Project Summary:
Chronic inflammation is a rising health issue that affects millions of people worldwide. Emerging evidence shows
that dysbiosis of the gut microbiota can lead to changes in the production of microbial-derived metabolites
(MDMs), which contribute to inflammation and the onset of inflammatory diseases, such as cancer, non-alcoholic
fatty liver disease, and inflammatory bowel syndrome. MDMs are absorbed into host circulation through the gut
and regulate immune responses. A key immune cell type at the interface of host-microbe interactions is
macrophages, which maintain tissue homeostasis, and are key contributors to chronic inflammation. To date,
few MDMs with well-studied cellular and molecular mechanisms describing the interplay between microbes and
our immune system are known. Using metabolomics data from a dietary intervention study that found distinct
immunological trajectories based on microbiota diversity, as well as data from a 176 gut microbiota strain library
we identified 18 human-immune associated MDMs. Here we aim to determine the regulatory role of MDMS on
the host immune system through a direct effect on macrophages. The impact of these MDMs on host molecular
pathways will be characterized using murine and human macrophage cells, NF¿B reporter lines, CRISPR/Cas9
systems, GPCR reporter lines and in vivo using IBD murine models (Aim1). On the microbe end, I will determine
the metabolic pathways responsible to produce these immune-associated MDMs and generate knock-out or
knock-in bacterial strains. I will perform a series of highly-controlled mouse experiments to determine the specific
microbial components responsible for MDMs immune modulating effects (Aim2). My previous experience in
immune regulation and animal models make me well-equipped to analyze and perform these technical
experiments, and the expertise in microbial genetics and metabolomics facilities honed by my mentoring team
make Stanford University an ideal location to learn the skills I will need to perform these experiments. Completion
of these aims will increase the understanding of the microbiota-host interaction during times of homeostasis and
acute or chronic inflammation, which will pave the way for the development of precision therapeutic strategies to
reduce chronic inflammation and prevent acute disease.
