Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin Province, China.
Department of Breast Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
Microbiome. 2022 Dec 1;10(1):205. doi: 10.1186/s40168-022-01402-z.
Mounting experimental evidence has shown that the gut microbiota plays a significant role in the pathogenesis of mastitis, and clinical investigations have found that the occurrence of mastitis is correlated with ruminal dysbiosis. However, the underlying mechanism by which the ruminal microbiota participates in the development of mastitis remains unknown.
In the present study, we found that cows with clinical mastitis had marked systemic inflammation, which was associated with significant ruminal dysbiosis, especially enriched Proteobacteria in the rumen. Ruminal microbiota transplantation from mastitis cows (M-RMT) to mice induced mastitis symptoms in recipient mice along with increased mammary proinflammatory signature activation of the TLR4-cGAS-STING-NF-κB/NLRP3 pathways. M-RMT also induced mucosal inflammation and impaired intestinal barrier integrity, leading to increased endotoxemia and systemic inflammation. Moreover, we showed that M-RMT mirrored ruminal microbiota disruption in the gut of recipient mice, as evidenced by enriched Proteobacteria and similar bacterial functions, which were correlated with most proinflammatory parameters and serum lipopolysaccharide (LPS) levels in mice. Recurrent low-grade LPS treatment mirrored gut dysbiosis-induced endotoxemia and caused severe mastitis in mice. Furthermore, we found that gut dysbiosis-derived LPS reduced host alkaline phosphatase activity by activating neuraminidase (Neu), which facilitates low-grade LPS exposure and E. coli-induced mastitis in mice. Conversely, treatment with calf intestinal alkaline phosphatase or the Neu inhibitor zanamivir alleviated low-grade LPS exposure and E. coli-induced mastitis in mice.
Our results suggest that ruminal dysbiosis-derived low-grade endotoxemia can cause mastitis and aggravate pathogen-induced mastitis by impairing host anti-inflammatory enzymes, which implies that regulating the ruminal or gut microbiota to prevent low-grade systemic inflammation is a potential strategy for mastitis intervention. Video Abstract.
越来越多的实验证据表明，肠道微生物群在乳腺炎的发病机制中起着重要作用，临床研究发现乳腺炎的发生与瘤胃菌群失调有关。然而，瘤胃微生物群参与乳腺炎发展的潜在机制尚不清楚。
本研究发现，患有临床乳腺炎的奶牛表现出明显的全身炎症，这与瘤胃严重的菌群失调有关，尤其是瘤胃中变形菌门的富集。将乳腺炎奶牛的瘤胃液（M-RMT）移植到小鼠体内，可引起受体小鼠乳腺炎症状，同时激活 TLR4-cGAS-STING-NF-κB/NLRP3 通路的乳房产炎标志物的激活。M-RMT 还可诱导黏膜炎症和肠道屏障完整性受损，导致内毒素血症和全身炎症增加。此外，我们发现 M-RMT 反映了受体小鼠肠道中瘤胃微生物群的破坏，这表现在变形菌门的富集和相似的细菌功能上，这些与大多数促炎参数和血清脂多糖（LPS）水平相关。反复给予低剂量 LPS 可模拟肠道菌群失调引起的内毒素血症，并导致小鼠严重乳腺炎。此外，我们发现肠道菌群失调衍生的 LPS 通过激活神经氨酸酶（Neu）降低宿主碱性磷酸酶的活性，从而促进低剂量 LPS 暴露和大肠杆菌引起的乳腺炎。相反，用小牛肠碱性磷酸酶或 Neu 抑制剂扎那米韦治疗可减轻低剂量 LPS 暴露和大肠杆菌诱导的乳腺炎。
我们的研究结果表明，瘤胃菌群失调衍生的低水平内毒素血症可导致乳腺炎，并通过损害宿主抗炎酶加重病原体诱导的乳腺炎，这意味着调节瘤胃或肠道微生物群以预防低水平全身炎症可能是乳腺炎干预的一种潜在策略。视频摘要。
