Bacterial infection in weaned piglets promotes diarrhea by inducing the NLRP3 inflammasome-pyroptosis pathway

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.