Apolipoprotein APOL Specifically Binds Bacteroidales and Regulates Mucosal Homeostasis

The gut microbiota plays a pivotal role in maintaining host health through its complex and dynamic symbiotic relationship with the intestinal epithelium. Beyond aiding in nutrient absorption, commensal microbes modulate host immunity via metabolic products such as short-chain fatty acids and bile acids, as well as structural components including polysaccharide A and α-galactosylceramide. These microbial signals can induce Treg (regulatory T) cell differentiation and modulate NKT (natural killer T) cell activity. Despite these insights, how the host discriminates specific symbionts and establishes mutually beneficial interactions remains poorly understood. Classical intestinal defense mechanisms—including antimicrobial peptides, secretory IgA, and complement C3—lack the specificity required to target individual commensal species. Whether the host has evolved mechanisms to selectively recognize and regulate particular symbionts during coevolution remains an open and important question. Here, using integrative proteomics, the research team identify a novel class of host-derived apolipoproteins, APOL9a and APOL9b (collectively APOL9), that are secreted by murine intestinal epithelial cells and exhibit selective binding to Bacteroidales species—a dominant order of gut commensals. Functional assays demonstrate that both murine APOL9 and its human ortholog APOL2 recognize a unique lipid molecule on the bacterial surface, Cer1P (dihydroceramide-1-phosphate). Binding of APOL9 to target bacteria does not disrupt microbial viability but instead induces the release of OMVs (outer membrane vesicles). These OMVs stimulate dendritic cells and enhance IFN-γ (interferon-γ) production by T cells, leading to upregulation of MHC class II expression in intestinal epithelial cells. Consequently, this promotes the development of CD4⁺CD8αα⁺ IELs (intraepithelial lymphocytes), a specialized immune subset associated with mucosal immune defense. Functionally, this host-symbiont axis enhances resistance against enteric pathogens, including Salmonella enterica.

CSTR: 32200.14.cjcb.2025.07.0001