Department of Microbiology and Cell Science, Genetics Institute, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, USA.
Gut Microbes. 2023 Dec;15(2):2252447. doi: 10.1080/19490976.2023.2252447.
Shifts in the gut microbiota composition, called dysbiosis, have been directly associated with acute and chronic diseases. However, the underlying biological systems connecting gut dysbiosis to systemic inflammatory pathologies are not well understood. Phospholipids (PLs) act as precursors of both, bioactive inflammatory and resolving mediators. Their dysregulation is associated with chronic diseases including cancer. Gut microbial-derived lipids are structurally unique and capable of modulating host's immunity. N6.2 is a Gram-positive gut symbiont with probiotic characteristics. N6.2 reduces the incidence of autoimmunity in animal models of Type 1 Diabetes and improves general wellness in healthy volunteers by promoting, in part, local and systemic anti-inflammatory responses. By utilizing bioassay-guided fractionation methods with bone marrow-derived dendritic cells (BMDCs), we report here that N6.2 purified lipids induce a transcriptional signature that resembles that of migratory (mig) DCs. RNAseq-based analysis showed that BMDCs stimulated with total lipids upregulate maturation-mig related genes , , , along with immunoregulatory genes including , , , , , , and . Quantitative reverse transcription (qRT)-PCR analysis indicated that PLs are the bioactive lipids triggering the BMDCs response. Antibody-blocking of surface Toll-like receptor (TLR)2 resulted in boosted PL-mediated upregulation of pro-inflammatory . Chemical inhibition of the IKKα kinase from the non-canonical NF-κB pathway specifically restricted upregulation of and . Phenotypically, PL-stimulated BMDCs displayed an immature like-phenotype with significantly increased surface ICAM-1. This study provides insight into the immunoregulatory capacity of Gram-positive, gut microbial-derived phospholipids on innate immune responses.
肠道微生物群落组成的变化，称为菌群失调，与急性和慢性疾病直接相关。然而，将肠道菌群失调与全身炎症性病理联系起来的潜在生物学系统尚不清楚。磷脂（PLs）是生物活性炎症和解决介质的前体。它们的失调与包括癌症在内的慢性疾病有关。肠道微生物衍生的脂质具有独特的结构，能够调节宿主的免疫。N6.2 是一种革兰氏阳性肠道共生菌，具有益生菌特性。N6.2 通过促进局部和全身抗炎反应，降低 1 型糖尿病动物模型中自身免疫的发生率，并改善健康志愿者的整体健康状况。通过利用骨髓来源的树突状细胞（BMDC）的生物测定指导分级分离方法，我们在这里报告，N6.2 纯化的脂质诱导类似于迁移（mig）DC 的转录特征。基于 RNAseq 的分析表明，用总脂质刺激的 BMDC 上调成熟-迁移相关基因 、 、 、 以及包括 、 、 、 、 、 和 在内的免疫调节基因。定量逆转录（qRT）-PCR 分析表明，PL 是触发 BMDC 反应的生物活性脂质。阻断表面 Toll 样受体（TLR）2 的抗体导致 PL 介导的促炎基因 的上调增加。非经典 NF-κB 途径的 IKKα 激酶的化学抑制特异性限制了 和 的上调。表型上，PL 刺激的 BMDC 表现出不成熟的表型，表面 ICAM-1 显著增加。这项研究提供了关于革兰氏阳性、肠道微生物衍生的磷脂对固有免疫反应的免疫调节能力的见解。
