Low grade, chronic inflammation is a critical risk factor for immunologic dysfunction including autoimmune diseases. However, the multiplicity of complex mechanisms and lack of relevant murine models limit our understanding of the precise role of chronic inflammation. To address these hurdles, we took advantage of multi-omics data and a unique murine model with a low but chronic expression of IFN-γ, generated by replacement of the AU-rich element (ARE) in the 3’ UTR region of IFN-γ mRNA with random nucleotides. Herein, we demonstrate that low but differential expression of IFN-γ in mice by homozygous or heterozygous ARE replacement triggers distinctive gut microbial alterations, of which alteration is female-biased with autoimmune-associated microbiota. Metabolomics data indicates that gut microbiota-dependent metabolites have more robust sex-differences than microbiome profiling, particularly those involved in fatty acid oxidation and nuclear receptor signaling. More importantly, homozygous ARE-Del mice have dramatic changes in tryptophan metabolism, bile acid and long-chain lipid metabolism, which interact with gut microbiota and nuclear receptor signaling similarly with sex-dependent metabolites. Consistent with these findings, nuclear receptor signaling, encompassing molecules such as PPARs, FXR, and LXRs, was detectable as a top canonical pathway in comparison of blood and tissue-specific gene expression between female homozygous vs heterozygous ARE-Del mice. Further analysis implies that dysregulated autophagy in macrophages is critical for breaking self-tolerance and gut homeostasis, while pathways interact with nuclear receptor signaling to regulate inflammatory responses. Overall, pathway-based integration of multi-omics data provides systemic and cellular insights about how chronic inflammation driven by IFN-γ results in the development of autoimmune diseases with specific etiopathological features.

低度、慢性炎症是包括自身免疫性疾病在内的免疫功能障碍的关键危险因素。然而，复杂机制的多样性和相关小鼠模型的缺乏限制了我们对慢性炎症确切作用的理解。为了解决这些障碍，我们利用了多组学数据和一个独特的小鼠模型，该模型具有 IFN-γ 的低但慢性表达，通过替换 IFN-γ 3' UTR 区域中富含 AU 的元件 (ARE) 生成。带有随机核苷酸的γ mRNA。在此，我们证明了通过纯合子或杂合子 ARE 替代在小鼠中低但差异化的 IFN-γ 表达触发了独特的肠道微生物改变，其中改变是女性偏向于自身免疫相关微生物群的。代谢组学数据表明，肠道微生物群依赖性代谢物比微生物组分析具有更强大的性别差异，尤其是那些涉及脂肪酸氧化和核受体信号传导的代谢物。更重要的是，纯合 ARE-Del 小鼠在色氨酸代谢、胆汁酸和长链脂质代谢方面发生了巨大变化，它们与肠道微生物群和核受体信号相互作用，与性别依赖性代谢物类似。与这些发现一致，核受体信号传导，包括 PPARs、FXR 和 LXRs 等分子，在比较雌性纯合子与杂合子 ARE-Del 小鼠之间的血液和组织特异性基因表达时，可检测为顶级规范途径。进一步的分析表明，巨噬细胞中失调的自噬对于打破自我耐受和肠道稳态​​至关重要，而通路与核受体信号相互作用以调节炎症反应。总体而言，基于通路的多组学数据整合提供了关于 IFN-γ 驱动的慢性炎症如何导致具有特定病因病理学特征的自身免疫性疾病发展的系统和细胞见解。