Platform for Translating Microbiome Studies into Clinically Relevant Applications
(contingent on NCATS approval)
Using trans-generational gnotobiotic mice by transplanting healthy microbiomes and then introducing challenges, thus quantifying original microbiome effects without being confounded by disease or treatment disruptions
The introduced challenges will mimic a state of natural microbiome exposure followed by disease elicitation. This strategy will allow isolation of phenotypes that are clearly attributed to the gut microbiome, and in establishing contrasting mouse groups to be used for mechanistic studies.
Standard Approach
The human gut microbiome plays an important role in human health, progression of diseases, and response to therapy. To study effects of the human microbiome on the host, scientists use the gnotobiotic mouse model in which germ-free mice are colonized with different microbiomes then profiled under specific conditions.
There are several limitations to this model. First, most phenotypes studied using this model have been observed when comparing the effects of gut microbiomes derived from diseased and healthy humans. Thus, the actual mouse test is done using a microbiome state that is collected after the disease has been established in the human host, where microbiome composition is affected by the disease itself and by treatment, confounding cause and effect. Second, most phenotypes studied using this model have been observed after colonization of adult germ-free mice with the test microbiomes.
Thus, the studied mice develop to adulthood completely germ free before being exposed to a selected microbiome via transplantation, missing a crucial window of microbiome-host interaction during early development with clear importance for immune, metabolic and neurological maturation. These two major limitations of the state-of-the-art model have caused many microbiome studies to lack reproducibility, biological relevance, and mechanistic understanding, ultimately preventing us from successfully translating them into human applications.
Novel Approach
We propose to develop a new mouse model that overcomes these limitations, where we quantify host phenotypes that are bestowed by healthy microbiomes from diverse human donors as opposed to the typical healthy versus diseased comparison, and we study these effects in a trans-generational manner that allows the contribution of microbiome effects during early development.
We will generate transgenerational gnotobiotic mouse lines colonized with gut microbiome communities from healthy humans, then profile these lines extensively after exposure to diverse challenges, including bacterial infection, cancer, dietary challenges and gut inflammation. In a small feasibility study with four such lines, we have excitingly observed significant contribution of the microbiome to variability in the response to cancer, metabolic disease, and bacterial infection, establishing realistic bases for mechanistic studies.
Our overarching goal is to develop a disease-agnostic platform for microbiome research, to enable the elucidation of molecular mechanisms driving host phenotypes and to inform clinically relevant applications. If successful, we hope that this approach would be widely adapted in the field .
Project Aims
1. Establish the reproducibility of the mouse model across later generations.
2. Compare the results of the trans-generational mouse model to those of the current state of the art.
Element E3 Investigator
Mohamed S. Donia, PhD
Associate Professor of Molecular Biology
Department of Molecular Biology
Princeton University
donia@princeton.edu
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