Fu Jie, Jiang Zipeng, Wen Chaoyue, Su Weifa, Yang Mingzhi, He Huan, Liu Yalin, Gong Tao, Jiang Shouchuan, Wang Fengqin, Lu Zeqing, Jin Mingliang, Wang Yizhen
Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, 310063, China.
Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Hangzhou, 310063, China.
Sci China Life Sci. 2025 Jul 4. doi: 10.1007/s11427-024-2728-2.
Bacterial infections in weaned piglets are a major cause of diarrhea and even death. However, the mechanism by which bacterial infections in weaned piglets lead to diarrhea remains unclear. The NLRP3 inflammasome and pyroptosis are considered key factors in mucosal immune damage. Therefore, we aimed to investigate whether bacterial infections in weaned piglets promote diarrhea through the NLRP3 inflammasome-pyroptosis pathway. Our research findings indicate that compared with weaned healthy piglets, those with weaning diarrhea exhibit activation of the NLRP3 inflammasome and pyroptosis. Weaned piglets with diarrhea had reduced microbiota diversity in the gut, significant differences in β-diversity, a notable increase in the ratio of Firmicutes to Bacteroidetes, and a significant increase in the abundance of pathogens, such as Escherichia coli and Clostridium perfringens. Further infection experiments with enterotoxigenic Escherichia coli (ETEC) K88 and C. perfringen in weaned piglets revealed that these pathogens disrupt intestinal integrity, promote diarrhea incidence, increase serum IL-1β and IL-18 levels, and activate the NLRP3 inflammasome-pyroptosis pathway. Mechanistic studies using NLRP3 knockout mice showed significant alleviation of elevated serum IL-1β and IL-18 levels, intestinal inflammatory cell infiltration, downregulation of intestinal barrier protein gene expression, and reduction in diarrhea incidence caused by ETEC K88 and C. perfringen infection. Finally, we investigated the role of sow's breast-milk immunoglobulins in activating the NLRP3 inflammasome-pyroptosis pathway and the incidence of diarrhea in weaned piglets. The results demonstrate that sow's breast milk immunoglobulins are beneficial for protecting weaned piglets from pathogenic bacterial infection-induced NLRP3 inflammasome activation and diarrhea occurrence. In conclusion, our study elucidates the inflammatory mechanisms underlying diarrhea occurrence in piglets due to reduced levels of immunoglobulins from sow's breast milk after weaning, thereby promoting NLRP3 inflammasome-pyroptosis pathway activation mediated by pathogenic bacterial infection.
断奶仔猪的细菌感染是腹泻甚至死亡的主要原因。然而，断奶仔猪细菌感染导致腹泻的机制仍不清楚。NLRP3炎性小体和细胞焦亡被认为是黏膜免疫损伤的关键因素。因此，我们旨在研究断奶仔猪的细菌感染是否通过NLRP3炎性小体-细胞焦亡途径促进腹泻。我们的研究结果表明，与健康断奶仔猪相比，患断奶腹泻的仔猪表现出NLRP3炎性小体激活和细胞焦亡。患腹泻的断奶仔猪肠道微生物群多样性降低，β-多样性存在显著差异，厚壁菌门与拟杆菌门的比例显著增加，大肠杆菌和产气荚膜梭菌等病原体的丰度显著增加。用产肠毒素大肠杆菌（ETEC）K88和产气荚膜梭菌对断奶仔猪进行进一步感染实验发现，这些病原体会破坏肠道完整性，增加腹泻发生率，提高血清IL-1β和IL-18水平，并激活NLRP3炎性小体-细胞焦亡途径。使用NLRP3基因敲除小鼠进行的机制研究表明，血清IL-1β和IL-18水平升高、肠道炎性细胞浸润、肠道屏障蛋白基因表达下调以及由ETEC K88和产气荚膜梭菌感染引起的腹泻发生率均得到显著缓解。最后，我们研究了母猪母乳中的免疫球蛋白在激活NLRP3炎性小体-细胞焦亡途径以及断奶仔猪腹泻发生率方面的作用。结果表明，母猪母乳中的免疫球蛋白有利于保护断奶仔猪免受病原菌感染诱导的NLRP3炎性小体激活和腹泻发生。总之，我们的研究阐明了断奶后母猪母乳中免疫球蛋白水平降低导致仔猪腹泻发生的炎症机制，从而促进了病原菌感染介导的NLRP3炎性小体-细胞焦亡途径激活。
