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

The National Institutes of Health National Institute on Aging awarded $681,020 to Magee-Womens Research Institute and Foundation on June 15, 2026, under the Aging Research program (CFDA 93.866) to investigate microbial regulation of type 2 immunity in ovarian tissue remodeling and fibrosis. The research challenges the paradigm that reproductive decline results from inevitable follicle depletion, instead identifying ovarian tissue fibrosis as an environmentally modifiable process driven by dysregulated immune signaling. Studies reveal that gut microbiota established during critical early-life windows program immune circuits determining whether ovarian aging follows protective or pathological trajectories. Mice lacking a microbiota demonstrate premature reproductive aging with diminished ovarian reserve, compromised fertility, excessive interleukin-33 expression, expanded type 2 immune cells, and pathological collagen deposition, while microbial colonization at critical periods rescues these phenotypes. The research will employ single-cell immune profiling to identify specific immune populations driving IL-33-mediated tissue remodeling. Three specific aims address whether stromal or oocyte IL-33 drives fibrosis, define the immune cascade mediating IL-33-driven fibrosis, and validate microbiota-targeted interventions. Expected outcomes include identification of fundamental mechanisms by which environmental factors program immune circuits governing tissue aging and evidence that reproductive aging is modifiable rather than predetermined. Performance occurs in Pittsburgh, Pennsylvania, with a period of performance through February 28, 2031.

Abstract

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.