Nature is a heavyweight! Chinese scientists find molecular key to gut immunity

肠道免疫

z-bio

2025-05-23

4387

　　In the complex "microecological kingdom" of the human gut, trillions of symbiotic bacteria reside, forming intricate networks of interactions with their hosts. They not only help us break down food and synthesize nutrients, but also play a crucial role in the development and maintenance of the immune system's homeostasis.

　　However, how does the body "manage" these bacteria to help without causing trouble?

　　On May 14, 2025, Qian Youcun's team from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, together with Song Xinyang's team from the Center for Excellence and Innovation in Molecular Cell Science, Chinese Academy of Sciences (Yang Tao, Hu Xiaohu, Cao Fei as the co first author of the paper), published a research paper entitled Targeting symbols by apolipoprotein L proteins modules gut immunity on the international top journal Nature, revealing the unique strategy of mammalian intestines: by secreting apolipoprotein APOL9a/b, the host and Bacteroides bacteria have established a "win-win" immune regulation mechanism.

　　The 'molecular key' for accurately identifying beneficial bacteria

　　Research has found that mouse intestinal epithelial cells secrete a protein called APOL9a/b (the corresponding protein in the human body is APOL2), which functions like a "molecular navigator" and can accurately target Bacteroidetes bacteria (such as Bacteroidetes) in the intestine. The key to this specific recognition lies in a unique lipid molecule on the bacterial cell membrane - ceramide-1-phosphate (Cer1P).

　　APOL9a/b is like a "key" that can tightly bind to Cer1P through molecular interactions, thereby attaching to bacterial surfaces. It is worth noting that this combination does not "eliminate" bacteria, but rather initiates a mild immune regulatory program. Through proteomics and flow cytometry analysis, researchers found that APOL9a/b only targets specific bacterial groups and has no significant impact on the overall balance of gut microbiota, reflecting the high precision of host regulation.

　　Bacterial 'signal bubble' - outer membrane vesicle

　　When APOL9a/b binds to Bacteroidetes, the bacteria will make an interesting reaction - releasing a large number of outer membrane vesicles (OMVs). These nanoscale "small bubbles" are like "messengers" sent by bacteria, carrying various immune regulatory molecules that can cross the intestinal barrier and engage in dialogue with host cells.

　　Experiments have shown that OMVs can activate dendritic cells and T lymphocytes near intestinal epithelial cells, promoting their secretion of interferon - γ (IFN - γ). This cytokine further induces intestinal epithelial cells to express major histocompatibility complex class II molecules (MHC-II), which act as the "alarm" of the immune barrier, enhancing the intestinal monitoring ability for pathogens and maintaining immune tolerance to symbiotic bacteria.

　　It is worth mentioning that human APOL2 and mouse APOL9a/b are highly conserved in function, suggesting that this mechanism may have universality in evolution.

　　APOL9a/b deficiency leads to intestinal immune imbalance

　　What changes would occur in the intestine if APOL9a/b regulation is lost?

　　The APOL9a/b knockout mouse model constructed by researchers showed that the expression of MHC-II molecules in intestinal epithelial cells of mice lacking this protein was significantly reduced, and the intestinal immune barrier function was weakened. When faced with intestinal pathogens such as Salmonella, these mice showed higher mortality rates, more severe intestinal inflammation, and a tendency for bacteria to spread throughout the body.

　　Further experiments have found that oral supplementation of OMVs derived from Bacteroidetes can partially restore the immune function of knockout mice, confirming the core role of the APOL9a/b-OMVs pathway in host defense. This phenomenon also explains why the imbalance of intestinal flora will increase the risk of infectious diseases - the lack of interaction between specific beneficial bacteria and the host may directly lead to loopholes in the immune surveillance network.

　　This study reveals the tip of the iceberg of "smart symbiosis" between hosts and gut bacteria: APOL9a/b acts as a bridge, tightly connecting host immune regulation with bacterial metabolic activity, and achieving precise maintenance of gut immune homeostasis through the three-step process of "recognition induction activation".

　　In the future, a deeper understanding of this mechanism will not only help develop immunomodulatory therapies targeting the gut microbiota, but also provide a new direction for exploring the pathogenesis of diseases such as inflammatory bowel disease and infectious diarrhea. Perhaps in the near future, we can reorganize the harmonious network between gut microbiota and immune system by regulating these 'symbiotic coordination proteins'.