Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.
College of Pharmacy, Gachon University, Incheon, South Korea.
Nature. 2022 Aug;608(7921):168-173. doi: 10.1038/s41586-022-04985-7. Epub 2022 Jul 27.
Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.
多项研究已经确立了人类肠道细菌与宿主生理学之间的关联，但确定这些关联的分子机制一直具有挑战性。阿克曼氏菌（Akkermansia muciniphila）与宿主代谢的积极全身效应、癌症免疫治疗中检查点阻断的有利结果以及体内平衡免疫之间存在着强有力的关联。在这里，我们报告了从阿克曼氏菌细胞膜中鉴定出的一种脂质，该脂质在基于细胞的测定中重现了阿克曼氏菌的免疫调节活性。分离出的免疫原是一种具有两个支链的二酰基磷脂酰乙醇胺（a15:0-i15:0PE），通过光谱分析和化学合成对其进行了表征。a15:0-i15:0PE 的免疫原性具有高度受限的结构-活性关系，其免疫信号需要出乎意料的 Toll 样受体 TLR2-TLR1 异二聚体。该磷脂的一些活性特征值得注意：它的效力明显低于已知的天然和合成 TLR2 激动剂；它优先诱导一些炎症细胞因子，但不诱导其他细胞因子；并且，在低剂量（EC 的 1%）下，它重置了免疫信号的激活阈值和反应。确定该分子及其等效的合成类似物、其非典型的 TLR2-TLR1 信号通路、其免疫调节选择性以及其低剂量免疫调节作用，为阿克曼氏菌调节免疫基调的能力及其在健康和疾病中的多种作用提供了分子机制。
