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Here, comparing germ\u2010free (GF) and specific pathogen\u2010free (SPF) mice using spatial transcriptomics, single\u2010cell RNA sequencing, and targeted bile acid metabolomics across multiple organs, we systematically assessed how the gut microbiota's absence affected organ morphology, immune homeostasis, bile acid, and lipid metabolism. Through integrated analysis, we detect marked aberration in B, myeloid, and T\/natural killer cells, altered mucosal zonation and nutrient uptake, and significant shifts in bile acid profiles in feces, liver, and circulation, with the alternate synthesis pathway predominant in GF mice and pronounced changes in bile acid enterohepatic circulation. Particularly, autophagy\u2010driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain\u2010containing protein (ZBTB20)\u2010Lipoprotein lipase (LPL) (ZBTB20\u2010LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota\u2013host interactions in the crosstalk between commensal gut bacteria and the host.<\/jats:p>","DOI":"10.1002\/imt2.272","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T13:34:36Z","timestamp":1739540076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Cross\u2010tissue multi\u2010omics analyses reveal the gut microbiota's absence impacts organ morphology, immune homeostasis, bile acid and lipid metabolism"],"prefix":"10.1002","volume":"4","author":[{"given":"Juan","family":"Shen","sequence":"first","affiliation":[{"name":"BGI Research Shenzhen China"},{"name":"Qingdao\u2010Europe Advanced Institute for Life Sciences BGI Research Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Liang","sequence":"additional","affiliation":[{"name":"BGI Research Shenzhen 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