Targeting symbionts by apolipoprotein L proteins modulates gut immunity

The mammalian gut harbours trillions of commensal bacteria that interact with their hosts through various bioactive molecules^1,2. 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.