Transgenerational effects of impaired metabolic adaptation during pregnancy

Principal Investigator

Scientific interest within the context of the graduate college:

We study development and function of the innate immune system, in particular of innate lymphoid cells (ILC). A current focus is to obtain a molecular understanding of how the innate immune system, by integrating environmental signals (such as those derived from nutrients, microbiota, circadian rhythm) contributes to tissue physiology. Recent studies have revealed ever more intriguing relationships between innate immune system components and basic developmental and biologic processes that are likely to reveal unsuspected pathways by which the immune system might be plumbed to improve health and healthspan. These lines of research have suggested new functions of the immune system for processes such as tissue homeostasis, morphogenesis, metabolism, regeneration and growth. Our research is developing by crossing boundaries of disciplines (immunology, microbiology, developmental biology, stem cell biology, tumor biology, regenerative medicine etc.) and is, by nature, highly interdisciplinary.

Project description:

Recent findings from our laboratory demonstrate that pregnancy and lactation are accompanied by significant intestinal growth in the mother. This physiological adaptation is essential to meet the increased metabolic demands associated with gestation and nursing. Importantly, we have identified that cues from the innate immune system are required to support this intestinal remodeling (manuscript in preparation).

In mouse models, impaired maternal intestinal growth and metabolic adaptation result in offspring with lower birth weights, which normalize within 2-3 weeks postpartum. However, these offspring exhibit a heightened susceptibility to inflammatory and metabolic diseases in adulthood. Using a TNF-driven model of inflammatory bowel disease (IBD), we observed that progeny of mothers with impaired intestinal adaptation have decreased frequencies of regulatory T cells (Tregs) and increased infiltration of pro-inflammatory neutrophils in affected tissues.

The mechanisms by which reduced nutrient availability during pregnancy and lactation predispose offspring to long-term inflammatory disorders are currently unknown. We hypothesize that impaired maternal metabolic adaptation leads to alterations in nutrient transfer, resulting in metabolic and epigenetic reprogramming of affected tissues (i.e., intestine) or the offspring’s immune system—particularly in primary immune organs such as the bone marrow and thymus.

In this proposal, we aim to define how impaired maternal intestinal and metabolic adaptation shapes the long-term immune landscape of the offspring.

Aim 1: Characterize the tissue architecture, transcriptional profiles, and epigenetic programs in offspring born to mothers with impaired intestinal growth and metabolic adaptation.  We will use high-resolution clonal lineage tracing, single-cell transcriptomics, and epigenomic profiling to identify changes in key metabolic and immune tissues over time.

Aim 2: Establish causal links between maternal metabolic perturbation and immune regulatory dysfunction in offspring. Using genetic and metabolic interventions, we will test whether restoring maternal intestinal adaptation can reverse immune dysregulation in the offspring and explore potential avenues for therapeutic modulation of inflammatory susceptibility.

This project will define a previously unappreciated link between maternal metabolic adaptation and immune programming in offspring. The outcomes are expected to provide foundational knowledge for developing early-life interventions to prevent chronic inflammatory diseases.

Application details

References