Research Advances on Probiotics-assisted Therapy for Metabolic Dysfunction-Associated Fatty Liver Disease
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摘要: 代谢功能障碍相关脂肪性肝病（metabolic dysfunction-associated steatotic liver disease，MASLD）是一种与肥胖、2型糖尿病、血脂异常和高血压等代谢紊乱密切相关的慢性肝病，其全球发病率持续攀升，已成为重大公共卫生问题。MASLD的发病机制复杂，“多重打击”学说指出，肝脏脂质沉积、胰岛素抵抗、氧化应激、肠道菌群紊乱及遗传因素共同驱动疾病进展。目前临床治疗以生活方式干预为基础，但缺乏特效药物，亟需探索新型辅助治疗策略。近年来，益生菌因其调节肠道微生态、改善胰岛素抵抗和减轻肝炎症的作用，在MASLD治疗中展现出潜在价值。系统综述了MASLD的发病机制与现有治疗手段的局限性，重点从动物实验和临床研究两个维度，总结益生菌辅助治疗MASLD的最新证据。通过分析不同菌种（如双歧杆菌、乳酸杆菌等）的作用靶点及分子机制，探讨益生菌在MASLD治疗中的转化应用前景，以期为未来研究提供理论依据和参考方向。
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关键词:
- 代谢功能障碍相关脂肪性肝病 /
- 发病机制 /
- 益生菌 /
- 辅助治疗
Abstract: Metabolic dysfunction-associated steatotic liver disease （MASLD） is a chronic liver condition intricately linked to metabolic abnormalities such as obesity, type 2 diabetes, dyslipidemia, and hypertension. The global prevalence of MASLD continues to rise, posing a significant public health challenge.The pathogenesis of MASLD is multifactorial, with the "multiple-hit" hypothesis suggesting that hepatic lipid accumulation, insulin resistance, oxidative stress, gut microbiota dysbiosis, and genetic factors collectively drive disease progression. Currently, clinical management primarily relies on lifestyle interventions; however, there is a lack of targeted pharmacological interventions, and there is an urgent need to investigate novel adjunctive therapeutic strategies. In recent years, probiotics have demonstrated potential value in MASLD treatment due to their capacity to modulate gut microbiota, enhance insulin sensitivity, and reduce liver inflammation. This review systematically examines the pathogenesis of MASLD and the limitations of existing therapeutic approaches, synthesizing the latest evidence of probiotics-assisted therapy for MASLD from the perspectives of animal studies and clinical trials.By analyzing the target mechanisms and molecular pathways of different strains （e.g., Bifidobacterium, Lactobacillus）, this review explores the translational potential of probiotics in MASLD treatment, aiming to provide a theoretical foundation and future research directions.-
Key words:
- MASLD /
- Pathogenic mechanism /
- Probiotics /
- Adjunctive therapy
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图 1 MASLD发病机制
注：IR：胰岛素抵抗，TG：甘油三酯，FAA：游离脂肪酸，FXR：法尼醇X受体，TGR5：G蛋白偶联胆汁酸受体1，TMAO：三甲胺-N-氧化物。TMA：三甲胺，FC：游离胆固醇，AMPK：AMP依赖的蛋白激酶，TNF-α：TNF-α为肿瘤坏死因子-α，IL-6：白介素6，CD68：分化簇68，TLR4：Toll样受体4，NFKB：核因子KB，KCs：库普弗细胞，SCFAs：短链脂肪酸，LPS：脂多糖。
Figure 1. Pathogenesis of MASLD
表 1 双歧杆菌辅助治疗MASLD的变量分析
Table 1. Variable analysis of bifidobacterium-assisted therapy for MASLD
类型 剂量 对象 时长 效果 文献来源 双歧杆菌V9 1.0×109 CFU/d 大鼠 4周 ↓AST、ALT、TG、FFA、Glu、TNF-α、IL-1β、IL-6、SREBP-1c、FAS、炎性反应、NF-κB；↑肝糖原、PPAR-α Yan et al[20] 动物双歧杆
菌乳亚种SF1.0×108
CFU/d（灌胃）小鼠 12周 ↓TG、TG、LDL-C、ALT、AST、肝损伤、SREBP-1c、HOMA-IR、氧化应激、NF-κB、TNF-α、IL-6；↑AMPK Lv et al[21] 青春双歧杆菌 4 × 1010 CFU/d 大鼠 16周 ↓体重、肝脏重量、Glu、IL-1β、TG、TC、ALT、AST、ALP、LDL-C、LDH、NF-κB；↑HDL-C Mohammadmahdi Meybodi et al[22] 两歧双歧杆菌 1007478 104、105、106 CFU/mL/d 斑马鱼 5周 ↓ALT、AST、TG、TC、BMI、ROS、MDA、SREBP-1、IL-6、IL-1β、TNF-α；↑ILA Chao Tian et al[23] 长双歧杆菌 5.0×1010 CFU/kg/d 小鼠 4周 ↓TC、脂肪组织质量、Glu Machado et al[24] 动物双歧杆菌
乳亚种MG7411.0×105或1.0×106 CFU/d 小鼠 12周 ↓肝脏脂肪变性、β-葡萄糖醛酸酶、TC、TNF-α、IL-1β、IL-6 Do et al[25] 假长双歧杆菌 3.0×108 CFU/周 小鼠 1月 ↑乙酸盐代谢物 Song et al[26] 动物双歧杆菌 1.0×108 CFU/d 人群 24周 ↓超声MASLD等级、ALT、AST、AKP、γ-GT、肝酶浓度 Bakhshimoghaddam et al[27] 长双歧杆菌 2.5 g药物 人群 24周 ↓AST、LDL-C、CRP、TNF-α、HOMA-IR、LPS、脂肪变性、NASH活动指数 Malaguarnera et al[28] 动物双歧杆菌
乳亚种BB-1210×1010 CFU/d 人群 10-14月 改变粪便微生物 Scorletti et al[29] 注：TNF-α：肿瘤坏死因子-α，Glu：血糖，NF-κB：核因子κB，PPAR-α：过氧化物酶体增殖物激活受体-ɑ，HOMA-IR：胰岛素抵抗指数，AMPK：AMP依赖的蛋白激酶，AKP：碱性磷酸酶，CRP：C反应蛋白，ILA：吲哚-3-乳酸。 
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表 2 乳酸杆菌辅助治疗MASLD的变量分析
Table 2. Variable analysis of lactobacillus adjunct therapy for MASLD
类型 剂量 对象 时长 效果 文献来源 嗜酸乳杆菌 312 mg/kg/d 大鼠 14周 ↓MASLD活动评分、ALT、
AST 、TG、TBA、TCLuo et al[30] 干酪乳杆菌Jlus66 1.0、2.0、4.0×
1010 CFU/d大鼠 20周 ↓TNF-α、IL-6、MDA、LPS；↑IL-10、
SOD、GSH-Px、厚壁菌门Wang et al[31] 鼠李糖乳杆菌GG 1.0×108 CFU/d 小鼠 13周 ↓体重、肝脂肪变性、肠系膜脂肪、肝脏；
↑胰岛素敏感性、ADPNKim et al[32] 鼠李糖乳杆菌GG 1.0×108 CFU/d 小鼠 13周 ↓TC、TG、皮下脂肪、肝脏脂肪 Kim et al[33] 鼠李糖乳杆菌GG / 人群 8周 ↓TNF-α、LPS、肠杆菌科；↑毛螺菌科 Bajaj et al[34] 植物乳杆菌NCU116 1.0×108 CFU/mL，1.0×109 CFU/mL
（1 kg/10 mL）大鼠 5周 ↓肝脂肪变性、ALT、AST、Tbil、MDA、
TC、TG、IL-6、LPS、TNF-α；
↑GSH-Px、CAT、T-AOC、IL-10Li et al[35] 植物乳杆菌FZU3013 1.0×109 CFU/d 小鼠 8周 ↓体重、TC、TG、LDL-C、肝脏、
附睾脂肪指数、BAs、FFA；↑NEFAChen et al[36] 副干酪乳杆菌N1115 2.2×109 CFU/d 小鼠 16周 ↓脂肪变性、TNF-α、TG、TC Yao et al[37] 沙克乳酸杆菌MJM60958 1.0×108 CFU/d，1.0× 109 CFU/d 小鼠 12周 ↓肝脏、Leptin、脂肪变性；↑ADPN Nguyen et al[38] 棒状乳杆菌T3 1.0×109 CFU/d 小鼠 6周 ↓肝脏脂肪、体重、WAT、IL-6、
TNF-α、TC、TG、AST、ALT、
MDA；↑iBAT指数、GSH-Px、SODSong et al[39] 罗伊氏乳杆菌 1.0×108 CFU/次，
每日2次人群 3月 ↓脂肪变性、体重、BMI、腰围 Ferolla et al[40] 鼠李糖乳杆菌GG 1.0×109 CFU/d 小鼠 9周 ↓体重、WAT Jang et al[41] 发酵乳杆菌CQPC06 1.0×109 CFU/kg/d 小鼠 8周 ↓体重、肝脏指数、ALT、AST、AKP、
TC、TG、LDL-C、LPS、HDL-C、gWATMu et al[42] 发酵乳杆菌LM1016 1.0×109 CFU/d 小鼠 8周 ↓体重、BAT、Glu、TC、Leptin Yoon et al[43] 植物乳杆菌 1.0×108 CFU/d 大鼠 12周 ↓体重、肾周脂肪指数、肝脂肪指数、肝脏总
脂肪含量、TGF-β1、SOD、GSH-Px、TBARSZhu et al[44] 嗜酸乳杆菌、发酵乳杆菌、植物乳杆菌、副干酪乳杆菌 1.0×109 CFU/d 小鼠 8周 ↓肝脏、TC、脂肪变性 Lee et al[45] 罗伊氏乳杆菌MJM60668 1.0×108 CFU/d、1.0×109 CFU/d 小鼠 12周 ↓体重、ALT、AST Werlinger et al[46] 罗伊氏乳杆菌MG5149 2.0×108 CFU/d 小鼠 8周 ↓体重、脂肪组织、ALT、AST、
TG、TC、LDL-C、血糖；↑ADPNChoi et al[47] 短乳酸杆菌 109 CFU / mL/d 小鼠 8周 ↓体重、TG、TC、LDL-C、Leptin、ALT、
AST、MDA、WAT、Glu、初级胆汁酸；
↑HDL-C、SOD、次级胆汁酸、有益菌Liping Zhou et al[48] 瑞士乳杆菌HY7804 109 CFU/kg/d 小鼠 7周 ↓ALT、AST、TG、TC、Glu、LDL-C、
TLR4、NF-κB、MASLD活动评分、
拟杆菌；↑乳酸杆菌、梭状芽孢杆菌Hyeonji Kim et al[49] 嗜酸乳杆菌 2.0×109 CFU/次，
每日3次人群 1月 ↓ALT、AST Abdel Monem et al[50] 鼠李糖乳杆菌GG 1.2×1010 CFU/d 人群 8周 ↓ALT、抗肽聚糖-多糖抗体 Vajro et al[51] 注：TBA：总胆汁酸，TBil：总胆红素水平，CAT：过氧化氢酶，T-AOC：总抗氧化能力，BAs：生物胺，NEFA：非酯化脂肪酸，Leptin：瘦素，WAT：白色脂肪组织，iBAT：肩胛间棕色脂肪组织，GSH：谷胱甘肽，BAT：棕色脂肪组织，gWAT：性腺白色脂肪组织，TBARS：具有代表性的有害脂质过氧化物。
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表 3 NGPs辅助治疗MASLD的变量分析
Table 3. Variable analysis of NGPs as adjunctive therapy for MASLD
类型 剂量 对象 时长 效果 文献来源 丁酸梭菌
MIYAIRI 5888.5×109 CFU/g/d 大鼠 50周 ↓TG、HOMA-IR、ALT、TNF-α、LPS Endo et al[52] 丁酸梭菌B1 1.0×109 CFU/d 小鼠 16周 ↓附睾脂肪组织指数、ALT、AST、
HOMA-IR 、Glu、MASLD评分、
肝脏脂肪、TG、TC；↑ISI、丁酸盐Zhou et al[53] 丁酸梭菌 5.0×107 CFU/kg/d 小鼠 6周 ↓Glu、LPS、TG、TC、IL-1β、TNF-α、
肝脏、ALT、AKP；↑GLP-1Yang et al[54] 丁酸梭菌 400 mg/次，每日3次 人群 6月 ↓TC、TG、FFA、TBIL、DBIL、PIIIP、C-IV、HA、LN、ALT、AST、TNF-α；↑IL-6 Zhu et al[55] 芽孢杆菌 1.0×108 CFU/d 小鼠 13周 ↓体重、肝脏、Glu、TG Kim et al[56] 凝结芽孢杆菌BC30 1.0×109 CFU/d 人群 12周 ↓ALT、γ-GT、TNF-α、肝脂肪变性 Abhari et al[57] 嗜黏蛋白阿克曼菌 1.0×109 CFU/
200 µL/d小鼠 4周 ↓TNF-α、IL-6、ALT、AST、Glu、TC、
TG、LDL-C、VLDL-C；↑IL-10Raftar et al[58] 嗜黏蛋白阿克曼菌 108 ～109 CFU/d 小鼠 10周 ↓TG、ALT、IL-6 Kim et al[59] 普拉梭菌 1.0×109 CFU/d 小鼠 12周 ↓体重、FFA、TC、TG、LDL-C、附睾脂肪指数、TNF-α、IL-6、MDA、IL-1β、Glu、HOMA-IR；↑HDL-C、SOD、GSH-Px Hu et al[60] 嗜黏蛋白阿克曼菌 2.0×108 CFU/d 大鼠 9周 ↓TG、脂肪变性、MASLD评分、
HOMA-IR；↑LeptinJuárez-Fernández
et al[61]嗜黏蛋白阿克曼菌 0.2×109 CFU/mL，每周3次 小鼠 20周 ↓体重、HOMA-IR、Glu、TC、TG、ALT、AST、肝脏指数、TNF-α、IL-6、IL-17A；↑IL-10 Fulin Nian et al[62] 嗜黏蛋白阿克曼菌 1.0×1010 CFU/d 人群 3月 ↓HOMA-IR、DPP-IV活性、TC、γ-GT、AST、LPS、LDH、CK、体重、脂肪量 Clara Depommier et al[63] 嗜黏蛋白阿克曼菌 1.0×109 CFU/
200 µL/d小鼠 4周 ↓TNF-α、IL-6、ALT、AST；↑IL-10 Raftar et al[64] 嗜黏蛋白阿克曼菌 2.0×109 CFU/d 小鼠 10周 ↓脂肪变性、MASLD活性评分、Glu、ALT Li et al[65] 嗜黏蛋白阿克曼菌 1.0×109 CFU/d 小鼠 20周 ↓体重、Glu、TC、ALT、AST、
肝脂肪变性、MASLD活性评分Han et al[66] 普拉梭菌 1.0× 108 CFU/d 小鼠 16周 ↓Glu、TG、TC、ALT、AST Shin et al[67] 注：ISI：胰岛素敏感指数，GLP-1：胰高血糖素样肽-1，TBIL：总胆红素，DBIL：直接胆红素，PIIIP：前胶原III肽，C-IV：胶原-IV，HA：透明质酸，LN：层粘连蛋白，VLDL- C：极低密度脂蛋白，DPP-IV：二肽基肽酶- IV，LDH：乳酸脱氢酶，CK：肌酸激酶。
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表 4 联合益生菌辅助治疗MASLD的变量分析
Table 4. Variable analysis of combined probiotic adjunctive therapy for MASLD
类型 剂量 对象 时长 效果 文献来源 6个乳酸杆菌+3个双歧杆菌 6.0×1010 CFU/d 大鼠 16周 ↓FFA、TG、IL-1β、
IL-18、ALTLiang et al[68] 干酪乳杆菌、鼠李糖乳杆菌、
嗜酸乳杆菌、长双歧杆菌和短双歧杆菌5.0×1010 CFU/d 人群 12周 ↓TG、ALT、AST、γ-GT、ALP、Hs-CRP Behrouz et al[69] MCP®BCMC®（嗜酸乳杆菌BCMC、
干酪乳杆菌BCMC、两歧双歧杆菌BCMC、
婴儿双歧杆菌BCMC、长双歧杆菌BCMC）2.0×107 CFU/g，
3 g/d人群 3月 ↓BMI、Glu、肝脂肪变性 Mohamad Nor
et al[70]MCP®BCMC® 2.0×107 CFU/g，
3 g/d人群 6月 ↓TC、TNF-α、IFN-γ、
ZO-1；↑IL-6Ayob et al[71] 双歧杆菌、乳酸杆菌、肠球菌 1 g/次，2次/d 人群 3月 ↓ALT 、AST、γ-GT、
TC、TG、HOMA-IR、MASLD评分Cai et al[72] 嗜酸乳杆菌、双歧双歧杆菌、长双歧杆菌、
德氏乳杆菌保加利亚亚种、瑞氏乳杆菌、
植物乳杆菌、鼠李糖乳杆菌、干酪乳杆菌、
乳酸乳球菌、嗜热链球菌3粒/d 人群 12周 ↓TG、ALT、MASLD
纤维化评分、
内脏肥胖指数Crommen et al[73] 嗜酸乳杆菌+双歧杆菌 1.0×109 CFU/d 人群 6月 ↓AST；APRI评分 Escouto et al[74] 鼠李糖乳杆菌HN001、嗜酸乳杆菌NCFM、
乳双歧杆菌HN019、副干酪乳杆菌LPC-374.0×109 CFU/g，
1 g/d人群 24周 ↓miR-122 Barcelos et al[75] VSL#3®（嗜热链球菌、长双歧杆菌、
短双歧杆菌、婴儿双歧杆菌、嗜酸乳杆菌、
植物乳杆菌、副干酪乳杆菌）2包/d 人群 3月 ↓TG、Hs-CRP、ALT、AST、γ-GT、AST/ALT、脂肪肝变性/改善/消失 Derosa et al[76] VSL#3® 2包/次，2次/d 人群 10周 ↑模式ASQ评分 Chong et al[77] 索氏厌氧丁酸菌、嗜黏蛋白阿克曼菌、
动物双歧杆菌、低聚果糖+FMT2粒/d、109、
1010、3×1010人群 24周 无 Quinten J J Augustijn et al[78] 注：Hs-CRP 为超敏C反应蛋白，IFN-γ为干扰素-γ，ZO-1为闭锁小带蛋白1，ASQ为纤维化评分声学结构量化。
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