Sunday, May 11, 2025
5/11/2025
New mouse models to investigate host-microbe dynamics in physiology and innate immunity - 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 establish valuable models to better understand host-mediated mechanisms to shape the gut microbiota, contributing insights on intestinal innate mucosal immunity, as well as providing foundations for application to other disciplines.
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