Abstract The prevalence of maternal obesity has gradually increased over successive decades, with over 50% of pre-pregnant women in the United States at present time classified as overweight or obese. Maternal obesity exerts deleterious effects on numerous pregnancy outcomes and imparts enduring negative health consequences on offspring, including elevating female offspring’s susceptibility to and mortality from breast cancer. Since the gut microbiome contributes to obesity and its adverse effects, and influences breast carcinogenesis, we investigated here whether gut dysbiosis, characterized by reduced fecal short-chain fatty acid (SCFA) levels, in mouse offspring born to diet-induced obese C57BL/6 dams (OB offspring) contributed to their higher E0771 mammary tumor burden, compared with control offspring. Fecal microbiota transplant (FMT) from OB offspring increased E0771 mammary tumor burden in control offspring host, suggesting a causality between gut dysbiosis and increased mammary tumorigenesis in OB offspring. Further, levels of SCFA receptor FFAR2 in CD4+ T cells, CD8+ T cells and Foxp3+ regulatory T cells in Peyer’s patches in gut and in CD8+ T cells in tumors were significantly lower in control offspring receiving FMT from OB offspring donor than from control offspring donor. To determine if increased mammary tumorigenesis in OB offspring can be reversed by increasing fecal SCFA production by dietary fiber, we employed the MMTV-PyMT mammary tumor model, in which mammary tumors develop “spontaneously” by 4 months of age. Our results indicated that MMTV-PyMT OB offspring exhibited significantly increased mammary tumor burden compared with controls. Supplementing offspring via drinking water with partially hydrolyzed guar gum (PHGG), a prebiotic fiber, exhibited significantly lower mammary tumorigenesis and higher fecal levels of SCFA propionic acid than OB offspring receiving maltodextrin (MDX) control. In contrast, control offspring receiving PHGG did not show changes in mammary tumorigenesis, although PHGG supplementation increased their fecal butyric acid levels. These results suggest that increased mammary tumorigenesis in OB offspring are linked to their gut dysbiosis. In addition, prebiotic fiber PHGG, consumed by adult OB offspring, reverses adverse effects of maternal obesity on both their gut microbiome and mammary tumorigenesis. Citation Format: Seema Yadav, Fabia Andrade, Melike Ozgul Onal, Sydney Shirk, Sercan Kenanogly, Christopher Staley, Leena Hilakivi-Clarke. Prebiotic fiber supplementation mitigates the effects of maternal obesity on offspring’s gut microbiome and mammary tumorigenesis 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 2864.
Yadav et al. (Fri,) studied this question.