Diarrhea kills hundreds of thousands of children each year, making it one of the leading causes of childhood mortality. It’s also rampant in the livestock industry, where it causes huge losses. Diarrhea can be induced or facilitated by disruption of the gut microbiome at the colonic mucosal barrier. However, the contributions of abnormalities in barrier components called mucin O-glycans remain unclear. To learn more, researchers recently investigated the changes in microbiota- associated mucin O-glycans in a piglet post-weaning diarrhea model. Diarrhea (D) altered the structure of the colon mucus layer and changed the O-glycan profile. For example, it reduced the abundance of acidic O- glycans while increasing that of truncated O-glycans. Subsequent changes in the microbiota disrupted barrier function, which increased inflammation and ultimately impaired piglet growth. Specifically, the piglets with diarrhea exhibited NLRP3 inflammasome activation and increased release of IL-1β and IL-18 as well as reduced autophagosome formation because of defective LC3A/BI–LC3A/BII conversion and p62 accumulation. Although additional verification is needed, the findings reveal that the mucin O-glycan–microbiota axis is associated with diarrhea in piglets and provide potential therapeutic targets for diarrheal diseases in both young livestock and human children.