Zhang Boqi, Wang Nan, He Guitian, Chen Tong, Zong Jinxin, Shen Caomeihui, Wang Yueying, Li Chuanghang, Yin Xuanqi, Meng Yang, Chang Fuqiang, Wang Sihui, Li Chunjin, Zhou Xu
College of Animal Sciences, Jilin University, Changchun, China.
Jilin Province Product Ouality Supervision and Inspection Institute, Changchun, China.
FASEB J. 2025 Jul 15;39(13):e70770. doi: 10.1096/fj.202500877RR.
Mastitis is a major disease affecting the dairy industry. Although antibiotics are the most prevalent treatment for mastitis, their overuse presents significant risks to public health. Probiotic therapy has emerged as a promising alternative for controlling mastitis, but there is a lack of comprehensive studies on the efficacy and mechanisms of specific probiotics in treating this condition. Here, we investigate the potential of Akkermansia muciniphila (A. muciniphila) and its derived outer membrane vesicles (AOMVs) as therapeutic agents for mastitis. Significant differences in microbial communities were identified through an analysis of the microbiota composition in milk from healthy and mastitis cows. Spearman's correlation analysis revealed a significant negative correlation between the relative abundances of Verrucomicrobia and Akkermansia and the levels of inflammatory cytokines in mastitis milk. Furthermore, we evaluated the roles of live and pasteurized A. muciniphila in lipopolysaccharide (LPS)-induced inflammatory responses in bovine mammary epithelial cells (MAC-T). Compared to pasteurized A. muciniphila, live A. muciniphila exhibited a stronger anti-inflammatory effect, notably inhibiting the TLR4 and NF-κB signaling pathways. We also demonstrated that these effects of A. muciniphila may be mediated through AOMVs. Subsequently, the therapeutic potential of AOMVs was evaluated in vivo using an LPS-induced mastitis mouse model. The results demonstrated that AOMVs targeted the mammary glands, alleviated LPS-induced damage, and reduced inflammatory cytokine levels and signaling pathway activation. Finally, we conducted a preliminary investigation to assess the therapeutic effects of A. muciniphila on mastitis in dairy cows. Administration of A. muciniphila significantly reduced somatic cell count (SCC) in the milk of cows with mastitis. Notably, four of the five treated cows showed a decrease in SCC to below 2 × 10 cells/mL, with negative results in the California Mastitis Test. Our findings provide compelling evidence for the therapeutic potential of A. muciniphila and AOMVs in the treatment of mastitis. These results not only highlight the anti-inflammatory properties of A. muciniphila as a potential probiotic, proposing novel strategies for developing alternatives to antibiotic therapies, but also provide a theoretical basis for exploring the role of outer membrane vesicles in the host-microbe interface.
乳腺炎是影响乳制品行业的一种主要疾病。尽管抗生素是治疗乳腺炎最常用的方法，但其过度使用对公众健康构成重大风险。益生菌疗法已成为控制乳腺炎的一种有前景的替代方法，但目前缺乏关于特定益生菌治疗该疾病的疗效和机制的全面研究。在此，我们研究了嗜黏蛋白阿克曼氏菌（A. muciniphila）及其衍生的外膜囊泡（AOMVs）作为乳腺炎治疗剂的潜力。通过分析健康奶牛和患乳腺炎奶牛乳汁中的微生物群组成，确定了微生物群落的显著差异。Spearman相关性分析显示，疣微菌门和阿克曼氏菌的相对丰度与乳腺炎乳汁中炎性细胞因子水平之间存在显著负相关。此外，我们评估了活的和巴氏杀菌的嗜黏蛋白阿克曼氏菌对牛乳腺上皮细胞（MAC-T）中脂多糖（LPS）诱导的炎症反应的作用。与巴氏杀菌的嗜黏蛋白阿克曼氏菌相比，活的嗜黏蛋白阿克曼氏菌表现出更强的抗炎作用，尤其抑制了TLR4和NF-κB信号通路。我们还证明，嗜黏蛋白阿克曼氏菌的这些作用可能是通过AOMVs介导的。随后，使用LPS诱导的乳腺炎小鼠模型在体内评估了AOMVs的治疗潜力。结果表明，AOMVs靶向乳腺组织，减轻了LPS诱导的损伤，并降低了炎性细胞因子水平和信号通路激活。最后，我们进行了一项初步研究，以评估嗜黏蛋白阿克曼氏菌对奶牛乳腺炎的治疗效果。给予嗜黏蛋白阿克曼氏菌显著降低了患乳腺炎奶牛乳汁中的体细胞计数（SCC）。值得注意的是，五头接受治疗的奶牛中有四头的SCC降至2×10⁵细胞/mL以下，加利福尼亚乳腺炎检测结果为阴性。我们的研究结果为嗜黏蛋白阿克曼氏菌和AOMVs治疗乳腺炎的潜力提供了有力证据。这些结果不仅突出了嗜黏蛋白阿克曼氏菌作为潜在益生菌的抗炎特性，为开发抗生素治疗替代方案提出了新策略，还为探索外膜囊泡在宿主-微生物界面中的作用提供了理论基础。
