# New mouse models to investigate host-microbe dynamics in physiology and innate immunity

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $240,500

## Abstract

Recent studies support the hypothesis that the host plays an active role in maintaining homeostatic symbiosis
with the gut microbiota. However, the host-specific mechanisms employed to sculpt the microbiota remain to
be fully elucidated, in part, due to shortcomings of current in vivo models. Data from our group and others
support that -defensins, abundant antimicrobial effector molecules of small-intestinal Paneth cells, help shape
the composition of the gut microbiota. Perturbations in Paneth cell function contribute to pathogenesis of
disease by disturbing the homeostatic balance of the microbiota (dysbiosis). Yet, little is known regarding the
role of Paneth cell effectors (e.g., -defensins) in mediating changes in the gut microbiota during dynamic
physiological (non-disease) processes. This proposal aims to develop two innovative mouse models valuable
for delineating host mechanisms that shape gut microbiota during processes intrinsic to mammalian biology.
During lactation, arguably one of the most strenuous physiological processes for mammals, intestinal biology
must adapt to the demands of reproductive biology. Our preliminary data demonstrate that in lactating dams,
rapid and dramatic changes in the small intestine at both the gross and molecular levels accompany a major
restructuring of gut-associated microbial communities. Concomitantly, during lactation a striking and
unsynchronized change in the expression of individual Paneth cell -defensins is observed at a scale far
greater than previously observed in other experimental settings, including enteric infection and inflammation.
We will address the hypothesis that during lactation, a period of extraordinary energy demand, a dramatic
alteration in α-defensin production drives changes in the microbiota that serve to benefit the dam (effective
energy harvest from foodstuffs). A corollary hypothesis that changes in the microbiota of the lactating dam
benefit the offspring (e.g., facilitation of vertical microbiota transmission) will be addressed in the future using
the model developed herein. Aim #1 will develop the lactating dam as a novel model to interrogate dynamic
and physiological host-microbiota interactions in mammals. Factors impacting dynamics of the host-microbe
interface will be systematically delineated to create a robust and reproducible model for study. Aim #2 will
develop a novel Paneth cell -defensin knockout mouse to explore the necessity of -defensins in driving
microbiota changes during lactation; this knockout model will also be invaluable to the field for other studies of
intestinal innate immunity. The paradigm of pronounced maternal intestinal remodeling during lactation and its
potential long-term influence on both maternal and offspring health has been largely unexplored. The
dynamically adapting intestine of the lactating dam may represent an ecosystem of host-microbe interactions
fundamental to mammalian life. Successful completion of these Aims will establ...

## Key facts

- **NIH application ID:** 10810507
- **Project number:** 1R21AI176012-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Charles L Bevins
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $240,500
- **Award type:** 1
- **Project period:** 2023-11-20 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810507

## Citation

> US National Institutes of Health, RePORTER application 10810507, New mouse models to investigate host-microbe dynamics in physiology and innate immunity (1R21AI176012-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10810507. Licensed CC0.

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