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Intractable or protracted infancy diarrhea is typically associated with feeding intolerance and malabsorption that is lethal for newborns. The objective of this study is to explore the regulatory effects of baizhu shaoyao decoction (BSD) on the gut microbiota and associated metabolites in weaned piglets, thereby elucidating the mechanism by which BSD mitigates weaning stress in piglets. Piglets were allocated into five groups, with each group receiving designated medication for a continuous 14\u2010day period: control, zaohu powder, as well as low\u2010, medium\u2010, and high\u2010dose BSD groups (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20096 piglets per group). To identify diarrhea\u2010related biomarkers, microbial communities, functions, and metabolites were compared between the early\u2010weaned piglets (control group) and those treated with 1.28\u2009g\/kg BSD (medium\u2010dose BSD group). Our findings revealed significant shifts in microbial composition, function, and metabolic profiles in piglets from the medium\u2010dose BSD group, intricately associated with the host's diarrhea status. Furthermore, carbohydrate metabolism and biosynthesis, lipid and amino acid metabolism, glycan activity, and carbohydrate digestive enzymes exhibited downregulation in piglets of the medium\u2010dose BSD group compared to those in the control group. Transcriptome analysis highlighted the pivotal role of the FoxO1\/3 transcription factor in mitigating weaning stress, particularly through the augmentation of CD4\n                    <jats:sup>+<\/jats:sup>\n                    \/CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell proportions. Our findings underscored that therapeutic effects of BSD on weaning stress involve intestinal barrier restoration, modulation of brain\u2013gut peptide expression, and a reduction in mast\u2010cell activity in the ileum. BSD has a significant effect on improving early weaning diarrhea in infants. Its mechanism of action involves improving the abundance of key intestinal microbiota\n                    <jats:italic>Lachnospiraceae_bacterium<\/jats:italic>\n                    ,\n                    <jats:italic>a<\/jats:italic>\n                    ffecting changes in intestinal bile acid metabolites (such as, chenodeoxyglycocholic acid, glycochenodeoxycholic acid) and thereby regulating intestinal mucosal immunity and gut\u2010brain peptides, achieving the effect of treating weaning stress.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500525r","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T07:34:50Z","timestamp":1752132890000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Omics Integration Reveals Gut Microbiota\u2010Bile Acid Crosstalk Underlying Baizhu Shaoyao Decoction's Therapeutic Efficacy in Weaning Stress of Piglets"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6674-5142","authenticated-orcid":false,"given":"Yuanyuan","family":"Wei","sequence":"first","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine China Agricultural University  Beijing China"},{"name":"Key Biology Laboratory of Chinese Veterinary Medicine Ministry of Agriculture and Rural Affairs  Beijing China"},{"name":"National Center of Technology Innovation for Medicinal Function of Food National Food and Strategic Reserves Administration  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine China Agricultural University  Beijing China"},{"name":"Key Biology Laboratory of Chinese Veterinary Medicine Ministry of Agriculture and Rural Affairs  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