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DTSTART;TZID=America/New_York:20241213T140000
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UID:48223-1734098400-1734105600@coe.northeastern.edu
SUMMARY:ChE PhD Dissertation Defense: Yuan Li
DESCRIPTION:Name:\nYuan Li \nTitle:\nEstablishing a Physiologically Relevant Upper Gastrointestinal In Vitro Model Incorporating Bile Salts and Simplified Commensal Microbial Consortium \nDate:\n12/13/2024 \nTime:\n2:00:00 PM \nCommittee Members:\nProf. Rebecca Carrier (Advisor)\nProf. Abigail Koppes\nProf. Erel Levine\nProf. Jiahe Li \nLocation:\nEXP 610-A \nAbstract:\nBacteria-epithelial-immune crosstalk plays crucial roles in intestinal physiology. Bile salts (BS) act as critical modulators of these interactions\, influencing health and disease. Tools for studying interactions between BS\, microbes\, and host cells within the human intestinal mucosa are lacking. \nIn this project\, we developed in vitro intestinal models for studying bacteria-epithelial-immune crosstalk. First\, the impacts of individual BS (sodium taurocholate\, NaTC; sodium glycochenodeoxycholate\, NaGCDC; and sodium tauroursodeoxycholate\, NaTUDC) on human primary intestinal epithelial monolayer co-cultures with Escherichia coli were studied. We observed that high BS concentrations disrupted barrier function\, as evidenced by reduced transepithelial electrical resistance (TEER)\, with NaGCDC causing the most significant damage. Interestingly\, the addition of phyosphatidylcholine (PC) and E. coli were observed to mitigate the BS-induced monolayer TEER reductions. \nTo enhance the model’s physiological relevance\, we next incorporated a simplified model bile (including NaTC\, NaGCDC\, NaTUDC\, and PC)\, an apical hypoxic environment\, dendritic cells\, and a simplified commensal microbial consortium (Streptococcus mitis\, Clostridium bifermentans\, Prevotella melaninogenica\, and Bifidobacterium longum). 4/1 mM concentrations of BS/PC micelles were observed to damage the epithelial barrier under hypoxic but not normoxic conditions. However\, incorporation of the bacterial consortium protected the epithelium from BS/PC – associated damage. Furthermore\, the presence of BS/PC alleviated barrier damage and inflammatory response induced by co-culture with the bacterial consortium\, potentially in part through modulation of bacterial growth. In addition\, we observed thicker mucus layers not only impacted the growth of consortium strains\, resulting in enhanced growth of the probiotic Bifidobacterium longum\, but also reduced inflammatory responses to bacteria and BS/PC-induced epithelial damage. In general\, our in vitro model revealed that commensal microbes mitigate BS and BS/PC toxicity to the epithelial monolayer\, while BS helps alleviate monolayer damage and inflammatory response caused by commensal microbes. \nIn preparation for transferring the developed model from static cell culture inserts to microfluidic devices for mimicking intestinal fluidic stimuli and enabling facile visualization of the mucosal interface\, we designed a gut-on-chip platform with a vertical hydrogel-cultured epithelial monolayer. Three hydrogels (crosslinked collagen type I\, PEG-VS\, and PEG-SG-PLL) were evaluated for compatibility with human primary intestinal epithelial stem cells (HPIESCs). Collagen type I and PEG-SG-PLL were found to support HPIESC adhesion and monolayer formation\, but collagen lost structural integrity under flow. PEG-VS\, though functionalized with cell-binding peptides\, only enabled partial monolayer formation. Notably\, encapsulating organoids in PEG-VS near the gel-medium interface enabled crypt-like monolayer formation through organoid-driven gel re-structuring. Furthermore\, we found that flow enhanced epithelial differentiation on PEG-SG-PLL and PEG-VS (encapsulation method)\, leading to thicker monolayers with taller columnar cells compared to static culture. These findings show PEG-SG-PLL and PEG-VS are good candidates for enabling transition of the bile-intestinal model to microfluidic chip platforms.
URL:https://coe.northeastern.edu/event/che-phd-dissertation-defense-yuan-li/
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