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Mucosal Landscape of the Gut: Development and Application of 3D Imaging Tools for Interrogation of Host-Microbe Mucosal Interface in Mice and Humans

Citation

Poceviciute, Roberta (2020) Mucosal Landscape of the Gut: Development and Application of 3D Imaging Tools for Interrogation of Host-Microbe Mucosal Interface in Mice and Humans. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/83t8-mv42. https://resolver.caltech.edu/CaltechTHESIS:09012020-121925511

Abstract

Mammalian gastrointestinal tract is inhabited by trillions of microbes that, in number, amount to the total number of cells in the human body. These microbes, collectively known as microbiota, are found on the skin and in body cavities, and come in close contact with the host on mucosal surfaces. Here, pivotal host-microbe interactions likely take place because close proximity to the host enhances the uptake of microbial metabolites by the host and enables direct contact. To aid the investigation of these interactions, we developed an imaging technology that preserves fragile mucosal structure, enables to explore large areas of mucosal surface, and image the structurally and biochemically complex host-microbe interface in 3D in a mouse. However, 3D imaging presents challenges, such as slow transport of large molecular weight reagents and low signal/background ratio at depth, and these challenges are further exacerbated in particularly thick samples, such as small intestinal samples with long finger-like villus protrusions and thick human gut samples. Therefore, we further advanced our technology to improve sensitivity and specificity at depth, and we have taken steps to translate our technology to precious resected human gut samples from inflammatory bowel disease patients. Finally, we applied these tools to interrogate Enterobacteriaceae – Bacteroidaceae interactions in the small intestine of a mouse weakened by malnutrition. Using complementary tools, we have first determined that Bacteroidaceae required malnutrition to increase in number in the jejunum digesta, whereas Enterobacteriaceae required both malnutrition and Bacteroidaceae. With imaging, we visualized that in malnourished mice not exposed to Enterobacteriaceae and Bacteroidaceae, bacteria were effectively cleared after digesta passage, whereas in exposed mice bacterial retention was detected, suggestive of bacterial adherence to and colonization of mucosa. Finally, we detected a rare event of abundant bacterial colonization of small intestinal mucosa and captured in 3D.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:3D imaging, tissue clearing, gut microbiota, small intestine, IBD, malnutrition, environmental enteropathy
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemical Engineering
Thesis Availability:Not set
Research Advisor(s):
  • Ismagilov, Rustem F.
Thesis Committee:
  • Mazmanian, Sarkis K. (chair)
  • Leadbetter, Jared R.
  • Brady, John F.
  • Ismagilov, Rustem F.
Defense Date:16 July 2020
Funders:
Funding AgencyGrant Number
Defense Advanced Research Projects Agency (DARPA)BRICS HR0011-15-C-0093
NSFMIKS 1137089
Army Research Office (ARO)MURI W911NF-17-1-0402
Defense Advanced Research Projects Agency (DARPA)CLIPS HR0011-17-2-0037
Kenneth Rainin Foundation Innovator Award2018–1207
Army Research Office (ARO)ICB W911NF-09-D-0001
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
Chemical Engineering Graduate Student FellowshipUNSPECIFIED
Record Number:CaltechTHESIS:09012020-121925511
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:09012020-121925511
DOI:10.7907/83t8-mv42
ORCID:
AuthorORCID
Poceviciute, Roberta0000-0002-6649-2170
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13861
Collection:CaltechTHESIS
Deposited By: Roberta Poceviciute
Deposited On:15 Sep 2020 15:50
Last Modified:13 Oct 2021 23:01

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