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.

Public Health Relevance

There are nearly trillions of bacteria in our intestines which play an important part in keeping us healthy. As a part of this project, I will find out how these bacteria control intestinal motility and movement of nutrients and bacteria along the intestines. I will focus on the serotonin pathway in the intestinal wall as a target system for the effect of these bacteria. I will also find out how diet drives the kind of bacteria present in our intestine, and how this affects intestinal motility. Finally, I aim to find out which specific substances produced by bacteria help to regulate normal intestinal motility. Overall, this has huge implications as we can engineer production of these substances by harmless bacteria and develop them as probiotics to regulate normal intestinal motility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK100638-01
Application #
8617551
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2014-03-03
Project End
2018-03-02
Budget Start
2014-03-03
Budget End
2015-03-02
Support Year
1
Fiscal Year
2014
Total Cost
$147,042
Indirect Cost
$10,892
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Grover, M; Kashyap, P C (2014) Germ-free mice as a model to study effect of gut microbiota on host physiology. Neurogastroenterol Motil 26:745-8
Williams, Brianna B; Van Benschoten, Andrew H; Cimermancic, Peter et al. (2014) Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe 16:495-503