PO.IM02.03 · 免疫学
母体肥胖促进子代肠道菌群失调、CD4⁺ T细胞重编程和前列腺癌增加
Maternal obesity promotes gut dysbiosis, CD4⁺ T-cell reprogramming and increased prostate cancer in offspring
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
母体肥胖（MO）是一个日益受到全球关注的问题，与子代的长期疾病风险相关，并可能也增加前列腺癌易感性，尽管其机制仍不清楚。我们检验了MO诱导的肠道菌群失调是否促进雄性子代的前列腺癌并重编程免疫功能。使用TRAMP-C1同种异体移植模型，我们评估了饲喂对照饮食或致肥饮食（OID）的母鼠所生雄性子代。通过16S rRNA测序和SCFA分析评估肠道菌群。使用抗生素清除和粪便微生物移植（FMT）检验因果关系，并使用部分水解瓜尔胶（PHGG）的益生元干预进一步研究微生物群调节。使用配对的RNA-seq和ATAC-seq分析活化的脾脏T细胞。MO增加了成年子代的前列腺肿瘤负荷，并诱导了以α多样性降低和粪便丁酸显著降低为特征的肠道菌群失调。肠道菌群清除逆转了MO诱导的肿瘤生长增加，而来自MO子代的FMT将促肿瘤表型转移给了对照小鼠。MO诱导了特异性针对CD4⁺ T细胞而非CD8⁺ T细胞的深度免疫重编程。RNA-seq数据揭示了Th2和促炎通路的激活，包括Th17分化（NES 1.96，p.adj 0.009）和JAK-STAT信号（NES 2.1，p.adj 0.0009）。我们还观察到抗原呈递（NES -2.24，p.adj 0.0007）和干扰素信号程序（NES -3.4，p.adj 8.39E-06）的降低，表明IFN驱动的激活受损。21个基因座表现出一致的染色质（ATAC-seq）和转录重塑，包括Th1分化调节因子Zbtb10和Ifrd1的抑制。这些分子变化在体内表现为脾脏中Th2（GATA3⁺）和Th17（RORγ⁺）细胞增加、Th1（Tbet⁺）细胞减少，以及肿瘤中CD8⁺IFNγ⁺细胞毒性受损。抗生素清除部分正常化了炎症特征，表明肠道菌群失调促成但不能完全解释MO驱动的免疫重塑。这些发现提示持久的表观遗传学改变与微生物组驱动的信号存在联合效应。增加SCFA产生的益生元PHGG减少了MO子代的肿瘤生长，证明微生物组靶向干预能够减轻MO诱导的癌症易感性。总体而言，我们的数据表明MO与子代前列腺癌风险的微生物群依赖性增加相关，同时伴有持久且表观遗传印记的CD4⁺ T细胞程序。
查看英文原文 English abstract
Maternal obesity (MO) is a growing global concern linked to long-term disease risk in offspring and may also increase prostate cancer susceptibility, although the mechanisms remain unclear. We tested whether MO-induced gut dysbiosis promotes prostate cancer in male offspring and reprograms immune function. Using a TRAMP-C1 allograft model, we evaluated male offspring from dams fed a control diet or an obesity-inducing diet (OID). Gut microbiota was assessed by 16S rRNA sequencing and SCFA profiling. Causality was tested using antibiotic ablation and fecal microbiota transplantation (FMT), and microbiota modulation was further examined using a prebiotic intervention with partially hydrolyzed guar gum (PHGG). Activated splenic T cells were analyzed with paired RNA-seq and ATAC-seq. MO increased prostate tumor burden in adult offspring and induced gut dysbiosis marked by reduced alpha-diversity and significantly lower fecal butyric acid. Gut microbiota ablation reversed the MO-induced increase in tumor growth, whereas FMT from MO offspring transferred the pro-tumor phenotype to control mice. MO induced profound immune reprogramming that was specific to CD4⁺ T cells and not observed in CD8⁺ T cells. RNA-seq data revealed activation of Th2 and pro-inflammatory pathways, including Th17 differentiation (NES 1.96, p.adj 0.009) and JAK-STAT signaling (NES 2.1, p.adj 0.0009). We also observed reduced antigen-presentation (NES -2.24, p.adj 0.0007) and interferon-signaling programs (NES -3.4, p.adj 8.39E-06), indicating impaired IFN-driven activation.Twenty-one loci exhibited concordant chromatin (ATACseq) and transcriptional remodeling, including repression of Zbtb10 and Ifrd1 , regulators of Th1 differentiation. These molecular changes manifested in vivo as increased Th2 (GATA3⁺) and Th17 (RORgamma⁺) cells and reduced Th1 (Tbet⁺) cells in spleen, and impaired CD8⁺IFNgamma⁺ cytotoxicity in tumors. Antibiotic ablation partially normalized inflammatory signatures, indicating that gut dysbiosis contributes to-but does not fully explain-MO-driven immune remodeling. These findings suggest a combined effect of long-lasting epigenetic alterations and microbiome-driven signals. Prebiotic PHGG, which increases SCFA production, reduced tumor growth in MO offspring, demonstrating that microbiome-targeted interventions can mitigate MO-induced cancer susceptibility. Overall, our data indicates that MO is associated with a microbiota-dependent increase in prostate cancer risk in offspring, alongside a durable and epigenetically imprinted CD4⁺ T-cell program.
利益披露 Disclosure
F. D. Andrade, None..
L. Jin, None..
M. Özgül Önal, None..
L. Hilakivi-Clarke, None.