Wang Ze, Huang Yi, Guo Ziyu, Sun Jianhua, Zheng Guoquan
Shihezi University School of Medicine, Shihezi University, Shihezi 832003, China.
Nankai University School of Medicine, Nankai University, Tianjin 300071, China.
Int J Mol Sci. 2025 Aug 16;26(16):7919. doi: 10.3390/ijms26167919.
Ankylosing spondylitis (AS) displays wide inter-patient variability that is not accounted for by HLA-B27 alone, suggesting that additional immune and metabolic modifiers contribute to disease severity. Using a genetically matched design, we profiled peripheral blood mononuclear cells from two brother pairs discordant for AS severity and one healthy brother pair. Strand-specific RNA-seq was analyzed with a family-blocked DESeq2 model, while untargeted metabolites were quantified using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). Differential features were defined as follows: differentially expressed genes (DEGs) (|logFC| ≥ 1 and FDR < 0.05) and metabolites (VIP > 1, FC ≥ 1.2, and BH-adjusted < 0.05). Pathway enrichment was performed with KEGG and Gene Ontology (GO). A total of 325 genes were differentially expressed. Type I interferon and neutrophil granule transcripts (e.g., , , ) were markedly up-regulated, whereas mitochondrial β-oxidation genes (, , ) were repressed. Metabolomics revealed 110 discriminant features, including 25 MS/MS-annotated metabolites. Primary bile acid intermediates were depleted, whereas oxidized fatty acid derivatives such as 12-Z-octadecadienal and palmitic amide accumulated. Spearman correlation identified two antagonistic modules (i) interferon/neutrophil genes linked to pro-oxidative lipids and (ii) lipid catabolism genes linked to bile acid species that persisted when severe and mild siblings were compared directly. Enrichment mapping associated these modules with viral defense, neutrophil degranulation, fatty acid β-oxidation, and bile acid biosynthesis pathways. This sibling-paired peripheral blood mononuclear cell (PBMC) dual-omics study delineates an interferon-driven lipid-bile acid axis that tracks AS severity, supporting composite PBMC-based biomarkers for future prospective validation and highlighting mitochondrial lipid clearance and bile acid homeostasis as potential therapeutic targets.
强直性脊柱炎（AS）在患者之间表现出很大的变异性，仅HLA - B27无法解释这种变异性，这表明其他免疫和代谢调节因子也会影响疾病的严重程度。我们采用基因匹配设计，对两对AS严重程度不一致的兄弟和一对健康兄弟的外周血单个核细胞进行了分析。使用家族阻断DESeq2模型分析链特异性RNA测序，同时使用气相色谱 - 质谱联用（GC - MS）和液相色谱 - 质谱联用（LC - MS）对非靶向代谢物进行定量。差异特征定义如下：差异表达基因（DEGs）（|logFC|≥1且FDR < 0.05）和代谢物（VIP > 1，FC≥1.2且BH校正 < 0.05）。使用KEGG和基因本体（GO）进行通路富集分析。共有325个基因差异表达。I型干扰素和中性粒细胞颗粒转录本（如 ， ， ）显著上调，而线粒体β - 氧化基因（ ， ， ）受到抑制。代谢组学揭示了110个判别特征，包括25个经MS/MS注释的代谢物。初级胆汁酸中间体减少，而氧化脂肪酸衍生物如12 - Z - 十八碳二烯醛和棕榈酰胺积累。Spearman相关性分析确定了两个拮抗模块：（i）与促氧化脂质相关的干扰素/中性粒细胞基因，以及（ii）与胆汁酸种类相关的脂质分解代谢基因，在直接比较重度和轻度患者的兄弟姐妹时，这些基因仍然存在差异。富集图谱将这些模块与病毒防御、中性粒细胞脱颗粒、脂肪酸β - 氧化和胆汁酸生物合成途径相关联。这项基于兄弟姐妹配对的外周血单个核细胞（PBMC）的双组学研究描绘了一条干扰素驱动的脂质 - 胆汁酸轴，该轴与AS严重程度相关，支持基于PBMC的复合生物标志物用于未来的前瞻性验证，并突出线粒体脂质清除和胆汁酸稳态作为潜在的治疗靶点。
