摘要
肠道微生物群与宿主的共生关系是维持机体健康的核心。作为共栖者,这些微生物除了辅助吸收营养物质外,也能积极通过分泌代谢产物(如短链脂肪酸、胆汁酸)和结构分子(如多糖A、α-半乳糖神经酰胺)调控宿主免疫,例如诱导调节性T细胞(Treg)分化或调节自然杀伤T细胞活性。然而,宿主如何精准识别特定共生菌并建立互惠机制仍不明确。已知的肠道防御因子(如抗菌肽、分泌型IgA、补体C3)虽能清除病原体,但其作用缺乏菌群特异性。针对肠道中数量众多的共生菌,在长期共进化过程中宿主是否发展出精准识别和调控这些微生物的能力,仍待深入探索。针对该问题,该团队通过多重蛋白组学技术鉴定发现小鼠肠上皮细胞可分泌产生一类新型载脂蛋白APOL9a/b(APOL9),其具有共生细菌结合能力。结合流式细胞术与微生物组测序技术,团队意外发现APOL9及其人类同源蛋白APOL2能特异性结合一类常见的拟杆菌目(Bacteroidales)肠道细菌。进一步研究表明APOL9可以特异性结合细菌表面特殊的脂质分子——神经酰胺-1-磷酸(Cer1P),结合目标细菌后,可以诱导其释放外膜囊泡(OMVs),外膜囊泡可以激活树突状细胞,促进T细胞分泌干扰素γ,进而诱导上皮细胞MHC-Ⅱ表达,最终推动一类CD4^(+)CD8αα^(+)肠上皮内淋巴细胞(IELs)的发育,从而提升肠道对外来病原微生物(如沙门氏菌)的抗感染能力。
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 andα-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.
作者
杨涛
胡孝虎
钱友存
YANG Tao;HU Xiaohu;QIAN Youcun(Laboratory of Immunology and Disease,Shanghai Institute of Nutrition and Health,University of Chinese Academy of Sciences,Shanghai 200031,China)
出处
《中国细胞生物学学报》
2025年第7期1477-1484,共8页
Chinese Journal of Cell Biology
基金
国家重点研发计划(批准号:2020YFA0509100)
国家自然科学基金(批准号:81830018)资助的课题。
