Microbial regulation of type 2 immunity in ovarian tissue remodeling and fibrosis

Early menopause and accelerated reproductive aging affect millions of women worldwide, dramatically increasing risks for cardiovascular disease, bone fractures, and premature death. This burden intensifies as societal trends toward delayed childbearing create unprecedented barriers to conception, fertility, and systemic health. Challenging the longstanding paradigm that reproductive decline represents inevitable follicle depletion, this research identifies ovarian tissue fibrosis as an active, environmentally modifiable process driven by dysregulated immune signaling. Our studies reveal that gut microbiota established during critical early-life windows program immune circuits that determine whether ovarian aging follows protective or pathological trajectories. Mice lacking a microbiota show premature reproductive aging characterized by a diminished ovarian reserve, compromised fertility, excessive interleukin-33 (IL-33) expression, expansion of type 2 immune cells, and pathological collagen deposition, while microbial colonization at critical periods rescues these phenotypes. Using single-cell immune profiling, we identify the specific immune populations driving IL-33-mediated tissue remodeling in ovaries. The central hypothesis is that microbial-derived signals calibrate IL-33 signaling to prevent pathological type 2 immune activation, thereby maintaining tissue homeostasis and preserving reproductive function. Three specific aims will: (1) determine whether stromal or oocyte IL-33 drives fibrosis; (2) define the immune cascade mediating IL-33-driven fibrosis; and (3) validate microbiota-targeted interventions. This research establishes fundamental mechanisms by which environmental factors program immune circuits that govern tissue aging, providing the first evidence that reproductive aging is modifiable rather than predetermined. Expected outcomes include identification of specific bacterial taxa and metabolites that prevent ovarian fibrosis, mechanistic understanding of immune-stromal interactions driving tissue remodeling, and translatable dietary interventions for clinical implementation. By demonstrating that reproductive aging can be prevented through targeted interventions during critical developmental windows, this work fundamentally reframes approaches to women's health from treatment-focused to prevention-focused, offering evidence-based strategies to extend reproductive healthspan and reduce the substantial disease burden associated with premature menopause. Project Number: 1R01AG100456-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Eldin Jasarevic | Institution: MAGEE-WOMEN'S RES INST AND FOUNDATION, Pittsburgh, PA | Award Amount: $681,020 | Activity Code: R01 | Study Section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER] View on NIH RePORTER: https://reporter.nih.gov/project-details/11347494