Characterization of Microbiota Metabolites Involved in the Gut-Brain Axis.
Alden, Nicholas.
2019
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The gut microbiota
have been the subject of vigorous research in the last 20 years. Perturbation of normal
microbial communities, in the gut have been linked with negative health outcomes
including diabetes, obesity, and opportunistic pathogen infections such as Clostridium
difficile. More recently, connections between these microorganisms and the host's brain
have been proposed with implications ... read morein research on mental health and development. The
route through which this communication is affected has not been fully elucidated. In
this dissertation, I will describe our recent efforts to understand one possible route
of communication between the microbiota and host: direct transport of microbial
metabolites from the gut to the brain via the bloodstream. To accomplish this, we
developed a novel workflow that applies biological context for the annotation of
metabolites in untargeted liquid chromatography mass spectrometry metabolomics
experiments. This workflow that we dubbed Biologically Consistent Annotation of
Metabolomics Data, or BioCAn, outperforms existing metabolomics annotation tools by
proposing more correct annotations for metabolites. Using this workflow, we profiled
metabolites associated with the microbiota in the gut, blood, and brain of mice treated
with an antibiotic cocktail to eliminate the bacteria in their gut. Through this
approach, we confirmed existing studies that have linked the microbiota to carbohydrate
metabolism and metabolism of plant secondary metabolites. In addition, we observed
possible evidence of leucine biosynthesis by mouse microbiota which has not been
previously described in the literature. Finally, we selected 4 metabolites that were
significantly depleted or significantly accumulated in the gut of antibiotic treated
mice indicating an association with the microbiota to test in an in vitro model of the
blood-brain barrier (BBB). These metabolites were also detected in the serum and brain
and are known participants in microbial metabolism. One of these metabolites,
p-hydroxyphenyllactic acid (p-HPLA), was shown to be moderately permeable across the BBB
compared to caffeine, a metabolite that is known to be highly permeable. These results
suggest microbial-associated metabolites have the capacity to travel from the gut to the
brain where they may affect function.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Chemical and Biological Engineering.
Advisor: Kyongbum Lee.
Committee: Arul Jayaraman, David Kaplan, and Nikhil Nair.
Keyword: Chemical engineering.read less - ID:
- fn107b86q
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