Aerobic and resistance exercise interventions in a mouse model of nonalcoholic fatty liver disease: correlation between gut microbiota and irisin

doi:10.12307/2026.656

Abstract

Abstract: BACKGROUND: Nonalcoholic fatty liver disease is a liver disease with abnormal accumulation of lipid in hepatocytes and inflammatory response. Aerobic exercise can regulate the homeostasis of intestinal microenvironment, and then alleviate inflammatory response and improve nonalcoholic fatty liver disease through the "microbiotic-gut-liver" axis. However, it is unclear whether the motility factor irisin mediates the regulation of the gut microbiota, and whether different exercise methods such as resistance exercise can also improve nonalcoholic fatty liver disease through the above mechanism has not been reported.
OBJECTIVE: To study the effects of different exercise methods on inflammatory response in mice with nonalcoholic fatty liver disease, and to explore the correlation between gut microbiota and inflammatory response and exercise factor irisin.
METHODS: After adaptive feeding for 1 week, 48 C57BL/6J mice were randomly divided into a control group (n=12) and a high-fat diet group (n=36). The mice in the control group were fed with normal diet, while in the high-fat diet group, nonalcoholic fatty liver disease models were induced by feeding with 60% fat diet for 12 weeks. The successful model mice were randomly subdivided into high-fat group, aerobic exercise group and resistance exercise group, and the intervention continued in the latter two groups for 8 weeks. During the intervention, the high-fat group, aerobic exercise group and resistance exercise group were fed with high-fat diet until the end of the experiment. 16S rRNA gene sequencing was used to analyze the composition of gut microbiota in each group, hematoxylin-eosin staining was used to observe the steatosis score of hepatocytes in each group, and microplate method was used to detect blood lipids and liver function related indicators in each group. Western blot assay was used to detect the protein expression levels of nucleotide-binding oligomerization domain-like receptor protein 3, nuclear factor-κB, interleukin-1β, tumor necrosis factor-α and irisin in the liver of mice in each group.
RESULTS AND CONCLUSION: (1) Compared with the control group, mice in the high-fat group exhibited significant increases in serum total cholesterol, triglycerides, and low-density lipoprotein (P < 0.05), while high-density lipoprotein levels were significantly decreased (P < 0.05). The indicators of exercise capacity, namely grip strength and anti-fatigue ability, deteriorated (P < 0.05). The mouse liver showed a large number of vacuoles and inflammatory cell infiltration (P < 0.05). The protein expression of nucleotide-binding oligomerization domain-like receptor protein 3, nuclear factor-κB, interleukin-1β, and tumor necrosis factor-α was significantly upregulated (P < 0.05), while irisin protein expression was significantly downregulated (P < 0.01). (2) Compared with the high-fat group, both aerobic exercise and resistance exercise significantly improved the aforementioned physiological indicators, reducing serum total cholesterol, triglycerides, and low-density lipoprotein levels (P < 0.05) while upregulating high-density lipoprotein levels (P < 0.05). These interventions also reduced liver vacuoles and inflammatory cell infiltration, enhanced exercise capacity (P < 0.05), downregulated the protein expression of nucleotide-binding oligomerization domain-like receptor protein 3, nuclear factor-κB, interleukin-1β, and tumor necrosis factor-α (P < 0.05), and promoted irisin protein expression (P < 0.05). The improvement effects of aerobic exercise were more pronounced. (3) Microbiota α-diversity analysis revealed significant differences in the sobs, chao, and coverage indices among the four groups (P < 0.05). Compared with the control group, the sob and chao indices in the high-fat group were significantly decreased (P < 0.05), while the coverage index was significantly increased (P < 0.05). β-diversity analysis showed significant separation between the control group and the other three groups at both the operational taxonomic unit and genus levels (P < 0.01). At the phylum level, the Firmicutes/Bacteroidota ratio was significantly higher in the high-fat and resistance exercise groups than in the control group (P < 0.01), but was significantly reduced in the aerobic exercise group compared with the control group (P < 0.01). Differential microbiota analysis indicated that aerobic exercise could adjust the increased abundance of Escherichia-Shigella and Leuconostoc in the high-fat group (P < 0.05). (4) Correlation analysis showed a highly significant negative correlation between irisin and Escherichia-Shigella. To conclude, compared with resistance exercise, aerobic exercise can more effectively improve peripheral lipid metabolic disorders, enhance exercise capacity, inhibit the activation of the nuclear factor-κB/nucleotide-binding oligomerization domain-like receptor protein 3 inflammatory signaling pathway, and reshape the gut microbiota composition. Moreover, under the pathological background of fatty liver, the anti-inflammatory effects of irisin may be related to changes in the gut microbiota composition.

Key words: nonalcoholic fatty liver disease, gut microbiota, hepatic inflammation, irisin, aerobic exercise, resistance exercise

CLC Number:

Wu Fangjia, Lei Senlin, Li Xianhui, Yang Yang. Aerobic and resistance exercise interventions in a mouse model of nonalcoholic fatty liver disease: correlation between gut microbiota and irisin[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(12): 3029-3043.

Figures/Tables 12

2.1 实验动物数量分析初始时共购入48只小鼠，第12周造模后将对照组和造模组分别处死2只，运动过程中剔除3只无法完成训练小鼠，其中有氧运动组1只，抗阻运动组2只，余41只纳入结果分析，其中对照组10只、高脂组10只、有氧运动组11只、抗阻运动组10只。 2.2 非酒精性脂肪肝小鼠造模结果造模期间各组小鼠饮食、活跃度等身体状态良好。如图1所示，高脂饲养12周后，苏木精-伊红染色显示模型组肝脏出现大量空泡、细胞排列紊乱；模型组小鼠血清三酰甘油(P < 0.05)、总胆固醇(P < 0.05)水平显著高于对照组，表明模型组小鼠出现明显肝脏脂肪变性，非酒精性脂肪肝模型构建成功。 2.3 行为学实验结果如图2所示，与对照组相比，高脂组转棒疲劳时间、运动距离显著降低(P < 0.01)；与高脂组相比，有氧运动组和抗阻运动组转棒疲劳时间、运动距离均显著增加(P < 0.05)。与对照组相比，高脂组前肢抓力显著降低(P < 0.01)；与高脂组相比，有氧运动组和抗阻运动组前肢抓力均显著增加(P < 0.05)；与有氧运动组相比，抗阻运动组前肢抓力显著增加(P < 0.05)。 2.4 小鼠体质量、Lee’s指数、体质量指数、肝指数如图3A所示，与高脂组相比，有氧运动组第16周开始出现体质量显著降低(P < 0.05)，抗阻运动组第20周体质量显著降低(P < 0.05)，实验结果表明有氧运动比抗阻运动减脂效果更具优势。如图3B，C所示，与对照组相比，高脂组Lee’s指数、体质量指数显著升高(P < 0.01)；与高脂组相比，有氧运动组Lee’s指数、体质量指数显著降低(P < 0.05)，抗阻运动组Lee’s指数、体质量指数相对下调但无显著性差异(P > 0.05)；与有氧运动组相比，抗阻运动组Lee’s指数、体质量指数显著升高(P < 0.05)。如图3D所示，与对照组相比，高脂组肝指数升高(P < 0.01)；与高脂组相比，有氧运动组和抗阻运动组肝指数显著降低(P < 0.05)。 2.5 各组小鼠血清生化指标检测结果如图4所示，与对照组相比，高脂组血清总胆固醇、三酰甘油、低密度脂白显著增高(P < 0.05)，高密度脂蛋白显著降低(P < 0.01)；与高脂组相比，有氧运动组和抗阻运动组血清总胆固醇、三酰甘油、低密度脂蛋白显著降低(P < 0.05)，高密度脂蛋白显著升高(P < 0.05)。与对照组相比，高脂组血清丙氨酸氨基转氨酶、天门冬氨酸氨基转移酶活力显著升高(P < 0.01)；与高脂组相比，有氧运动组和抗阻运动组血清丙氨酸氨基转氨酶、天门冬氨酸氨基转移酶活力显著降低 (P < 0.05)。与有氧运动组相比，抗阻运动组血清三酰甘油和低密度脂蛋白水平、天门冬氨酸氨基转移酶活力显著升高(P < 0.05)，其余指标组间比较无显著差异。 2.6 苏木精-伊红染色结果如图5所示，对照组肝脏细胞状态完好，形态规整，无空泡和炎症病变；与对照组相比，高脂组肝细胞脂肪变性评分极显著增加(P < 0.01)，且出现大量空泡、细胞排列紊乱；与高脂组相比，有氧运动组(P < 0.01)、抗阻运动组 (P < 0.05)空泡数量显著减少，炎性浸润得到明显改善；有氧运动组肝脏改善显著优于抗阻运动组(P < 0.05)。 2.7 各组小鼠肝组织蛋白表达如图6所示，与对照组相比，高脂组NLRP3、核因子κB、白细胞介素1β、肿瘤坏死因子α蛋白表达量显著上调(P < 0.05)，鸢尾素蛋白表达量显著下调(P < 0.01)；与高脂组相比，有氧运动组和抗阻运动组NLRP3、核因子κB、白细胞介素1β、肿瘤坏死因子α蛋白表达量显著下调(P < 0.05)，鸢尾素蛋白表达量显著上调(P < 0.05)。与有氧运动组相比，抗阻运动组肿瘤坏死因子α蛋白表达量显著上调(P < 0.05)，鸢尾素蛋白表达量显著下调(P < 0.05)，NLRP3、核因子κB、白细胞介素1β蛋白表达量无显著差异(P > 0.05)。 2.8 肠道菌群分析 2.8.1 α多样性分析通过对盲肠内容物进行16S rRNA测序，分析了不同运动方式干预对非酒精性脂肪肝小鼠肠道菌群结构和组成的影响。韦恩图结果显示(图7A)，在所有样本中共同包含338个操作分类单元，其中对照组、高脂组、有氧运动组和抗阻运动组分别包含467，105，156，99个独特的操作分类单元。基于操作分类单元的Shannon指数和Simpson指数表明随着物种数量的增加，指数曲线逐渐趋于平缓(图7B，C)，这表明样本的群落丰富度和多样性良好，且测序深度足以反映小鼠盲肠内容物中绝大多数肠道微生物信息。α多样性分析数据显示，sobs(P=0.04)、chao(P=0.038)和coverage(P=0.042)指数在4个组别间存在显著差异(图7D-F)。与对照组相比，高脂组的sobs和chao指数显著降低(P < 0.05)，而coverage指数则显著增加(P < 0.05)。结果表明，非酒精性脂肪肝小鼠肠道菌群的多样性在各个组别中存在差异。 2.8.2 β多样性分析通过主坐标分析和非度量多维尺度分析(non-metric multidimensional scaling，NMDS)评估了各组肠道菌群的β多样性，以分析其组成的相似性和差异性。主坐标分析结果表明(图8A-C)，在操作分类单元水平(R=0.341 1，P=0.001)和属水平(R=0.295 5，P=0.002)，对照组独立成簇，与其他组别显著分离，而其余3组的样本相互聚集。在门水平(R=0.096 5，P=0.077)，所有组别均相互聚集，无法分离。NMDS分析结果(图8D-F)显示，在操作分类单元水平(R2=0.289 4，P=0.001)和属水平(R2=0.283 5，P=0.001)，对照组同样独立成簇，与其他组别显著分离；而在门水平(R2=0.304 2，P=0.032)，所有组别再次相互聚集，无法分离。结果表明，对照组的肠道菌群组成与其他组别存在显著差异，而高脂组、有氧运动组和抗阻运动组的肠道菌群组成多样性则较为相似。 2.8.3 组间差异菌群分析群落分析(图9A-C)显示，在门水平上，Firmicutes、Desulfobacterota、Actinobacteriota、Bacteroidota和Proteobacteria是4个组别中的优势菌群。与对照组相比，高脂组和抗阻运动组中Firmicutes和Actinobacteriota的相对丰度增加，而Bacteroidota的相对丰度降低；有氧运动组则与高脂组和抗阻运动组相反。Firmicutes/Bacteroidota(F/B)比值是脂代谢紊乱的一个重要指标，结果显示，与对照组相比，高脂组和抗阻运动组的F/B比值显著增加(P < 0.05)，而有氧运动组的F/B比值则显著降低(P < 0.05)。在属水平上，Dubosiella、Lactobacillus、Faecalibaculum、unclassified_f__Lachnospiraceae 和Lachnospiraceae_NK4A136_group在4个组别中为优势菌属。利用线性判别分析效应量(LEfSe)分析从门到属水平丰度显著变化的物种(图9D)，设定LDA值> 3，在4个组别中筛选出各个组别中显著富集的菌群(图9E)，结果显示：对照组显著富"

集g__Lachnospiraceae_NK4A136_group (LDA=4.83，P=0.023)、o__Bacteroidales(LDA=4.83，P=0.039)、c__Bacteroidia (LDA=4.83，P=0.039)、p__Bacteroidota(LDA=4.831，P=0.039)、f__Muribaculaceae (LDA=4.77，P=0.024)、g__norank_f__Muribaculaceae(LDA=4.77，P=0.024)等菌群。高脂组显著富集g__Faecalibaculum(LDA=5.08，P=0.024)、f__Peptostreptococcaceae(LDA=4.07，P=0.005)、g__Romboutsia(LDA=4.77，P=0.024)、f__Bifidobacteriaceae(LDA=3.88，P=0.031)、o__Enterobacterales(LDA=3.25，P=0.022)、g__Escherichia-Shigella(LDA=3.19，P=0.033)等菌群。有氧运动组显著富集g__Enterococcus(LDA=3.25，P=0.014)和f__Enterococcaceae(LDA=3.25，P=0.014)菌群。抗阻运动组显著富集g__Blautia(LDA=4.17，P=0.01)、f__Streptococcaceae(LDA=3.54，P=0.041)、g__Streptococcus(LDA=3.47，P=0.037)和g__Bilophila(LDA=3.01，P=0.025)菌群。以LDA值> 3进行两组比较分析，筛选出相较于对照组而言高脂组显著富集的菌属，相较于高脂组而言有氧运动组和抗阻运动组中显著富集的菌属，并采用Wilcoxon秩和检验对上述筛选出的富集菌属进行组间差异分析，进一步探究不同方式的运动干预对高脂组vs.对照组中显著差异的菌属是否具有回调效果。图10结果显示，与对照组相比，高脂组g__Faecalibaculun(P=0.002 5)、Coriobacteriaceae_UCG-002(P=0.006)、g__Blautia (P=0.01)、g__Romboutsia(P=0.002)和g__Escherichia- Shigella(P=0.012)的相对丰度均显著增加。与高脂组相比，有氧运动组中g__Bilophila显著富集，且g__Bifidobacterium(P=0.015)、g__Erysipelatoclostridium (P=0.012)、g__Escherichia-Shigella (P=0.018)、g__Leuconostoc(P=0.019)和g__Sporobacter(P=0.037)的相对丰度显著降低，其中g__Escherichia-Shigella和g__Leuconostoc为回调的差异菌属(高脂组vs.对照组)。与高脂组相比，抗阻运动组显著富集的菌属g__norank_o__Clostridia_UCG-014(P=0.015)和g__Psychrobacter(P=0.002)的相对丰度均显著降低，抗阻运动组中未发现回调的差异菌属。 2.9 肠道菌群与生理、炎症指标相关性分析将上述显著富集和回调的核心菌属与生理、炎症相关的指标进行相关性分析(图11A)，结果发现：g__Escherichia-Shigella与总胆固醇 (r=0.458 8，P=0.024 1)、低密度脂蛋白(r=0.413 6，P=0.044 6)及白细胞介素1β(r=0.476 8，P=0.018 5)呈正相关，与高密度脂蛋白(r=-0.406 0，P=0.049 0)及鸢尾素(r= -0.541 5，P=0.006 3)呈负相关；g__Faecalibaculum与总胆固醇(r=0.655 8，P=0.000 5)、三酰甘油(r= 0.514 6，P=0.010 1)、低密度脂蛋白(r=0.531 3，P=0.007 5)及丙氨酸氨基转氨酶(r=0.462 6，P=0.022 8)、天门冬氨酸氨基转移酶(r=0.407 0，P=0.048 4)呈正相关，与高密度脂蛋白(r=-0.500 9，P=0.012 7)及鸢尾素(r=-0.533 9，P=0.007 2)呈负相关；g__Leuconostoc 与总胆固醇(r=0.397 9，P=0.054 1)、低密度脂蛋白(r=0.403 1，P=0.050 8)及丙氨酸氨基转氨酶(r=0.484 2，P=0.016 5)、天门冬氨酸氨基转移酶(r=0.538 3，P=0.006 7)、核因子κB(r=0.462 7，P=0.022 8 )呈正相关，与鸢尾素(r=-0.498 7，P=0.013 1)呈负相关；g__Blautia 与 Lee’s 指数(r=0.549 6，P=0.005 4)、体质量指数(r=0.508 7，P=0.011 1)、三酰甘油(r=0.532 8，P=0.007 3)、低密度脂蛋白 (r=0.548 7，P=0.005 5)及丙氨酸氨基转氨酶(r=0.486 1，P=0.016 0)呈正相关，与高密度脂蛋白(r=-0.490 4，P=0.015 0)及鸢尾素(r=-0.436 5，P= 0.033 0)呈负相关。此外，代谢指标与炎症指标存在显著关联，相关性分析结果显示(图11B)，肿瘤坏死因子α与体质量指数(r=0.503，P=0.013)、低密度脂蛋白(r=0.465，P=0.023)及天门冬氨酸氨基转移酶(r=0.663，P < 0.001)呈正相关；白细胞介素1β与体质量指数(r=0.516，P=0.011)、低密度脂蛋白(r=0.576，P=0.004)、天门冬氨酸氨基转移酶(r=0.670，P < 0.001)及肿瘤坏死因子α(r=0.754，P < 0.001)均呈强正相关；NLRP3炎症小体则与体质量指数(r=0.450，P=0.029)、总胆固醇(r=0.477，P=0.019)及天门冬氨酸氨基转移酶(r=0.608，P=0.002)呈显著正相关，核因子κB不仅与肿瘤坏死因子α(r=0.774，P < 0.001)和白细胞介素1β(r=0.516，P=0.011)呈正相关，还与肝损伤指标天门冬氨酸氨基转移酶(r=0.813，P < 0.001)、体质量指数(r=0.721，P < 0.001)及低密度脂蛋白(r=0.573，P=0.004)呈强正相关。鸢尾素与血脂、肥胖指标及肝损伤指标呈极显著负相关(P < 0.001)，与核因子κB(r=-0.660，P < 0.001)、肿瘤坏死因子α (r=-0.506，P=0.013)等促炎因子呈显著负相关。"

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