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Amuc_1100, the most abundant outer membrane protein of Akkermansia muciniphila, alleviates high-fat diet (HFD)-induced hepatic lipid accumulation and modulates gut microbiota in fish; however, its mechanism and mediators remain unknown. Using zebrafish model, this study aims to determine the mechanism by which Amuc_1100 reduces HFD-induced hepatic lipid accumulation through modulation of gut microbiota.
In main study, 1-month-old zebrafish were fed a low-fat diet (LFD), HFD, or HFD supplemented with 0.01% Amuc_1100 (AM0.01) for 4 weeks. Body weight gain, hepatic lipid accumulation, microbial translocation, and gut microbiota composition were evaluated. In parallel, larvae at 5 d post-fertilization were fed the same diets for 7 d and analyzed by Oil Red O staining. In validation experiments, germ-free (GF) zebrafish received microbiota transplants from donor fish fed HFD or AM0.01. Antibiotics (ABS)-treated zebrafish were fed LFD, HFD, or AM0.01 for 4 weeks. Intestinal protein interacting with Amuc_1100 was identified via pull-down and co-immunoprecipitation, and its role was confirmed using protein-protein interaction (PPI) inhibitor BV02 and gene knockdown. Data were analyzed by Student's t-test or one-way ANOVA.
Compared with HFD group, zebrafish in AM0.01 group showed lower body weight gain, reduced hepatic lipid accumulation, and decreased microbial translocation (P < 0.05). AM0.01 feeding increased Bacillus abundance while reducing Acinetobacter, Plesiomonas and Aeromonas abundances relative to HFD (P < 0.05). GF zebrafish colonized with microbiota from AM0.01-fed donors showed less hepatic lipid accumulation than those receiving microbiota from HFD-fed donors (P < 0.05). In contrast, ABS-treated zebrafish showed no significant difference in hepatic triacylglycerol content between HFD and AM0.01 groups (P > 0.05). Using pull-down assays with intestinal proteins from LFD-fed zebrafish, we identified 14-3-3β/α-A as an interacting protein of Amuc_1100. When 14-3-3β/α-A PPI was inhibited by BV02, Amuc_1100 failed to alter the HFD-induced gut microbiota profile in 1-month-old zebrafish (P > 0.05). Moreover, either BV02 treatment or 14-3-3β/α-A knockdown abolished the protective effect of Amuc_1100 against hepatic lipid accumulation in conventional and GF zebrafish (P < 0.05).
Amuc_1100 reduces hepatic lipid accumulation by modulating gut microbiota through intestinal 14-3-3β/α-A, highlighting its potential as a therapeutic target.
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| 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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