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 α-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 (RORγ+) cells and reduced Th1 (Tbet+) cells in spleen, and impaired CD8+IFNγ+ 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. Citation Format: Fabia de Oliveira Andrade, Lu Jin, Melike Özgül Önal, Seema Yadav, Sercan Kenanoglu, Christopher Staley, Leena Hilakivi-Clarke. Maternal obesity promotes gut dysbiosis, CD4+ T-cell reprogramming and increased prostate cancer in offspring abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2869.
Andrade et al. (Fri,) studied this question.