坏，改善肠道功能屏障，缓解肝损伤^[71]。植物乳植杆菌FB091可减少ALD引起的肝细胞气球样扩张和炎症细胞浸润，减轻结肠组织结构损伤，降低AST水平，增加乙醇脱氢酶活性，促进酒精代谢，是ALD潜在的替代药物^[72]。

鼠李糖乳酪杆菌是一类属于乳酸菌乳酪杆菌属(Lacticaseibacillus)的益生菌，临床试验显示，鼠李糖乳酪杆菌(Lactobacillus rhamnosus) R0011和瑞士乳杆菌(Lactobacillus helveticus) R0052可改善ALD肠道菌群组成，89例ALD患者补充益生菌7 d后增加了类杆菌比例(Bacteroides, 147%)、减少了变形杆菌(Proteobacteria, 30%)和梭杆菌(Fusobacterium)的比例，同时降低脂多糖含量，改善肠道功能屏障，缓解ALD肝炎^[73]。据报道，鼠李糖乳酪杆菌CCFM1107、GG和NKU FL1-8可降低血清AST、ALT、TC、TG、TNF‑α和脂多糖水平，改善双歧杆菌等有益菌丰度，抑制肠道有害菌生长，激活AMPKα1缓解ALD损伤^[74-76]。

双歧杆菌是一种革兰氏阳性厌氧菌，对改善肠道功能屏障具有重要的生物学活性，研究发现双歧杆菌四联活菌制剂可联合多烯磷脂酰胆碱改善ALD大鼠肝功能指标，抑制肝脏脂质积累和肝脂肪变性，减轻ALD肝脏炎症^[77]。临床研究发现，Sal川芎嗪注射剂联合多烯磷脂酰胆碱可增加ALD患者肠道有益菌双歧杆菌的相对丰度^[54]，双歧杆菌三联活菌溶菌胶囊联合蒙脱石散(smectite powder)可有效治疗ALD患者22例(73.3%)，有效缓解2例(6.7%)，无效6例(20%)，治疗期间1例(3.3%)出现便秘，无严重不良反应，疗效较安全^[78]。此外，假小链双歧杆菌(Bifidobacterium pseudocatenulatum)可减少致病性菌丰度，增加有益菌双歧杆菌和布劳特氏菌(Blautia)丰度，并可下调肝脏脂肪生成基因分化簇36 (cluster of differentiation 36, Cd36)、脂肪酸合酶(fatty acid synthase, Fasn)、乙酰辅酶A羧化酶α (acetyl-coa carboxylase α, Accα)、促炎细胞因子Il-1β、趋化因子(C-C基元)配体2 [chemokine (C-C motif) ligand 2, CCL2]和TNF‑α的表达，缓解ALD肝脂肪变性和炎症反应^[79]。长双歧杆菌亚种BL21 (Bifidobacterium longum subsp. longum) BL21可改善ALD肝脏氧化应激、炎症反应和肝脂肪变性^[80]。

枯草芽孢杆菌是一种革兰氏阳性需氧杆状细菌，而屎肠球菌是一种革兰氏阳性厌氧球菌，两者均是微生态调节剂中常用的益生菌菌株，一项针对117名ALD患者的临床研究表明，枯草芽孢杆菌及屎肠球菌混合制剂可改善ALD患者AST、ALT、碱性磷酸酶、GGT和TBIL的血清含量，抑制大肠埃希氏菌丰度，降低TNF‑α和脂多糖水平，改善患者肠道功能屏障和肝功能指标^[81]。

中国卫生部2010年4月发布了一种由15种可食用菌种制成的复合细菌制剂，包含动物双歧杆菌乳亚种(Bifidobacterium animalis subsp. lactis) HN019、Bi-07，两歧双歧杆菌Bb06，动物双歧杆菌(Bifidobacterium animalis) BB-12，长双歧杆菌(Bifidobacterium longum) R175、B94，鼠李糖乳酪杆菌GG、R11，干酪乳酪杆菌(Lacticaseibacillus casei) LC11，瑞士乳杆菌(Lactobacillus helveticus) R52，类干酪乳酪杆菌(Lacticaseibacillus paracasei) Lpc-37，植物乳植杆菌R1012，罗伊特氏黏液乳杆菌(Limosilactobacillus reuteri) HA188，嗜酸乳杆菌(Lactobacillus acidophilus) NCFM和唾液链球菌嗜热亚种(Streptococcus salivarius subsp. thermophilus) St21，研究发现其可抑制肝脏TLR4/NF-κB信号通路，激活AMPK-PPARα信号通路，减轻肝脂肪变性与炎症反应，修复肠道屏障功能，改善酒精诱导的肝损伤^[82]。

4.2 改善ALD的益生元

益生元是一类不能被人体消化吸收，但能被肠道有益菌选择性利用的物质。HRFP-Ⅱ-a、HRFP-Ⅱ-b和HRFP-Ⅱ-c是从沙棘果实中分离的3种果胶多糖，是缓解ALD潜在的益生元，研究发现HRFP-Ⅱ-a、HRFP-Ⅱ-b和HRFP-Ⅱ-c可维持人肝细胞系THLE-2细胞完整性，抑制细胞炎症因子分泌，增强细胞抗氧化应激能力，减轻酒精诱导的细胞损伤；同时，HRFP-Ⅱ可抑制ALD小鼠AST、ALT、TG、TC和MDA血清含量，升高CAT、SOD和GSH水平，降低增稠拟杆菌(Bacteroides thickeningii)与普通拟杆菌(Bacteroides vulgatus)的比例、增加肠道有益菌群丰度，并抑制有害菌生长，改善ALD肠道菌群稳态；此外，HRFP-Ⅱ还可上调肠道闭锁小带蛋白1 (zonula occludens 1, ZO-1)和闭合蛋白(Occludin)蛋白表达，修复ALD肠道黏膜屏障，调控肠-肝循环，改善ALD肝损伤^[83]。壳寡糖(chitosan oligosaccharide)可促进双歧杆菌等多种有益菌生长，是一类具有食品开发潜力的益生元^[84]。研究发现，壳寡糖可降低ALD肝脏代谢酶CYP2E1的表达，激活Kelch样ECH相关蛋白1 (Kelch-like ECH-associated protein 1, Keap-1)/Nrf2/HO-1通路，抑制NF-κB和MAPK通路，改善肝脂肪变性和炎症反应，缓解ALD^[85]。

4.3 改善ALD的后生元

后生元是一类益生菌经处理或代谢后产生的无生命活性成分，据报道，热灭活的强生乳杆菌(Lactobacillus johnsonii) HKLJ可上调肠道溶菌酶(lysozyme)的表达，促进肠道细菌生成免疫调节物质，可激活核苷酸结合寡聚结构域2 (nucleotide-binding oligomerization domain 2, NOD2)/白细胞介素23 (interleukin 23, IL-23)/白细胞介素22 (interleukin 22, IL-22)信号通路；上调抗菌肽的合成，抑制幽门螺杆菌(Helicobacter pylori)的相对丰度，改善肠道稳态，并激活肝脏STAT3通路调节“肠-肝轴”稳态，缓解ALD^[86]。类干酪乳酪杆菌坚韧亚种(Lacticaseibacillus paracasei subsp. tolerans) S-NB中提取的荚膜多糖(capsular polysaccharide, CPS)和表面层蛋白(surface layer protein, SLP)可增加ALD肠道拟杆菌、双歧杆菌等益生菌丰度，抑制大肠埃希氏菌、布鲁氏菌属(Brucella)、柠檬酸杆菌属(Citrobacter)和梭杆菌属(Fusobacterium)等病原菌的生长，改善肠道功能屏障，缓解ALD肝损伤^[87]。

4.4 改善ALD的合生元

合生元是一类改善宿主肠道菌群稳态的益生菌+益生元的协同组合制剂，例如凝结芽孢杆菌(Bacillus coagulans)联合果胶(pectin)、脆弱拟杆菌(Bacteroides fragilis)联合果胶、植物乳植杆菌联合儿茶素(epigallocatechin gallate, EGCG)等。凝结芽孢杆菌是一类可产孢和乳酸的功能益生菌，果胶是一类常见的益生元，凝结芽孢杆菌联合果胶可显著减少ALD肝脏炎症反应和脂质积累，降低促炎因子TNF-α和IL-1β的水平，促进肠道有益菌鼠杆状菌科(Muribaculaceae)的生长，增加短链脂肪酸的生成，促进肠道黏膜黏液分泌，增强肠道屏障功能，缓解ALD肝损伤^[88]。脆弱拟杆菌ATCC25285是一类可产生短链脂肪酸增强肠道屏障的益生菌，据报道其联合果胶可改善ALD肠道菌群组成，促进色氨酸代谢和增强肠道免疫功能，改善ALD肝损伤^[89]。此外，植物乳植杆菌与EGCG联用可降低ALD大鼠模型酒精、内毒素和肝酶水平，抑制炎症相关因子NF-κB、TNF-α、白细胞介素-12 (interleukin-12, IL-12)和信号分子TLR4、分化簇14 (cluster of differentiation 14, CD14)、髓样分化因子2 (myeloid differentiation factor 2, MD2)、髓样分化初级反应蛋白88 (myeloid differentiation primary response 88, MyD88)和环氧化酶2 (cyclooxygenase 2, COX-2)的水平，是缓解ALD的重要策略^[90]。

综上所述，益生菌、益生元、后生元和合生元等多种微生态调节剂可促进肠道双歧杆菌等有益菌生长，抑制大肠埃希氏菌等有害菌生长，并通过修复肠道功能屏障构成ALD防治的重要微生态干预体系，从而抑制ALD肝脏炎症、肝脂肪变性和氧化应激损伤，是Sal联合用药干预ALD的重要研发方向。微生态调节剂治疗ALD的作用机制总结如表3所示。

5 Sal联合微生态调节剂改善ALD的研究进展

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Sal不仅对ALD具有良好的疗效^[91]，还可改善肠道菌群稳态，调控多种疾病进程，例如肾衰竭^[92]、高胆固醇血症^[93]和NAFLD^[94]等。研究发现，丹酚酸B与葛根、水飞蓟联合用药可提高小鼠肠道阿克曼氏菌等有益菌丰度，并通过调控胆汁酸代谢缓解NAFLD肝损伤^[95]。丹酚酸A可与益生菌干酪乳酪杆菌及嗜酸乳杆菌联合使用改善NAFLD^[96]，这些研究结果提示调控肠道菌群稳态是Sal联合用药干预ALD的潜在研究方向。益生菌是微生态调节剂的核心组成部分，临床研究发现复方丹参注射液联合枯草杆菌、肠球菌活菌胶囊对NAFLD患者的疗效(93%)明显高于单独用药组(83%)^[97]，且枯草芽孢杆菌可改善ALD患者肠道功能屏障和肝功能^[82]。丹参多糖(Salvia miltiorrhiza polysaccharide, SalP)可与植物乳植杆菌X或双歧杆菌V联合应用改善小鼠胰岛素抵抗，缓解NAFLD肝脂肪变性^[98]。据报道，植物乳植杆菌FB091可减少ALD小鼠结肠组织损伤，缓解ALD肝损伤^[72]。Sal可联合多烯磷脂酰胆碱改善ALD肝功能，增加患者肠道双歧杆菌相对丰度^[54]，并且双歧杆菌活菌溶菌胶囊可联合蒙脱石散有效治疗ALD患者22例(73.3%)^[78]。此外，壳聚糖是一类益生元，可降低ALD小鼠血液中酒精和乙醛的含量^[99]，与丹酚酸B联合用药可显著降低小鼠AST、ALT、α-平滑肌动蛋白(α-smooth muscle actin, α-SMA)、Ⅰ型胶原(collagen type Ⅰ, COL I)和IL-6水平，并增加双歧杆菌等多种有益菌丰度，改善小鼠肝纤维化^[100]。因此，微生态调节剂是Sal联合用药干预ALD的重要研发方向，具有良好的临床应用潜力。

6 总结与展望

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ALD是全球高发的慢性肝病，发病机制复杂，临床缺乏高效低毒的特效方案，因此开发ALD新的干预策略已成为临床研究的核心需求。多项研究证实，Sal及其活性单体可联合多种天然产物、抗氧化剂和其他保肝药物提高对ALD的疗效，但现有的Sal联合用药策略仍未能满足ALD的临床需求，开发Sal联合用药新策略是改善ALD临床局限性的重要研究思路。肠道菌群稳态对改善ALD具有重要的生物学功能，人源化菌群动物模型和临床研究发现，益生菌、益生元、后生元及合生元等多种微生态调节剂可调控肠道菌群稳态，增强肠道屏障功能，对缓解ALD具有重要的药用价值，是Sal联合用药干预ALD的重要研发方向，具有潜在的临床应用前景。聚焦微生态调节剂，开发高效低毒的Sal联合用药新策略，对优化ALD临床给药方案，提高疗效并改善患者预后具有重要的临床意义，也是未来临床转化的重要方向。Sal联合用药治疗ALD的干预策略总结如图1所示。

基金

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浙江省尖兵领雁+X项目(2024C03069)

参考文献

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文献

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2026年第66卷第10期

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doi: 10.13343/j.cnki.wsxb.20260233

接收时间：2026-03-21
首发时间：2026-10-13
出版时间：2026-10-04

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收稿日期：2026-03-21
录用日期：2026-05-17

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Zhejiang Province Vanguard Leading Geese+X Project(2024C03069)

浙江省尖兵领雁+X项目(2024C03069)

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^1.浙江工业大学生物工程学院，浙江省生物有机合成重点实验室，浙江杭州

^2.杭州医学院附属人民医院(浙江省人民医院)，超声医学科肿瘤中心，浙江杭州

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Drugs	Targets	Results	References
Sal	PPARα, TLR4, HO-1	Its crude extract can reduce ALT and TG levels, alleviate liver inflammation and ALD-related liver damage, activate PPARα to promote 4-HNE degradation, and down-regulate the mRNA expression of TLR4 and HO-1	[31-32]
SalA	Sirt1	SalA can regulate the Sirt1 expression, reduce the levels of ALT, AST, TG, and TC, enhance hepatocyte vitality, and alleviate ALD	[33-34]
SalB	Sirt1, CRP, TNF-α, IL-6	SalB can activate Sirt1, inhibit the expression of CRP, reduce the levels of pro-inflammatory factors such as TNF-α and IL-6, inhibit the increase of serum transaminase, and alleviate ALD	[35]
CTS	AMPK, Sirt1, Nrf2, CYP2E1	CTS can activate AMPK, Sirt1 pathways, and phosphorylate Nrf2, meanwhile, it can also inhibit CYP2E1 expression, suppress alcohol-induced hepatic steatosis, liver inflammatory response and oxidative stress injury, and alleviate ALD damage	[36-37]
Tan ⅡA	RXRα	Tan ⅡA can reverse abnormal RXRα expression, promote fatty acid oxidation, reduce hepatic lipid accumulation, and alleviate ALD-induced liver injury	[38]

Drugs

Targets

Results

References

Sal

PPARα, TLR4, HO-1

Its crude extract can reduce ALT and TG levels, alleviate liver inflammation and ALD-related liver damage, activate PPARα to promote 4-HNE degradation, and down-regulate the mRNA expression of TLR4 and HO-1

[31-32]

SalA

Sirt1

SalA can regulate the Sirt1 expression, reduce the levels of ALT, AST, TG, and TC, enhance hepatocyte vitality, and alleviate ALD

[33-34]

SalB

Sirt1, CRP, TNF-α, IL-6

SalB can activate Sirt1, inhibit the expression of CRP, reduce the levels of pro-inflammatory factors such as TNF-α and IL-6, inhibit the increase of serum transaminase, and alleviate ALD

[35]

CTS

AMPK, Sirt1, Nrf2, CYP2E1

CTS can activate AMPK, Sirt1 pathways, and phosphorylate Nrf2, meanwhile, it can also inhibit CYP2E1 expression, suppress alcohol-induced hepatic steatosis, liver inflammatory response and oxidative stress injury, and alleviate ALD damage

[36-37]

Tan ⅡA

RXRα

Tan ⅡA can reverse abnormal RXRα expression, promote fatty acid oxidation, reduce hepatic lipid accumulation, and alleviate ALD-induced liver injury

[38]

Types	Drugs	Total target subjects	Results	References
Natural products	CG	152 ALD patients	It significantly improved serum AST and ALT levels, thereby ameliorating liver function in ALD patients when combined with Sal	[40-41]
	SIL	112 ALD patients	It can improve serum TBIL and hepatic fibrosis markers, with no significant adverse reactions in ALD patients when combined with Sal	[44]
	PN, DPE	ALD model	They can increase the expression level of PPARα mRNA and inhibit alcohol-induced hepatic steatosis when combined with Sal	[45]
	SC, PUE, SIL	ALD model	They can inhibit the TGF-β/Smad signaling pathway, a key pathway involved in hepatic fibrosis, thereby alleviating liver fibrosis when combined with Sal	[46]
	GLPS, PUE, AM	ALD model	They can inhibit hepatic oxidative stress, lipid accumulation and apoptosis in mice with acute ALD when combined with Sal	[47]
	MA, CP, AO, PUE, AM	ALD model	They can restore alcohol-suppressed hepatic levels of PPARα and MTP, thereby alleviating ALD when combined with Sal	[48-49]
Antioxidant	GSH	270 ALD patients	It can reduce the levels of serum transaminase and liver fibrosis indicators in patients (60 cases), when combined with Sal, and has other clinical effective rate 90.48% (126 cases) and 95.24% (84 cases) with a significant synergistic effect	[51-53]
	PPC	118 ALD patients	It increases the abundance of intestinal Bifidobacterium bifidum, reduces the serum levels of LP and LPO when combined with Sal	[54]
Hepatoprotective drugs	Tiopronin	246 ALD patients	Its combined therapy was more effective than monotherapy when combined with Sal	[55-57]
	Magnesium sulfate	76 ALD patients	The combination of high-dose Sal and magnesium sulfate has a significant therapeutic effect on ALD cirrhosis, with mild toxic side effects	[59]
	Bicyclol	70 ALD patients	It downregulated TBIL and fibrosis markers, leading to significant improvement in ALD liver function, when combined with Sal	[60]

Types

Drugs

Total target subjects

Results

References

Natural products

152 ALD patients

It significantly improved serum AST and ALT levels, thereby ameliorating liver function in ALD patients when combined with Sal

[40-41]

SIL

112 ALD patients

It can improve serum TBIL and hepatic fibrosis markers, with no significant adverse reactions in ALD patients when combined with Sal

[44]

PN, DPE

ALD model

They can increase the expression level of PPARα mRNA and inhibit alcohol-induced hepatic steatosis when combined with Sal

[45]

SC, PUE, SIL

ALD model

They can inhibit the TGF-β/Smad signaling pathway, a key pathway involved in hepatic fibrosis, thereby alleviating liver fibrosis when combined with Sal

[46]

GLPS, PUE, AM

ALD model

They can inhibit hepatic oxidative stress, lipid accumulation and apoptosis in mice with acute ALD when combined with Sal

[47]

MA, CP, AO, PUE, AM

ALD model

They can restore alcohol-suppressed hepatic levels of PPARα and MTP, thereby alleviating ALD when combined with Sal

[48-49]

Antioxidant

GSH

270 ALD patients

It can reduce the levels of serum transaminase and liver fibrosis indicators in patients (60 cases), when combined with Sal, and has other clinical effective rate 90.48% (126 cases) and 95.24% (84 cases) with a significant synergistic effect

[51-53]

PPC

118 ALD patients

It increases the abundance of intestinal Bifidobacterium bifidum, reduces the serum levels of LP and LPO when combined with Sal

[54]

Hepatoprotective drugs

Tiopronin

246 ALD patients

Its combined therapy was more effective than monotherapy when combined with Sal

[55-57]

Magnesium sulfate

76 ALD patients

The combination of high-dose Sal and magnesium sulfate has a significant therapeutic effect on ALD cirrhosis, with mild toxic side effects

[59]

Bicyclol

70 ALD patients

It downregulated TBIL and fibrosis markers, leading to significant improvement in ALD liver function, when combined with Sal

[60]

Ecological regulators	Types	Targets	Results	References
Akkermansia muciniphila	Probiotics	ALD model	It can regulate the intestinal functional barrier, inhibit bacterial endotoxins from entering the circulatory system, and alleviate ALD liver injury	[67-69]
Lactiplantibacillus plantarum	Probiotics	ALD model	It can regulate the EGFR-dependent mechanism prevents and alleviates alcohol-induced disruption of colonic epithelial tight junctions and liver injury	[71]
Lactiplantibacillus plantarum FB091	Probiotics	ALD model	It can reduce ballooning degeneration of liver cells and infiltration of inflammatory cells in ALD, alleviate the damage to the colonic tissue structure, promote alcohol metabolism, and relieve ALD liver injury	[72]
Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0052	Probiotics	89 ALD patients	They can reduce the levels of Proteus, Fusobacterium, and LPS, protect the intestinal barrier, and alleviate hepatitis	[73]
Lactobacillus rhamnosus CCFM1107	Probiotics	ALD model	It significantly inhibited the increase in the levels of serum aminotransferase, endotoxin, TG and TC, and ameliorated ALD liver injury	[74]
Lactobacillus rhamnosus NKU FL1-8	Probiotics	ALD model	It can decrease the levels of AST, ALT, MDA, SOD and GSH, relieve oxidative stress and decrease hepatic inflammation	[75]
Lactobacillus rhamnosus GG	Probiotics	ALD model	It ameliorates ALD liver injury through modulating antioxidant defenses	[76]
Bifidobacterium and PPC	Probiotics	ALD model	They can ameliorate liver function indicators in ALD rats, inhibit lipid accumulation and hepatic steatosis in ALD liver	[77]
Bifidobacterium and smectite powder	Probiotics	60 ALD patients	They can ameliorate ALD liver injury, without serious adverse reactions, and have the relatively safe therapeutic effect	[78]
Bifidobacterium pseudocatenulatum	Probiotics	ALD model	It can regulate the expression of Cd36, Fasn, Accα, Il-1β, CCL2 and TNF‑α, and ameliorate ALD liver injury	[79]
Bifidobacterium longum subsp. longum BL21	Probiotics	ALD model	It reduced the ethanol-induced abnormal elevation of serum AST and ALT levels in ALD mice	[80]
Bacillus subtilis and Enterococcus faecium	Probiotics	117 ALD patients	They can regulate the expression of TNF‑α, and alleviate ALD liver injury	[81]
Compound probiotic preparation	Probiotics	ALD model	It can alleviate hepatic inflammation, repair the intestinal barrier, reshape the intestinal flora, and alleviate ALD-induced injury	[82]
HRFP-Ⅱ-a, HRFP-Ⅱ-b, HRFP-Ⅱ-c	Prebiotics	ALD model	They can protect ALD mice via antioxidant, anti-inflammatory, lipid metabolism regulation and intestinal flora improvement	[83]
Chitosan oligosaccharide	Prebiotics	ALD model	It can reduce the expression of the liver metabolic enzyme CYP2E1 in ALD, activate the Keap1/Nrf2/HO-1 pathway, inhibit the NF-κB and MAPK pathways, alleviate ALD oxidative damage, hepatic steatosis and inflammation	[85]
Lactobacillus johnsonii HKLJ	Postbiotics	ALD model	It can activate the nucleotide-binding NOD2/IL-23/IL-22 signaling pathway, improve intestinal homeostasis, activate the hepatic STAT3 pathway, and alleviate ALD	[86]
CPS and SLP	Postbiotics	ALD model	It can promote short-chain fatty acid production, improve the intestinal functional barrier, and alleviate ALD injury	[87]
Bacillus coagulans and pectin	Synbiotics	ALD model	It can enhance intestinal barrier function and alleviate ALD liver injury	[88]
Bacteroides fragilis ATCC25285 and pectin	Synbiotics	ALD model	It can promote tryptophan metabolism, enhance intestinal immune function and alleviate ALD liver injury	[89]
Lactiplantibacillus plantarum and EGCG	Synbiotics	ALD model	They can inhibit the level of NF-κB, TNF-α, IL-12, TLR4, CD14, MD2, MyD88, COX-2, and alleviate ALD	[90]

Ecological regulators

Types

Targets

Results

References

Akkermansia muciniphila

Probiotics

ALD model

It can regulate the intestinal functional barrier, inhibit bacterial endotoxins from entering the circulatory system, and alleviate ALD liver injury

[67-69]

Lactiplantibacillus plantarum

Probiotics

ALD model

It can regulate the EGFR-dependent mechanism prevents and alleviates alcohol-induced disruption of colonic epithelial tight junctions and liver injury

[71]

Lactiplantibacillus plantarum FB091

Probiotics

ALD model

It can reduce ballooning degeneration of liver cells and infiltration of inflammatory cells in ALD, alleviate the damage to the colonic tissue structure, promote alcohol metabolism, and relieve ALD liver injury

[72]

Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0052

Probiotics

89 ALD patients

They can reduce the levels of Proteus, Fusobacterium, and LPS, protect the intestinal barrier, and alleviate hepatitis

[73]

Lactobacillus rhamnosus CCFM1107

Probiotics

ALD model

It significantly inhibited the increase in the levels of serum aminotransferase, endotoxin, TG and TC, and ameliorated ALD liver injury

[74]

Lactobacillus rhamnosus NKU FL1-8

Probiotics

ALD model

It can decrease the levels of AST, ALT, MDA, SOD and GSH, relieve oxidative stress and decrease hepatic inflammation

[75]

Lactobacillus rhamnosus GG

Probiotics

ALD model

It ameliorates ALD liver injury through modulating antioxidant defenses

[76]

Bifidobacterium and PPC

Probiotics

ALD model

They can ameliorate liver function indicators in ALD rats, inhibit lipid accumulation and hepatic steatosis in ALD liver

[77]

Bifidobacterium and smectite powder

Probiotics

60 ALD patients

They can ameliorate ALD liver injury, without serious adverse reactions, and have the relatively safe therapeutic effect

[78]

Bifidobacterium pseudocatenulatum

Probiotics

ALD model

It can regulate the expression of Cd36, Fasn, Accα, Il-1β, CCL2 and TNF‑α, and ameliorate ALD liver injury

[79]

Bifidobacterium longum subsp. longum BL21

Probiotics

ALD model

It reduced the ethanol-induced abnormal elevation of serum AST and ALT levels in ALD mice

[80]

Bacillus subtilis and Enterococcus faecium

Probiotics

117 ALD patients

They can regulate the expression of TNF‑α, and alleviate ALD liver injury

[81]

Compound probiotic preparation

Probiotics

ALD model

It can alleviate hepatic inflammation, repair the intestinal barrier, reshape the intestinal flora, and alleviate ALD-induced injury

[82]

HRFP-Ⅱ-a, HRFP-Ⅱ-b, HRFP-Ⅱ-c

Prebiotics

ALD model

They can protect ALD mice via antioxidant, anti-inflammatory, lipid metabolism regulation and intestinal flora improvement

[83]

Chitosan oligosaccharide

Prebiotics

ALD model

It can reduce the expression of the liver metabolic enzyme CYP2E1 in ALD, activate the Keap1/Nrf2/HO-1 pathway, inhibit the NF-κB and MAPK pathways, alleviate ALD oxidative damage, hepatic steatosis and inflammation

[85]

Lactobacillus johnsonii HKLJ

Postbiotics

ALD model

It can activate the nucleotide-binding NOD2/IL-23/IL-22 signaling pathway, improve intestinal homeostasis, activate the hepatic STAT3 pathway, and alleviate ALD

[86]

CPS and SLP

Postbiotics

ALD model

It can promote short-chain fatty acid production, improve the intestinal functional barrier, and alleviate ALD injury

[87]

Bacillus coagulans and pectin

Synbiotics

ALD model

It can enhance intestinal barrier function and alleviate ALD liver injury

[88]

Bacteroides fragilis ATCC25285 and pectin