MECHANISMS OF ALTERATION OF GASTROINTESTINAL MOTILITY BY GUT MICROBIOTA

Project: Research project

Description

Abstract
The human gut harbors trillions of microorganisms that benefit the host by enabling harvest of nutrients/energy
from otherwise indigestible components of our diet. Remarkably, the complex signaling between microbes and
their human host, and the resulting impact on normal physiological functions, are still poorly understood.
Gastrointestinal (GI) motility and the gut microbiota are clearly associated and environmental factors, including
diet, can modify the relationship between GI motility and the gut microbiota. Serotonin (5-hydroxytryptamine; 5-
HT) released from the enterochromaffin (EC) cells serves as an important paracrine messenger involved in
motor and sensory transduction modulating GI motility. My preliminary studies strongly suggest the gut
serotonergic pathway as a target for gut microbiota. My overall hypothesis is that gut microbiota alters GI
motility in diet-dependent manner by release of specific metabolites, including tryptamine, which affect the gut
serotonergic pathway. I will use germ-free (GF), gnotobiotic (defined/simplified microbiota), and humanized
(ex-GF colonized by human-derived microbes) mice to address physiological effects of human gut microbes on
the host in a mouse model. As GF mice completely lack microbiota they can be colonized with defined
communities of bacteria to create distinct states of colonization. In specific aim 1, I will explore the effect of
microbiota on the gut serotonergic pathway in GF and humanized mice. In specific aim 2, I will determine the
differential effect on GI motility of decreasing the complexity of dietary polysaccharides with resulting alteration
in gut microbiota. Finally, in specific aim 3, I will investigate the role of microbial metabolites such as tryptamine
in modulating 5-HT biosynthesis and modulating GI motility. I have developed both ex vivo (organ bath) and in
vivo (colonic manometry) physiological techniques as well as a screening strategy to use EC-like cell lines to
test metabolites for their effect on synthesis and release of 5-HT using ultra performance liquid
chromatography coupled with mass spectrometry. My previous research training in GI physiology delineating
complex mechanisms regulating GI motility, as well as my recent training in microbial ecology as it relates to
host function, along with my clinical training in Gastroenterology with a specific focus on GI motility disorders,
gives me the ability to address these biologically sound and clinically relevant questions. This career
development award will allow me to combine my skills in two very distinct areas of research,
Neurogastroenterology and Microbial Ecology, to address important aspects of human biology. My mentorship
team is comprised of Dr. Gianrico Farrugia at Mayo Clinic and Dr. Justin Sonnenburg at Stanford University;
both are internationally renowned in their areas of research and have a successful track record in training
young faculty. Dr. Gianrico Farrugia is an international leader in Neurogastroenterology, having made seminal
contributions in elucidating roles of interstitial cells of Cajal in GI motility disorders. His long record of
successful mentorship is evidenced by mentorship of 31 fellows. Dr. Sonnenburg is an evolutionary minded
glycobiologist who is internationally renowned for his ground-breaking work on carbohydrate utilization by gut
microbes and the application of gnotobiotic mouse models to understanding microbial interactions in the gut.
Both of their expertise will be invaluable for this cross-disciplinary project.
StatusFinished
Effective start/end date3/3/143/2/18

Funding

  • National Institutes of Health: $147,042.00
  • National Institutes of Health: $147,042.00
  • National Institutes of Health: $147,042.00

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Gastrointestinal Motility
Serotonin
Mentors
Microbiota
Germ-Free Life
Ecology
Diet
Enterochromaffin-like Cells
Research
Microbial Interactions
Enterochromaffin Cells
Interstitial Cells of Cajal
Gastrointestinal Microbiome
Manometry
Gastroenterology
Baths
Polysaccharides
Mass Spectrometry
Carbohydrates
Bacteria