Platform for Translating Microbiome Studies into Clinically Relevant Applications
(contingent on NCATS approval)
Using trans-generational germ-free mice transplanted with healthy microbiomes and then exposed to different challenges, the original effects of the microbiome are measured without interference from disease or treatment-related changes.
The challenges will model natural microbiome exposure followed by disease development. This approach will help identify traits that are directly caused by the gut microbiome and create contrasting mouse groups for future mechanistic studies.
Standard Approach
The human gut microbiome — the community of microbes living in our intestines — has a major influence on health, disease, and how people respond to treatments. To study this, scientists often use special “germ-free” mice that are raised without any microbes. Researchers then introduce different human microbiomes into these mice and observe how the animals respond under controlled conditions. However, this approach has important limitations.
First, researchers usually compare microbiomes taken from healthy people and from people who already have a disease. By the time the microbiome is collected, the disease itself — as well as medications or other treatments — may have already changed the microbial community. This makes it difficult to tell whether the microbiome caused the disease or was simply altered by it.
Second, these experiments are typically done in adult germ-free mice. This means the mice grow up without any microbes and are only exposed to a microbiome later in life through transplantation. As a result, they miss a critical early-development period when microbes help shape the immune system, metabolism, and brain function.
Because of these limitations, many microbiome studies have been difficult to reproduce and may not fully reflect what happens in humans. This has slowed progress in understanding how the microbiome works and in developing effective microbiome-based therapies.
Novel Approach
We propose to create a new mouse model that addresses current limitations in microbiome research. Instead of comparing healthy and diseased microbiomes, we will study how healthy microbiomes from different human donors influence health outcomes. We will also examine these effects across generations to understand how the microbiome affects early development.
We will create germ-free mouse lines colonized with gut microbiomes from healthy human donors and study how they respond to different challenges, including bacterial infection, cancer, diet-related stress, and gut inflammation. In an initial pilot study using four mouse lines, we found that the microbiome significantly affected differences in responses to cancer, metabolic disease, and bacterial infection, showing strong potential for future mechanistic studies.
Our overall goal is to build a broadly applicable platform for microbiome research that is not limited to a single disease. This platform will help uncover the molecular mechanisms through which the microbiome shapes health and disease and could support future clinical applications. If successful, we expect this approach to be widely adopted by 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
>>View Bio