微生物学报

病因 Etiology	涉及的GM变化 Implicated changes in gut microbiota	参考文献 References
乙型肝炎病毒 HBV	丰度上升：拟杆菌门、毛螺菌科未分类菌；丰度降低：瘤胃球菌属、栖粪杆菌属、梭菌属、双歧杆菌属 Increase in abundance: Bacteroidota, Lachnospiraceae incertae sedis; Decrease in abundance: Ruminococcus, Faecalibacterium, Clostridium, Bifidobacterium	[8]
丙型肝炎病毒 Hepatitis C virus (HCV)	丰度上升：肠杆菌科、链球菌属、拟杆菌属、肠球菌属、葡萄球菌属；丰度降低：双歧杆菌属、乳杆菌属、梭菌属 Increase in abundance: Enterobacteriaceae, Streptococcus, Bacteroides, Enterococcus, Staphylococcus; Decrease in abundance: Bifidobacterium, Lactobacillus, Clostridium	[8-9]
非酒精性脂肪性肝病 NAFLD	丰度上升：新洋葱伯克霍尔德氏菌、藤黄微球菌、假单胞菌门、乳杆菌属；丰度降低：嗜酸乳杆菌、龙包茨氏菌属、解纤维素拟杆菌、放线菌纲、拟杆菌门、双歧杆菌属 Increase in abundance: Burkholderia cenocepacia, Micrococcus luteus, Pseudomonadota, Lactobacillus; Decrease in abundance: Lactobacillus acidophilus, Romboutsia, Bacteroides cellulosilyticus, Actinomycetes, Bacteroidota, Bifidobacterium	[10-11]
酒精性肝病 ALD	丰度上升：梭菌属、霍尔德曼菌属、萨特氏菌属；丰度降低：栖粪杆菌属 Increase in abundance: Clostridium, Holdemania, Sutterella; Decrease in abundance: Faecalibacterium	[12]

病因 Etiology	涉及的GM变化 Implicated changes in gut microbiota	参考文献 References
乙型肝炎病毒 HBV	丰度上升：拟杆菌门、毛螺菌科未分类菌；丰度降低：瘤胃球菌属、栖粪杆菌属、梭菌属、双歧杆菌属 Increase in abundance: Bacteroidota, Lachnospiraceae incertae sedis; Decrease in abundance: Ruminococcus, Faecalibacterium, Clostridium, Bifidobacterium	[8]
丙型肝炎病毒 Hepatitis C virus (HCV)	丰度上升：肠杆菌科、链球菌属、拟杆菌属、肠球菌属、葡萄球菌属；丰度降低：双歧杆菌属、乳杆菌属、梭菌属 Increase in abundance: Enterobacteriaceae, Streptococcus, Bacteroides, Enterococcus, Staphylococcus; Decrease in abundance: Bifidobacterium, Lactobacillus, Clostridium	[8-9]
非酒精性脂肪性肝病 NAFLD	丰度上升：新洋葱伯克霍尔德氏菌、藤黄微球菌、假单胞菌门、乳杆菌属；丰度降低：嗜酸乳杆菌、龙包茨氏菌属、解纤维素拟杆菌、放线菌纲、拟杆菌门、双歧杆菌属 Increase in abundance: Burkholderia cenocepacia, Micrococcus luteus, Pseudomonadota, Lactobacillus; Decrease in abundance: Lactobacillus acidophilus, Romboutsia, Bacteroides cellulosilyticus, Actinomycetes, Bacteroidota, Bifidobacterium	[10-11]
酒精性肝病 ALD	丰度上升：梭菌属、霍尔德曼菌属、萨特氏菌属；丰度降低：栖粪杆菌属 Increase in abundance: Clostridium, Holdemania, Sutterella; Decrease in abundance: Faecalibacterium	[12]

肠道菌群 Gut microbiota	相关代谢酶 Related metabolic enzymes	肠道菌群代谢产物 Gut microbiota-derived metabolites	靶向细胞 Target cells	参考文献 References
肠杆菌科 Enterobacteriaceae	\	脂多糖 LPS	Kupffer细胞 Kupffer cell	[15]
裂解梭菌 Clostridium scindens	7α-脱羟基化酶 7α-dehydroxylase	牛磺熊去氧胆酸、牛磺去氧胆酸、ω-鼠胆酸、甘氨石胆酸 TUDCA, TDCA, ω-MCA, GLCA	肝窦内皮细胞 LSECs	[16]
布劳特氏菌属 Blautia	色氨酸酶 Tryptophanase	吲哚-3-乙酸 IAA	肝细胞 Hepatocyte	[17]
梭菌属、瘤胃球菌 Clostridium, Ruminococcaceae	7α-脱羟基化酶 7α-dehydroxylase	鹅脱氧胆酸、牛磺去氧胆酸 CDCA, TDCA	肝细胞 Hepatocyte	[18]
瘤胃球菌属、丁酸球菌属 Ruminococcus, Butyricicoccus	乙酰辅酶A转移酶、丁酸激酶 Acetyl-CoA transferase, butyrate kinase	丁酸盐 Butyrate	自然杀伤细胞 NK cell	[19]
假长双歧杆菌 Bifidobacterium pseudolongum	乙酰辅酶A转移酶、磷酸转乙酰酶 Acetyl-CoA transferase, phosphate transacetylase	乙酸盐 Acetate	肝细胞 Hepatocyte	[20]

肠道菌群 Gut microbiota	相关代谢酶 Related metabolic enzymes	肠道菌群代谢产物 Gut microbiota-derived metabolites	靶向细胞 Target cells	参考文献 References
肠杆菌科 Enterobacteriaceae	\	脂多糖 LPS	Kupffer细胞 Kupffer cell	[15]
裂解梭菌 Clostridium scindens	7α-脱羟基化酶 7α-dehydroxylase	牛磺熊去氧胆酸、牛磺去氧胆酸、ω-鼠胆酸、甘氨石胆酸 TUDCA, TDCA, ω-MCA, GLCA	肝窦内皮细胞 LSECs	[16]
布劳特氏菌属 Blautia	色氨酸酶 Tryptophanase	吲哚-3-乙酸 IAA	肝细胞 Hepatocyte	[17]
梭菌属、瘤胃球菌 Clostridium, Ruminococcaceae	7α-脱羟基化酶 7α-dehydroxylase	鹅脱氧胆酸、牛磺去氧胆酸 CDCA, TDCA	肝细胞 Hepatocyte	[18]
瘤胃球菌属、丁酸球菌属 Ruminococcus, Butyricicoccus	乙酰辅酶A转移酶、丁酸激酶 Acetyl-CoA transferase, butyrate kinase	丁酸盐 Butyrate	自然杀伤细胞 NK cell	[19]
假长双歧杆菌 Bifidobacterium pseudolongum	乙酰辅酶A转移酶、磷酸转乙酰酶 Acetyl-CoA transferase, phosphate transacetylase	乙酸盐 Acetate	肝细胞 Hepatocyte	[20]

措施 Interventions	研究对象 Object of study	结果 Results	总结 Conclusion	参考文献 References
补充益生菌(鼠李糖乳酪杆菌) Probiotic supplementation (Lacticaseibacillus rhamnosus)	肝硬化患者 Patient with liver cirrhosis	1. 减轻内毒素血症，减少促炎因子的分泌；2. 改善GM失衡及其相关代谢紊乱 1. Alleviate endotoxemia and reduce the secretion of pro-inflammatory cytokines; 2. Ameliorate GM dysbiosis and its associated metabolic disorders	益生菌干预可能通过延缓肝硬化进展，从而降低HCC的发病风险 Probiotic intervention may delay the progression of liver cirrhosis, thereby reducing the risk of HCC	[37]
粪菌移植 FMT	晚期HCC患者 Patients with advanced-stage HCC	1. 激活HCC患者全身性及肿瘤局部的抗肿瘤免疫应答；2. 升高患者体内益生菌丰度 1. Activate systemic and tumor-localized antitumor immunity in HCC patients; 2. Increase the abundance of probiotics in HCC patients	FMT可通过重塑GM组成和功能来改善HCC FMT may suppress HCC progression through restructuring the composition and function of the GM	[38]
	HCC小鼠 HCC mice	1. 升高小鼠体内益生菌丰度；2. 抑制肿瘤血管生长并减轻组织坏死；3. 升高乙酸盐水平，减少IL-17A的分泌 1. Increase the abundance of probiotics in mice; 2. Suppress tumor angiogenesis and reduce tumor necrosis; 3. Increase acetate levels, thereby reducing IL-17A secretion	产乙酸盐的GM可通过减少肿瘤内产生IL-17A的3型固有淋巴细胞的浸润，从而抑制HCC的进展 Acetate-producing GM can suppress the progression of HCC by reducing the intratumoral infiltration of IL-17A-producing ILC3s	[39-40]
联合免疫药物治疗(索拉非尼) Combination immunotherapeutic drug therapy (Sorafenib)	晚期HCC患者 Patients with advanced-stage HCC	1. 重塑肿瘤微环境，促进IL-12和IFN-γ等的分泌，并增加IFN-γ⁺CD8⁺ T细胞的比例；2. 诱导HCC细胞发生铁死亡 1. Remodel the tumor microenvironment and promote the secretion of IL-12 and IFN-γ, thereby increasing the proportion of IFN-γ⁺CD8⁺T cells; 2. Induce ferroptosis in HCC cells	特定GM在免疫药物靶向治疗HCC中起重要作用，可增强免疫药物治疗HCC的效果 Specific GM plays a crucial role in targeted immunotherapy for HCC, which can enhance the efficacy of targeted immunotherapy against HCC	[41]
联合手术治疗(肝切除术) Combination surgical therapy (hepatic resection)	HCC肝切除术后患者 patients after HCC hepatic resection	1. 缓解肝脏炎症反应及肝纤维化进程；2. 降低术后恢复延迟率，缩短住院时间并提高1年总生存率 1. Alleviate hepatic inflammatory response and the progression of hepatic fibrosis; 2. Reduce the rate of postoperative recovery delay, shorten the length of hospital stay, and improve the 1-year overall survival rate	特定GM可改善HCC患者的术后预后 Specific GM plays an essential role in enhancing the efficacy of targeted immunotherapy for HCC by modulating treatment responses	[42]
补充益生菌(嗜酸乳杆菌) Probiotic supplementation (Lactobacillus acidophilus)	NAFLD-HCC小鼠 NAFLD-HCC mice	1. 延缓小鼠NAFLD-HCC的发病过程；2. 升高小鼠肠道戊酸盐水平，戊酸盐结合肝细胞表面GPR41/43受体，抑制Rho-GTPase通路活性，从而发挥抗癌效应 1. Delay the disease process of NAFLD-HCC in mice; 2. The anticancer effect is mediated through elevated gut valerate, which acts via GPR41/43 receptors on hepatocytes to inhibit the Rho-GTPase pathway	益生菌可抑制NAFLD-HCC小鼠的发生发展 Probiotics exert a protective effect against the development of NAFLD-HCC in mice	[10]
使用抗生素 (万古霉素) Rational antibiotic use (vancomycin)	T5KO小鼠 T5KO mice	1. 调控胆汁酸代谢，提高结合型与游离型胆汁酸比例，抑制其异常合成；2. 有效改善小鼠代谢表型，使小鼠体重、脂肪质量及血糖水平等均恢复正常 1. Modulate bile acid metabolism by increasing the conjugated/unconjugated bile acid ratio and suppressing aberrant synthesis; 2. Ameliorate the metabolic phenotype in mice, thereby normalizing body weight, fat mass, blood glucose levels, and other relevant indices	合理使用抗生素可能延缓小鼠的HCC进展 Administration of antibiotics leads to suppressed progression of HCC in mice	[43]

措施 Interventions	研究对象 Object of study	结果 Results	总结 Conclusion	参考文献 References
补充益生菌(鼠李糖乳酪杆菌) Probiotic supplementation (Lacticaseibacillus rhamnosus)	肝硬化患者 Patient with liver cirrhosis	1. 减轻内毒素血症，减少促炎因子的分泌；2. 改善GM失衡及其相关代谢紊乱 1. Alleviate endotoxemia and reduce the secretion of pro-inflammatory cytokines; 2. Ameliorate GM dysbiosis and its associated metabolic disorders	益生菌干预可能通过延缓肝硬化进展，从而降低HCC的发病风险 Probiotic intervention may delay the progression of liver cirrhosis, thereby reducing the risk of HCC	[37]
粪菌移植 FMT	晚期HCC患者 Patients with advanced-stage HCC	1. 激活HCC患者全身性及肿瘤局部的抗肿瘤免疫应答；2. 升高患者体内益生菌丰度 1. Activate systemic and tumor-localized antitumor immunity in HCC patients; 2. Increase the abundance of probiotics in HCC patients	FMT可通过重塑GM组成和功能来改善HCC FMT may suppress HCC progression through restructuring the composition and function of the GM	[38]
	HCC小鼠 HCC mice	1. 升高小鼠体内益生菌丰度；2. 抑制肿瘤血管生长并减轻组织坏死；3. 升高乙酸盐水平，减少IL-17A的分泌 1. Increase the abundance of probiotics in mice; 2. Suppress tumor angiogenesis and reduce tumor necrosis; 3. Increase acetate levels, thereby reducing IL-17A secretion	产乙酸盐的GM可通过减少肿瘤内产生IL-17A的3型固有淋巴细胞的浸润，从而抑制HCC的进展 Acetate-producing GM can suppress the progression of HCC by reducing the intratumoral infiltration of IL-17A-producing ILC3s	[39-40]
联合免疫药物治疗(索拉非尼) Combination immunotherapeutic drug therapy (Sorafenib)	晚期HCC患者 Patients with advanced-stage HCC	1. 重塑肿瘤微环境，促进IL-12和IFN-γ等的分泌，并增加IFN-γ⁺CD8⁺ T细胞的比例；2. 诱导HCC细胞发生铁死亡 1. Remodel the tumor microenvironment and promote the secretion of IL-12 and IFN-γ, thereby increasing the proportion of IFN-γ⁺CD8⁺T cells; 2. Induce ferroptosis in HCC cells	特定GM在免疫药物靶向治疗HCC中起重要作用，可增强免疫药物治疗HCC的效果 Specific GM plays a crucial role in targeted immunotherapy for HCC, which can enhance the efficacy of targeted immunotherapy against HCC	[41]
联合手术治疗(肝切除术) Combination surgical therapy (hepatic resection)	HCC肝切除术后患者 patients after HCC hepatic resection	1. 缓解肝脏炎症反应及肝纤维化进程；2. 降低术后恢复延迟率，缩短住院时间并提高1年总生存率 1. Alleviate hepatic inflammatory response and the progression of hepatic fibrosis; 2. Reduce the rate of postoperative recovery delay, shorten the length of hospital stay, and improve the 1-year overall survival rate	特定GM可改善HCC患者的术后预后 Specific GM plays an essential role in enhancing the efficacy of targeted immunotherapy for HCC by modulating treatment responses	[42]
补充益生菌(嗜酸乳杆菌) Probiotic supplementation (Lactobacillus acidophilus)	NAFLD-HCC小鼠 NAFLD-HCC mice	1. 延缓小鼠NAFLD-HCC的发病过程；2. 升高小鼠肠道戊酸盐水平，戊酸盐结合肝细胞表面GPR41/43受体，抑制Rho-GTPase通路活性，从而发挥抗癌效应 1. Delay the disease process of NAFLD-HCC in mice; 2. The anticancer effect is mediated through elevated gut valerate, which acts via GPR41/43 receptors on hepatocytes to inhibit the Rho-GTPase pathway	益生菌可抑制NAFLD-HCC小鼠的发生发展 Probiotics exert a protective effect against the development of NAFLD-HCC in mice	[10]
使用抗生素 (万古霉素) Rational antibiotic use (vancomycin)	T5KO小鼠 T5KO mice	1. 调控胆汁酸代谢，提高结合型与游离型胆汁酸比例，抑制其异常合成；2. 有效改善小鼠代谢表型，使小鼠体重、脂肪质量及血糖水平等均恢复正常 1. Modulate bile acid metabolism by increasing the conjugated/unconjugated bile acid ratio and suppressing aberrant synthesis; 2. Ameliorate the metabolic phenotype in mice, thereby normalizing body weight, fat mass, blood glucose levels, and other relevant indices	合理使用抗生素可能延缓小鼠的HCC进展 Administration of antibiotics leads to suppressed progression of HCC in mice	[43]

肠道菌群失衡在肝癌发病机制与靶向干预中的研究进展

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邓萧琴 , 姜润秋 ^* , 李祥云 ^*

微生物学报 | 综述 2026,66(3): 975-989

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微生物学报 | 综述 2026, 66(3): 975-989

肠道菌群失衡在肝癌发病机制与靶向干预中的研究进展

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邓萧琴, 姜润秋^*, 李祥云^*

作者信息

安徽医科大学第一附属医院检验科，安徽合肥

Research progress in the pathogenesis of liver cancer mediated by gut microbiota dysbiosis and the targeted interventions

Xiaoqin DENG, Runqiu JIANG^*, Xiangyun LI^*

Affiliations

Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

出版时间: 2026-03-04 doi: 10.13343/j.cnki.wsxb.20250708

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摘要

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肝癌作为全球高发且预后不良的恶性肿瘤，其病理进程与肠道菌群(gut microbiota, GM)密切相关。近年来，在肝炎-肝纤维化-肝硬化-肝癌这一病理进展过程中GM参与肝癌发生发展的相关研究日益受到关注。GM失衡可通过多种途径影响肝癌进程，具体包括通过GM及其代谢产物调控肝脏免疫微环境、介导表观遗传修饰及外泌体信号、与肝癌危险因素协同作用等。肝癌患者普遍存在GM多样性降低且致病菌群增多的特征，这为靶向GM的治疗方法提供了理论依据，具体涵盖益生菌干预、合理使用抗生素、粪菌移植、GM与传统治疗手段联合应用以及整合性治疗方案等。本文主要综述近年来GM失衡在肝癌中的发病机制及靶向GM干预的相关研究进展，为今后肝癌发病机制的研究及治疗提供参考。

关键词

肠道菌群 / 肝癌 / 发病机制 / 靶向干预

Abstract

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As a globally prevalent malignancy with poor prognosis, liver cancer exhibits a well-established pathological association with the gut microbiota (GM). In recent years, increasing attention has been paid to the role of the GM in the initiation and pathological progression of liver cancer, which often evolves through stages of hepatitis, liver fibrosis, cirrhosis, and ultimately liver cancer. The GM influences the development of liver cancer through multiple mechanisms, including the regulation of the hepatic immune microenvironment by the GM and its metabolites, the mediation of epigenetic modifications and exosomal signaling pathways, and the synergy with other risk factors. Notably, patients with liver cancer commonly demonstrate reduced GM diversity and enriched pathogenic bacteria. These findings offer a new theoretical foundation and suggest potential therapeutic strategies such as probiotic supplementation, rational antibiotic use, fecal microbiota transplantation, combination therapies integrating GM modulation with conventional treatments, and integrated treatment regimens based on the above methods. This article reviews the pathogenesis of liver cancer mediated by GM dysbiosis and the research advances in GM-targeted interventions in recent years, providing reference for future studies on the pathogenesis and treatment of liver cancer.

Key words

gut microbiota / liver cancer / pathogenesis / targeted intervention

引用本文

邓萧琴, 姜润秋, 李祥云. 肠道菌群失衡在肝癌发病机制与靶向干预中的研究进展. 微生物学报, 2026 , 66 (3) : 975 -989 . DOI: 10.13343/j.cnki.wsxb.20250708

Xiaoqin DENG, Runqiu JIANG, Xiangyun LI. Research progress in the pathogenesis of liver cancer mediated by gut microbiota dysbiosis and the targeted interventions[J]. Acta Microbiologica Sinica, 2026 , 66 (3) : 975 -989 . DOI: 10.13343/j.cnki.wsxb.20250708

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肝癌是全球高发的消化系统常见恶性肿瘤，其中肝细胞癌(hepatocellular carcinoma, HCC)作为主要病理亚型，占比超过80%^[1]。流行病学数据显示，肝癌发病率在恶性肿瘤中居第6位，死亡率居第3位，该疾病已成为全球面临的重大公共卫生挑战^[2]。由此可见，深入阐明肝癌发生发展的具体机制意义重大，这为制定针对性治疗方案提供了理论基础。肝癌致病因素多样，包括病毒性肝炎、非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)、酒精性肝病(alcoholic liver disease, ALD)、肝硬化及罕见肝脏疾病等，上述因素可诱发慢性炎症反应，驱动肝炎-肝纤维化-肝硬化-肝癌的病理进程，进而促进肝癌的发生发展^[3]。近年来，肠道菌群(gut microbiota, GM)已被证实与肝癌的发生发展密切相关，但其潜在调控机制复杂，尚未完全阐明。人体胃肠道内微生物数量高达数万亿个，这些微生物与宿主肠道微环境共同构成处于动态平衡的肠道微生态系统，健康状态下的GM可通过参与营养物质分解吸收、免疫功能调节、代谢过程调控及屏障防御等多项重要生理活动维持机体稳态平衡^[4-5]。本文系统探讨GM与肝癌发生发展的关系及靶向干预潜力，以期为肝癌防治策略提供新的理论依据。

1 GM在肝癌患者中的变化

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近年来大量研究表明，肝癌患者GM组成发生显著变化。与健康人群相比，肝癌患者体内副拟杆菌属(Parabacteroides)、梭菌属(Clostridium)和芽殖菌属(Gemmiger)等丰度显著升高，而双歧杆菌属(Bifidobacterium)和乳杆菌属(Lactobacillus)等丰度显著降低^[6]；与肝硬化患者相比，HCC患者肠道内小鼠盲肠拟杆菌(Bacteroides caecimuris)和小韦荣氏球菌(Veillonella parvula)等丰度显著升高^[7]。值得注意的是，肝癌患者的GM组成与其不同致病因素[如乙型肝炎病毒(hepatitis B virus, HBV)感染、NAFLD、ALD等]相关，且呈现特征性差异(表1)。例如，NAFLD是肝癌的重要诱因之一，GM失衡在NAFLD-HCC的全病程进展(肝炎-肝纤维化-肝硬化-肝癌)中发挥核心驱动作用，其结构变化呈现阶段特异性。在非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)阶段，乳杆菌属(Lactobacillus)和双歧杆菌属(Bifidobacterium)等丰度轻度下降，而黏螺菌属(Mucispirillum)、脱硫弧菌属(Desulfovibrio)和厌氧棍状菌属(Anaerotruncus)等丰度开始升高，导致牛磺胆酸(taurocholic acid, TCA)水平升高、3-吲哚丙酸(indolyl-3-propionic acid, IPA)水平降低，从而促进肝内脂质积蓄并诱导炎症反应；到肝纤维化阶段，上述GM变化持续存在，同时促纤维化菌属[如活泼瘤胃球菌(Ruminococcus gnavus)等]丰度进一步升高，加剧肠道屏障受损与脂多糖(lipopolysaccharide, LPS)易位，激活肝星状细胞(hepatic stellate cells, HSCs)，推动肝纤维化进展；进入NAFLD相关肝硬化阶段，上述GM变化呈现特征性稳定，其代谢产物显著紊乱并持续作用于肝脏，一方面加剧肝脏慢性炎症与氧化应激，另一方面抑制外周免疫应答，推动HCC发生发展；最终在NAFLD-HCC阶段，除上述GM持续失衡外，蛇形螺杆菌(Helicobacter ganmani)仅在该阶段呈特异性丰度升高，GM失衡通过抑制树突状细胞及细胞毒性T细胞功能削弱抗肿瘤免疫，同时促进肿瘤微环境中血管生成因子分泌，加速肿瘤增殖进程^[13-14]。此外，在乙型肝炎病毒相关性肝癌(HBV-HCC)患者中，瘤胃球菌属(Ruminococcus)、栖粪杆菌属(Faecalibacterium)等产丁酸盐菌丰度显著降低；在肿瘤负荷较高的HBV-HCC患者中，拟杆菌门(Bacteroidota)及毛螺菌科未分类菌(Lachnospiraceae incertae sedis)丰度均升高^[8]。

2 GM失衡影响肝癌发生发展的作用机制

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GM失衡通过多维度协同机制促进肝癌发生发展。首先，GM及其代谢产物通过调控肝脏免疫微环境影响肝癌进展(图1)，其中相关代谢产物作为关键免疫调节因子，可靶向多种细胞并调控其免疫功能(表2)；其次，GM及其代谢产物可通过表观遗传修饰及外泌体信号调控等途径，调控肝癌相关基因表达与肝内细胞功能状态，进而影响肝癌进展；此外，GM失衡还可与肝癌危险因素(如NAFLD、ALD等)产生协同作用，共同加速肝癌进展。上述机制相互关联，共同构成由GM失衡驱动肝癌发生发展的复杂调控网络。

2.1 GM及其代谢产物对肝脏免疫微环境的调控

2.1.1 GM失衡介导LPS释放

LPS作为一种典型的促癌因子，其促癌作用始于革兰氏阴性菌过度增殖所导致的LPS大量释放，当肠道屏障完整性受损时LPS进入血液循环诱发内毒素血症^[15]。LPS通过结合Toll样受体4 (Toll-like receptor 4, TLR4)介导HSCs的活化，进而促使活化态HSCs高表达表皮调节素，从而直接刺激肝细胞异常增殖，并加速肝纤维化进展，最终显著提高肝癌发生风险^[21]。同时LPS与其结合蛋白形成复合物后可被Kupffer细胞表面TLR4受体特异性识别，通过髓系分化初级反应蛋白质88 (myeloid differentiation primary response protein 88, MyD88)依赖性信号转导通路激活核因子κB (nuclear factor κB, NF-κB)通路，进而促使Kupffer细胞高表达并释放白介素-6 (interleukin-6, IL-6)、肿瘤坏死因子α (tumor necrosis factor-α, TNF-α)等促炎细胞因子，加剧肝脏炎症反应^[22]，持续存在的炎症微环境为肝癌的发生发展提供了有利条件。

2.1.2 短链脂肪酸代谢紊乱

与LPS的促癌作用不同，短链脂肪酸(short-chain fatty acids, SCFAs)主要作为关键抑癌因子发挥保护作用。外源性补充假长双歧杆菌(Bifidobacterium pseudolongum)可促进乙酸盐生成，乙酸盐一方面能够修复肠道屏障功能，减少LPS易位进入血液循环，从而间接维持肝脏免疫微环境稳定；另一方面，乙酸盐还可与肝细胞表面介导SCFAs信号转导的G蛋白偶联受体43 (G protein-coupled receptor 43, GPR43)结合，通过抑制IL-6/非受体型酪氨酸蛋白激酶1 (Janus kinase 1, JAK1)/信号转导及转录激活因子3 (signal transducer and activator of transcription 3, STAT3)信号通路活化直接阻断促炎信号传导，从而改善肝脏免疫微环境^[20]。丁酸盐可通过诱导肝癌细胞分泌C-X-C基序趋化因子配体11 (C-X-C motif chemokine 11, CXCL11)，特异性趋化自然杀伤(natural killer, NK)细胞浸润肿瘤组织来发挥抗肿瘤效应；然而，肝癌患者体内瘤胃球菌属(Ruminococcus)、丁酸球菌属(Butyricicoccus)等产丁酸盐菌丰度显著降低，导致丁酸盐合成障碍，最终削弱NK细胞介导的抗肿瘤免疫效应，加速肝癌恶性进展^[19]。此外，肠道内产酸拟杆菌(Bacteroides acidifaciens)、羊毛状臭气杆菌(Odoribacter laneus)及内脏臭气杆菌(Odoribacter splanchnicus)等丰度升高，可通过促进SCFAs生成激活AMP活化蛋白激酶-哺乳动物雷帕霉素靶蛋白(AMP-activated protein kinase-mammalian target of rapamycin, AMPK-mTOR)信号通路，发挥抗肿瘤效应，该通路激活能上调NK细胞和T细胞中的AMPK，同时抑制mTOR信号通路，从而下调程序性死亡蛋白-1 (programmed death-1, PD-1)表达并促进γ干扰素(interferon-γ, IFN-γ)分泌，延缓T细胞耗竭，最终提高对肝癌细胞的识别与清除效率^[23]。

2.1.3 胆汁酸代谢紊乱

胆汁酸代谢紊乱在肝癌进展中通过促癌与抑癌双重机制发挥作用。在促癌方面，主要表现为特定胆汁酸异常蓄积所引发的炎症免疫失衡。例如，甘氨鹅脱氧胆酸(glycochenodeoxycholic acid, GCDCA)是一种重要的结合型初级胆汁酸，内脏臭气杆菌(Odoribacter splanchnicus)丰度下降导致GCDCA水平升高，破坏肠道屏障完整性，促使LPS经门静脉易位至肝脏，进而激活肝内Kupffer细胞的TLR4/NF-κB信号通路，释放TNF-α、IL-1β等促炎因子，最终加剧肝脏慢性炎症与免疫微环境失衡^[24]。同时，NAFLD患者体内梭菌科(Clostridiaceae)丰度显著升高，导致次级胆汁酸过度蓄积，通过激活mTOR等通路加剧炎症反应，干扰肠-肝循环并抑制肝脏中法尼醇X受体(farnesoid X receptor, FXR)活化，从而可能推动NAFLD向肝癌的进展^[25]。在抑癌方面，特定GM介导的保护性次级胆汁酸生成具有关键作用。例如，部分革兰氏阳性菌[如裂解梭菌(Clostridium scindens)等]可介导肝脏分泌的初级胆汁酸[如牛磺胆酸(taurocholic acid, TCA)、鹅脱氧胆酸(chenodeoxycholic acid, CDCA)等]向次级胆汁酸[如牛磺熊去氧胆酸(tauroursodeoxycholate, TUDCA)等]转化，其丰度降低可能导致次级胆汁酸生成减少及初级胆汁酸相对蓄积，从而促使肝窦内皮细胞(liver sinusoidal endothelial cells, LSECs)高表达CXCL16，强烈趋化自然杀伤T细胞(natural killer T cell, NKT cell)并募集其浸润肝脏，最终抑制肝癌进展^[16]。此外，活性地中海杆菌(Mediterraneibacter gnavus)可将CDCA转化为熊脱氧胆酸(ursodeoxycholic acid, UDCA)，UDCA不仅能抑制氧化与内质网应激以维持肝细胞稳态，还可抑制HSCs的活化与增殖以发挥抗肝纤维化作用，且肝纤维化进展常伴随调节性T细胞等免疫抑制细胞的浸润，因此UDCA可通过阻断肝纤维化进程间接减少此类免疫细胞的聚集，进而改善肝脏免疫微环境，发挥抗肿瘤效应^[26]。

2.2 表观遗传修饰与外泌体信号调控机制

2.2.1 表观遗传修饰调控机制

GM可通过其代谢产物介导的表观遗传修饰调控肝癌相关基因的表达活性，进而影响肝癌的发生发展。GM失衡可引发胆汁酸代谢紊乱，其中武田G蛋白偶联受体5 (Takeda G protein‑coupled receptor 5, TGR5)被胆汁酸[如石胆酸(lithocholic acid, LCA)、CDCA等]以剂量依赖性方式激活，但其启动子高甲基化显著抑制自身转录，从而削弱对下游炎症信号通路的负向调控作用，加剧肝脏炎症损伤，临床研究证实肝癌患者TGR5启动子高甲基化发生率较高，提示该表观遗传修饰可能促进肝癌进展^[27]。此外，SCFAs可抑制组蛋白去乙酰化酶(histone deacetylase, HDACs)活性，乙肝X蛋白(hepatitis B X protein, HBx)可通过激活特定HDACs及DNA甲基转移酶，诱导肿瘤抑制基因沉默并激活原癌基因表达，从而驱动肝细胞恶性转化，表明SCFAs可能阻断肿瘤细胞异常增殖信号并逆转由HBx介导的部分表观遗传修饰效应^[28]，GM失衡引发SCFAs代谢紊乱，导致SCFAs对HDACs的负向调控作用减弱，这可能间接促进肝癌进展。在高果糖饮食诱导的小鼠肝癌模型中，GM将未被完全代谢的果糖转化为乙酸盐，而乙酸盐可靶向作用于肝癌细胞，升高肝癌细胞内谷氨酰胺及尿苷二磷酸-N-乙酰葡糖胺(uridine diphosphate-N-acetylglucosamine, UDP-GlcNAc)水平，进而增强蛋白质O-连接N-乙酰葡糖胺化(O-GlcNAcylation)修饰，最终强化肝癌细胞的增殖能力并加速肿瘤生长^[29]。

2.2.2 外泌体信号调控机制

外泌体通过递送生物活性分子至受体细胞，参与调控细胞间通讯及下游信号通路，GM失衡可通过影响外泌体的生成及其所携带的信号分子组成调控肝癌的进展。在ALD小鼠模型中GM失衡可诱导肠道内miR-194表达上调，进而抑制FXR的配体结合能力，加剧肝损伤，而鼠李糖乳酪杆菌(Lacticaseibacillus rhamnosus)来源外泌体通过抑制miR-194表达来恢复FXR信号通路活性，进而上调成纤维因子15 (fibroblast growth factor 15, FGF15)的表达，改善ALD病理表现^[30]，最终间接抑制肝癌进展。同时，双歧杆菌属(Bifidobacterium)来源的外泌体携带特定活性成分，可更精准地激活FXR信号通路，且该类外泌体还可包裹FXR通路相关基因的转录本或调控因子，通过递送这些功能性核酸分子有效延缓肝癌的进展^[27]。此外，肠道类器官分泌的外泌体干预经四氯化碳诱导的肝纤维化小鼠模型后，可显著抑制小鼠肝内纤维组织增生及假小叶结构形成，并降低血清中总胆红素、天冬氨酸转氨酶及丙氨酸转氨酶等肝损伤指标水平，提示该外泌体在缓解肝纤维化方面具有潜在治疗价值^[31]，而GM失衡可能破坏肠道上皮细胞功能，影响外泌体生物合成及功能特性，从而促进肝癌发生发展。

2.3 GM失衡与肝癌危险因素协同作用

GM失衡并非肝癌发生的独立驱动因素，而是通过与慢性肝炎病毒感染、NAFLD、ALD及肝硬化等危险因素协同作用共同加速肝癌的发生发展。Huang等^[32]研究发现，HBV-HCC患者肠道内拟杆菌属(Bacteroides)、毛螺菌科未分类菌(Lachnospiraceae incertae sedis)及梭菌属(Clostridium) XIVa群的丰度呈特征性升高，上述菌群不仅可通过其关联基因编码的代谢功能，调控T细胞受体信号通路、NK细胞活化通路等免疫相关通路，损害肝脏免疫监视功能，同时还协同紊乱的胆汁酸代谢重塑肿瘤微环境，从而共同促进肝癌的发生发展。NAFLD作为肝癌的重要致病因素之一，可导致肠道屏障完整性受损，并引发慢性肝脏炎症反应及肝纤维化，为肝癌发生奠定病理基础；同时NAFLD患者肠道内阿克曼氏菌属(Akkermansia)和双歧杆菌属(Bifidobacterium)等有益菌丰度降低，从而进一步削弱肠道屏障功能并加剧肝脏炎症反应，最终共同推动肝癌进展^[33]。在ALD背景下，长期酒精摄入导致过量乙醇在体内蓄积，引发代谢紊乱、氧化应激及肝脏慢性炎症等，且ALD相关的GM失衡还可进一步诱导胆汁酸代谢紊乱并加剧炎症反应，与上述因素共同驱动肝细胞恶性转化^[34]。肝硬化作为肝癌的关键癌前病变，酒精相关肝硬化的发生与酒精使用障碍密切相关，酒精使用障碍患者肠道内毛螺菌科(Lachnospiraceae)丰度升高、瘤胃球菌属(Ruminococcus)丰度降低，且伴随肠道通透性升高，该变化可与肝硬化固有的慢性炎症及肝纤维化形成协同效应，共同加速肝癌进程^[35]。此外，肝癌的病理状态也可反向重塑GM的组成结构，形成促进肝癌进展的正反馈环路。例如，Wang等^[36]研究发现，肝癌患者粪便样本中肺炎克雷伯氏菌(Klebsiella pneumoniae)丰度显著升高，其可通过降解肠道紧密连接蛋白、破坏黏液层完整性等方式，进一步加剧肠道屏障功能障碍。

3 靶向GM治疗肝癌

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GM与肝癌之间存在着密切关联，且GM可作为治疗肝癌的潜在靶点，通过调节GM干预肝癌的多种治疗方法为肝癌的防治提供了新的思路(表3)。同时，靶向GM的疗法尚处于探索阶段，其在临床转化中仍面临诸多挑战，且单一策略的局限性也促使整合性方案成为一种新的探索方向。

3.1 补充益生菌

益生菌通过调节GM稳态与改善肝脏代谢功能，在肝癌防治领域展现出潜在应用价值。NAFLD-HCC小鼠外源性补充嗜酸乳杆菌(Lactobacillus acidophilus)后可显著升高体内戊酸盐水平，戊酸盐通过结合肝细胞表面GPR41/43，抑制Rho GTPase的致癌信号通路活化，从而减轻肝脏炎症反应并减少肿瘤细胞异常增殖，同时抑制HDACs活性，协同发挥抗肿瘤效应^[10]。Duduyemi等^[44]研究表明，植物乳植杆菌(Lactiplantibacillus plantarum)可诱导肝癌细胞出现早期凋亡及衰老现象，在体外实验中展现出显著的抗癌活性，且其单独应用对HCC的治疗效果优于索拉非尼单药治疗效果。此外，在NAFLD小鼠模型中植物乳植杆菌(Lactiplantibacillus plantarum) X与两歧双歧杆菌(Bifidobacterium bifidum) V按1:2配比的复合制剂可增加拟杆菌门/芽孢杆菌门(Bacteroidota/Bacillota)比值，降低肝脏胆固醇和甘油三酯水平，有效延缓NAFLD进程，从而降低肝癌发生风险^[45]。由瑞士乳杆菌(Lactobacillus helveticus)、植物乳植杆菌(Lactiplantibacillus plantarum)、鼠李糖乳酪杆菌(Lacticaseibacillus rhamnosus)、嗜酸乳杆菌(Lactobacillus acidophilus)、类干酪乳杆菌(Lactobacillus paracasei)、短双歧杆菌(Bifidobacterium breve)、动物双歧杆菌乳亚种(Bifidobacterium animalis subsp. lactis)和唾液链球菌嗜热亚种(Streptococcus salivarius subsp. thermophilus)等菌株制成的益生菌混合制剂可减轻肝脏脂肪变性和炎症反应，并显著抑制NAFLD-HCC小鼠的肿瘤发展^[46]。目前运用益生菌干预肝癌在临床应用转化过程中仍面临多重挑战，如益生菌制剂在胃肠道环境中的耐受性不足、易受氧化应激损伤、其肠道滞留时间短以及靶向性差等问题，为应对上述挑战，近年来进行了一些关于开发新型递送与保护技术的研究。例如，利用螺旋藻(spirulina platensis, SP)作为天然载体，并结合壳聚糖涂层构建复合包封系统，借助SP所含天然抗氧化成分与益生菌所负载的AuCe纳米酶协同清除肠道活性氧，从而有效保护益生菌免受氧化损伤；或通过构建“内层金属-酚网络-外层多糖凝胶”的双层屏障体系，显著增强益生菌在胃肠传输过程中的稳定性与存活率^[47-48]。

3.2 合理使用抗生素

抗生素通过选择性调控GM组成与代谢功能在肝癌防治中发挥靶向调控作用。临床药物试验表明，万古霉素通过抑制革兰氏阳性菌肽聚糖合成特异性清除肠道中参与膳食纤维发酵及次级胆汁酸合成的菌群[如毛螺菌科(Lachnospiraceae)等]，导致次级胆汁酸等促癌代谢产物水平降低，从而抑制肝癌发生发展^[43]。利福昔明是一种肠道选择性抗生素，对NASH治疗具有潜在价值，在胆碱缺乏、l-氨基酸限定的高脂饮食诱导的NASH大鼠模型中，利福昔明干预可显著下调与肝癌细胞增殖相关的关键基因的表达，从而抑制肝癌的发生发展^[49]。γδT细胞可直接靶向并浸润肿瘤组织，其抗肿瘤功能可能受GM调节，使用特定抗生素可升高产IPA菌的丰度，进而刺激γδT细胞释放细胞毒性因子，从而增强其对肝癌细胞的杀伤作用并抑制肝癌进展；然而，抗生素仅能非特异性降低GM总量，无法精准保留有益菌或清除有害菌，因此未来可致力于开发窄谱抗生素以提高其靶向性，并结合合成生物学等技术改造GM以减少长期使用所致的抗生素依赖风险^[50]。此外，不同肝癌病因所对应的GM组成及功能也存在本质差异，从而导致抗生素的干预效果呈现显著异质性，但目前缺乏针对性方案，为实现精准调控，可构建评估模型以指导抗生素合理选择与使用时机，同时还可在使用抗生素24-48 h内进行粪菌移植(fecal microbiota transplantation, FMT)，重建GM平衡，可能抵消抗生素引起的GM失衡及其不良影响^[51]。

3.3 FMT

近年来大量临床研究证实，健康供体来源的FMT在癌症治疗领域中展现出巨大潜力，其作为一种创新疗法在早期肿瘤干预中已引起广泛关注^[52]。Deng等^[39]探讨了FMT对肝癌肝内转移模型小鼠的干预效应，健康供体来源的FMT可显著升高人结肠厌氧棍状菌(Anaerotruncus colihominis)和瓦隆卓越生物项目难闻杆菌(Dysosmobacter welbionis)等有益菌的丰度，从而减少肝癌肝内转移灶的数量和大小，降低肿瘤负荷并延长模型小鼠的生存期，这表明FMT可通过恢复GM稳态发挥抗肿瘤作用。高剂量的中药复方制剂可诱导肝癌细胞发生焦亡，进而触发肿瘤细胞的程序性死亡，与接受肿瘤模型组小鼠FMT的受体小鼠相比，接受高剂量中药复方制剂处理组小鼠FMT的受体小鼠肝脏内肿瘤的体积及数量均显著减少^[53]。在HCC小鼠移植经罗伊特氏黏液乳杆菌(Limosilactobacillus reuteri)处理的小鼠粪便菌群后，其肝脏内的肿瘤数量及相对大小均显著减少，进一步验证了健康供体FMT通过调节GM以抑制肝癌进展的潜力^[40]。FMT供体的应用效果高度依赖于供体的健康状况，由于HCC患者常合并肝脏基础疾病及接受免疫抑制治疗，其对FMT供体质量的要求更为严格，然而目前缺乏针对性的专用供体筛选标准，且存在移植菌群在受体肠道内存活率低且不稳定等问题，因此可在FMT前采用抗生素预处理以重塑GM结构，从而提高治疗效果；或联合补充膳食纤维为供体菌提供营养支持，从而提高其存活能力^[54]。此外，FMT在临床应用中仍面临制备工艺标准化不足与给药途径选择不统一等问题，为提升其可重复性与治疗效果，可建立统一FMT制备流程，并根据病变部位特点对给药途径进行分层选择，如针对上消化道相关肿瘤患者可优先采用肠溶胶囊口服给药，而对下消化道相关肿瘤患者则可优选结肠镜下直接输注以提升菌群存活率^[55]。

3.4 联合传统手段治疗

联合免疫治疗是不可切除HCC的一线标准治疗方案。Lee等^[26]研究显示，病毒性肝癌和NAFLD-HCC患者在接受联合免疫治疗后，肠道内地中海杆菌属(Mediterraneibacter)和双歧杆菌属(Bifidobacterium)丰度呈特征性升高，粪便中乙酸盐水平显著高于对照组，且生存分析显示乙酸盐水平与患者生存预后呈显著正相关，这提示可通过调节GM提升乙酸盐水平，从而改善联合免疫治疗的应答率和患者预后情况。索拉非尼作为晚期HCC的一线靶向药物，其临床耐药率较高，临床研究发现，对索拉非尼应答的患者肠道中屎肠球菌(Enterococcus faecium)丰度明显升高，其分泌的胞外多糖可诱导肿瘤微环境中IFN-γ⁺CD8⁺ T细胞显著增加，该细胞群分泌的IFN-γ与索拉非尼协同促进HCC细胞铁死亡，最终增强抗肿瘤效应；同时动物实验进一步证实，屎肠球菌(Enterococcus faecium)与索拉非尼联合应用可显著缩小肿瘤体积，效果优于索拉非尼单药治疗^[41]。Yu等^[42]研究表明，实验小鼠移植自肝癌手术后恢复缓慢患者的粪便菌群后，在口服长双歧杆菌(Bifidobacterium longum)后可改善肝功能，减轻肝脏炎症及纤维化，临床试验表明行肝切除术的患者围手术期补充长双歧杆菌可降低术后延迟恢复率、缩短住院时间并提高1年生存率，这提示长双歧杆菌可显著改善肝癌患者手术预后。

3.5 整合性治疗方案

当前靶向肝癌的治疗方法虽呈现多样化，但在临床转化过程中仍面临诸多挑战，可构建整合性治疗方案以实现GM调控与肝癌传统治疗手段的深度融合，该方案核心在于打破单一疗法的局限性，通过精准评估患者的GM状态与疾病进展阶段制定动态整合性治疗方案，从而最大化协同治疗效应，最小化治疗相关不良反应。治疗前阶段可根据患者状况进行GM调控预处理，使患者达到适宜接受后续治疗的状态。例如，对于NAFLD-HCC患者，可使用益生菌制剂进行预处理^[45]，并配合规律运动与健康饮食等生活方式调整^[56]以降低肝脏脂肪负荷；对于GM多样性严重降低的患者，可评估其FMT适应证，筛选匹配健康供体以重建健康GM结构^[57]。治疗阶段将GM调控与传统治疗手段进行结合，同步监测GM恢复情况。例如，对接受索拉非尼治疗的患者^[41]，动态检测其肠道内屎肠球菌(Enterococcus faecium)丰度，若其丰度偏低可补充活菌制剂，同时监测外周血中IFN-γ⁺CD8⁺ T细胞比例，据此调整屎肠球菌(Enterococcus faecium)剂量，以确保其与索拉非尼的协同抗肿瘤效应，若出现耐药情况可采用FMT或选择性抗生素干预，通过重塑GM来改善耐药状态；对接受肝切除术的患者，术后可给予长双歧杆菌(Bifidobacterium longum)制剂辅助恢复^[42]。治疗结束后，可根据患者的GM状态及肿瘤控制情况制定个体化的长期维持方案，长期随访阶段若发现GM再度失衡或肿瘤复发迹象应及时启动GM调控干预，必要时再次联合传统治疗手段以延缓疾病进展。

4 总结与展望

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GM通过多种机制参与肝癌的发生发展，主要包括GM及其代谢产物对肝脏免疫微环境的调控、介导表观遗传修饰及外泌体信号传递、与肝癌危险因素协同作用等，这些机制揭示了靶向GM在肝癌防治中的潜力。近年来，随着相关研究的不断深入，基于GM调控的肝癌治疗方法逐步发展。例如，补充益生菌可调节肝脏炎症与脂质代谢、延缓NAFLD-HCC进展、增强抗肿瘤免疫反应等，补充益生菌疗法有望成为肝癌治疗的新兴方向。此外，GM在抗生素精准治疗、FMT以及与传统疗法联合等方面也显示出一定的应用价值。然而，靶向GM治疗肝癌在临床转化中仍面临多重挑战：首先，个体间GM组成存在高度异质性，可能导致GM调控干预效果不一；其次，长期调节GM的方案安全性尚未完全明确。未来需推动整合性治疗策略的构建以实现靶向GM干预在肝癌防治中的有效转化。综上所述，尽管当前GM相关疗法仍处于探索阶段，但通过机制研究、技术整合与临床验证的协同推进，靶向GM仍有望为肝癌防治提供新思路。

基金

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安徽省博士后研究人员科研活动经费(2023B705)
国家自然科学基金(82100613)
国家自然科学基金(82173100)
国家自然科学基金(82472819)
安徽省优秀青年基金(2408085J043)
安徽医科大学第一附属医院(2023年)医学创新人才引进计划研究启动经费(1713)

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2026年第66卷第3期

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文章信息

doi: 10.13343/j.cnki.wsxb.20250708

接收时间：2025-09-16
首发时间：2026-03-12
出版时间：2026-03-04

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作者

出版历史

收稿日期：2025-09-16
录用日期：2025-11-03

基金

Research Fund Project of Postdoctor in Anhui Province(2023B705)

安徽省博士后研究人员科研活动经费(2023B705)

National Natural Science Foundation of China(82100613)

国家自然科学基金(82100613)

National Natural Science Foundation of China(82173100)

国家自然科学基金(82173100)

National Natural Science Foundation of China(82472819)

国家自然科学基金(82472819)

Anhui Excellent Youth Fund(2408085J043)

安徽省优秀青年基金(2408085J043)

First Affiliated Hospital of Anhui Medical University (2023) Talent Introduction Program Research Start-up Funding for Medical Innovation(1713)

安徽医科大学第一附属医院(2023年)医学创新人才引进计划研究启动经费(1713)

作者信息

安徽医科大学第一附属医院检验科，安徽合肥

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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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病因 Etiology	涉及的GM变化 Implicated changes in gut microbiota	参考文献 References
乙型肝炎病毒 HBV	丰度上升：拟杆菌门、毛螺菌科未分类菌；丰度降低：瘤胃球菌属、栖粪杆菌属、梭菌属、双歧杆菌属 Increase in abundance: Bacteroidota, Lachnospiraceae incertae sedis; Decrease in abundance: Ruminococcus, Faecalibacterium, Clostridium, Bifidobacterium	[8]
丙型肝炎病毒 Hepatitis C virus (HCV)	丰度上升：肠杆菌科、链球菌属、拟杆菌属、肠球菌属、葡萄球菌属；丰度降低：双歧杆菌属、乳杆菌属、梭菌属 Increase in abundance: Enterobacteriaceae, Streptococcus, Bacteroides, Enterococcus, Staphylococcus; Decrease in abundance: Bifidobacterium, Lactobacillus, Clostridium	[8-9]
非酒精性脂肪性肝病 NAFLD	丰度上升：新洋葱伯克霍尔德氏菌、藤黄微球菌、假单胞菌门、乳杆菌属；丰度降低：嗜酸乳杆菌、龙包茨氏菌属、解纤维素拟杆菌、放线菌纲、拟杆菌门、双歧杆菌属 Increase in abundance: Burkholderia cenocepacia, Micrococcus luteus, Pseudomonadota, Lactobacillus; Decrease in abundance: Lactobacillus acidophilus, Romboutsia, Bacteroides cellulosilyticus, Actinomycetes, Bacteroidota, Bifidobacterium	[10-11]
酒精性肝病 ALD	丰度上升：梭菌属、霍尔德曼菌属、萨特氏菌属；丰度降低：栖粪杆菌属 Increase in abundance: Clostridium, Holdemania, Sutterella; Decrease in abundance: Faecalibacterium	[12]

病因

Etiology

涉及的GM变化

Implicated changes in gut microbiota

参考文献

References

乙型肝炎病毒

HBV

丰度上升：拟杆菌门、毛螺菌科未分类菌；

丰度降低：瘤胃球菌属、栖粪杆菌属、梭菌属、双歧杆菌属

Increase in abundance: Bacteroidota, Lachnospiraceae incertae sedis;

Decrease in abundance: Ruminococcus, Faecalibacterium, Clostridium, Bifidobacterium

[8]

丙型肝炎病毒

Hepatitis C virus (HCV)

丰度上升：肠杆菌科、链球菌属、拟杆菌属、肠球菌属、葡萄球菌属；

丰度降低：双歧杆菌属、乳杆菌属、梭菌属

Increase in abundance: Enterobacteriaceae, Streptococcus, Bacteroides, Enterococcus, Staphylococcus;

Decrease in abundance: Bifidobacterium, Lactobacillus, Clostridium

[8-9]

非酒精性脂肪性肝病

NAFLD

丰度上升：新洋葱伯克霍尔德氏菌、藤黄微球菌、假单胞菌门、乳杆菌属；

丰度降低：嗜酸乳杆菌、龙包茨氏菌属、解纤维素拟杆菌、放线菌纲、拟杆菌门、双歧杆菌属

Increase in abundance: Burkholderia cenocepacia, Micrococcus luteus, Pseudomonadota, Lactobacillus;

Decrease in abundance: Lactobacillus acidophilus, Romboutsia, Bacteroides cellulosilyticus, Actinomycetes, Bacteroidota, Bifidobacterium

[10-11]

酒精性肝病

ALD

丰度上升：梭菌属、霍尔德曼菌属、萨特氏菌属；丰度降低：栖粪杆菌属

Increase in abundance: Clostridium, Holdemania, Sutterella; Decrease in abundance: Faecalibacterium

[12]

肠道菌群 Gut microbiota	相关代谢酶 Related metabolic enzymes	肠道菌群代谢产物 Gut microbiota-derived metabolites	靶向细胞 Target cells	参考文献 References
肠杆菌科 Enterobacteriaceae	\	脂多糖 LPS	Kupffer细胞 Kupffer cell	[15]
裂解梭菌 Clostridium scindens	7α-脱羟基化酶 7α-dehydroxylase	牛磺熊去氧胆酸、牛磺去氧胆酸、ω-鼠胆酸、甘氨石胆酸 TUDCA, TDCA, ω-MCA, GLCA	肝窦内皮细胞 LSECs	[16]
布劳特氏菌属 Blautia	色氨酸酶 Tryptophanase	吲哚-3-乙酸 IAA	肝细胞 Hepatocyte	[17]
梭菌属、瘤胃球菌 Clostridium, Ruminococcaceae	7α-脱羟基化酶 7α-dehydroxylase	鹅脱氧胆酸、牛磺去氧胆酸 CDCA, TDCA	肝细胞 Hepatocyte	[18]
瘤胃球菌属、丁酸球菌属 Ruminococcus, Butyricicoccus	乙酰辅酶A转移酶、丁酸激酶 Acetyl-CoA transferase, butyrate kinase	丁酸盐 Butyrate	自然杀伤细胞 NK cell	[19]
假长双歧杆菌 Bifidobacterium pseudolongum	乙酰辅酶A转移酶、磷酸转乙酰酶 Acetyl-CoA transferase, phosphate transacetylase	乙酸盐 Acetate	肝细胞 Hepatocyte	[20]

肠道菌群

Gut microbiota