Targeting symbionts by apolipoprotein L proteins modulates gut immunity

Tao Yang, Xiaohu Hu, Fei Cao, Fenglin Yun, Kaiwen Jia, Mingxiang Zhang, Gaohui Kong, Biyu Nie, Yuexing Liu, Haohao Zhang, Xiaoyu Li, Hongyan Gao, Jiantao Shi, Guanxiang Liang, Guohong Hu, Dennis L. Kasper, Xinyang Song () and Youcun Qian ()
Additional contact information
Tao Yang: Chinese Academy of Sciences
Xiaohu Hu: Chinese Academy of Sciences
Fei Cao: University of Chinese Academy of Sciences
Fenglin Yun: Chinese Academy of Sciences
Kaiwen Jia: University of Chinese Academy of Sciences
Mingxiang Zhang: ShanghaiTech University
Gaohui Kong: Chinese Academy of Sciences
Biyu Nie: Chinese Academy of Sciences
Yuexing Liu: Chinese Academy of Sciences
Haohao Zhang: University of Chinese Academy of Sciences
Xiaoyu Li: Tongji University School of Medicine
Hongyan Gao: Tsinghua University
Jiantao Shi: University of Chinese Academy of Sciences
Guanxiang Liang: Tsinghua University
Guohong Hu: Chinese Academy of Sciences
Dennis L. Kasper: Harvard Medical School
Xinyang Song: University of Chinese Academy of Sciences
Youcun Qian: Chinese Academy of Sciences

Nature, 2025, vol. 643, issue 8070, 210-218

Abstract: Abstract The mammalian gut harbours trillions of commensal bacteria that interact with their hosts through various bioactive molecules1,2. However, the mutualistic strategies that hosts evolve to benefit from these symbiotic relationships are largely unexplored. Here we report that mouse enterocytes secrete apolipoprotein L9a and b (APOL9a/b) in the presence of microbiota. By integrating flow cytometry sorting of APOL9-binding bacterial taxa with 16S ribosomal RNA gene sequencing (APOL9-seq), we identify that APOL9a/b, as well as their human equivalent APOL2, coat gut bacteria belonging to the order of Bacteroidales with a high degree of specificity through commensal ceramide-1-phosphate (Cer1P) lipids. Genetic abolition of ceramide-1-phosphate synthesis pathways in gut-dominant symbiote Bacteroides thetaiotaomicron significantly decreases the binding of APOL9a/b to the bacterium. Instead of lysing the bacterial cells, coating of APOL9a/b induces the production of outer membrane vesicles (OMVs) from the target bacteria. Subsequently, the Bacteroides-elicited outer membrane vesicles enhance the host’s interferon-γ signalling to promote major histocompatibility complex class II expression in the intestinal epithelial cells. In mice, the loss of Apol9a/b compromises the gut major histocompatibility complex class II-instructed immune barrier function, leading to early mortality from infection by intestinal pathogens. Our data show how a host-elicited factor benefits gut immunological homeostasis by selectively targeting commensal ceramide molecules.

Date: 2025
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DOI: 10.1038/s41586-025-08990-4

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