Journal Article

Cross‐tissue multi‐omics analyses reveal the gut microbiota's absence impacts organ morphology, immune homeostasis, bile acid and lipid metabolism

Liu, Jiazhe, Huang, Li, Zhao, Ruizhen, Chen, Yang, Liu, Yanmin, Deng, Haohao, Leung, Elaine Lai‐Han, Mei, Junpu, Karsten, Kristiansen, Deng, Yusheng, Chen, Xueting, Han, Lijuan, Wei, Hong, Chen, Rouxi, Pan, Shanshan, Zhang, Lu, Pang, Li, Yang, Zhimin, Yue, Zhen, Chai, Tailiang, Chen, Silian, Wang, Linying, Luo, Wen, Zhang, Yin, Cheng, Wei, Qiu, Qinwei, Huang, Yufen, Zhang, Zhao, Liang, Weiming, Ye, Jingjing, Fang, Xiaodong, Li, Wanshun, Huang, Xiao, Shen, Juan, Jiang, Xuanting, Yang, Huanjie

2025

Overview

The gut microbiota influences host immunity and metabolism, and changes in its composition and function have been implicated in several non‐communicable diseases. Here, comparing germ‐free (GF) and specific pathogen‐free (SPF) mice using spatial transcriptomics, single‐cell 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‐driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain‐containing protein (ZBTB20)‐Lipoprotein lipase (LPL) (ZBTB20‐LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota–host interactions in the crosstalk between commensal gut bacteria and the host. We present a multi‐organ single‐cell, spatial transcriptomics, and BA omics atlas of specific pathogen‐free (SPF) and germ‐free (GF) mice. We found plasma cell aggregation displays significant tissue heterogeneity depending on the gut microbiota. GF mice exhibit impaired follicular and marginal zone B cell maturation, linked to microbiota‐mediated modulation of Cr2 gene expression. The microbiota regulates the development and survival of neutrophils in the bone marrow, influences the development and differentiation of T cells in the thymus, and modulates intraepithelial γδ T cell composition and lipid absorption in the small intestine. The absence of microbiota in GF mice alters the intestinal mucosa zonation and triggers coordinated dynamics in intestinal lipid absorption, transport, chylomicron synthesis, lipid droplet formation, lipolysis, and fatty acid oxidation in the small intestine enterocytes. The liver microbiota‐dependent zinc finger and BTB domain‐containing protein (ZBTB20)‐Lipoprotein lipase (LPL) axis plays a role in plasma lipid homeostasis. Highlights Single‐cell, spatial transcriptomics, and bile acidomics atlases in germ‐free mice. Marked aberration and tissue heterogeneity in B, myeloid, and T/NK cells in germ‐free mice. Microbiota shapes mucosal zonation and modulates lipid dynamics of the small intestine. Germ‐free mice show liver bile acid synthesis and ileal reabsorption anomalies.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: aggregation index / bile acid and lipid metabolism / Bone marrow / Cell cycle / Gene expression / germ‐free mice / Gut microbiota / Homeostasis / immune homeostasis / Immune system / Immunity (Disease) / lipid droplet / Lipids / Liver / Metabolism / Morphology / Physiology / Plasma / spatial transcriptomics and single‐cell RNA sequencing / Spleen / Thymus gland / zonation