Identify the regulatory roles of intestinal secretory cell lineages during gut inflammation
Xu, Guanying Bianca
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https://hdl.handle.net/2142/127340
Description
Title
Identify the regulatory roles of intestinal secretory cell lineages during gut inflammation
Author(s)
Xu, Guanying Bianca
Issue Date
2024-11-12
Director of Research (if dissertation) or Advisor (if thesis)
Chen, Hong
Doctoral Committee Chair(s)
Pan, Yuan-Xiang
Committee Member(s)
Miller, Michael
Mei, Wenyan
Department of Study
Food Science & Human Nutrition
Discipline
Food Science & Human Nutrition
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Intestinal epithelial cells
Colon inflammation
Tuft cells
Enteroendocrine cells
EECs
Serotonylation
Abstract
This thesis systematically investigates the roles of secretory intestinal epithelial cells, specifically tuft cells and enteroendocrine cells (EECs), in colonic inflammation, revealing novel cellular and molecular dynamics. The initial study utilized IEC-specific Hnrnp I knockout mice to demonstrate significant upregulation of pro-inflammatory cytokines such as Il1β, Cxcl1, and Ccl2. This animal model was thus validated in studying colitis progression and highlighted the potential of dietary interventions, such as the modified (MOD) diet, to alleviate inflammation.
Subsequent research focused on tuft cells, revealing their role in mediating interactions between the intestinal epithelium and the immune system. This was characterized by L1CAM-mediated activation of type 2 innate lymphoid cells (ILC2s), which promoted secretion of Th2 cytokines IL4, IL6, and IL13, thus enhancing inflammatory responses. This pathway presents a potential target for therapeutic intervention, particularly in managing colon inflammation and cancer.
The third study emphasized the regulatory role of EECs during colon inflammation, noting a significant increase in NR4A1 expression, which triggered immediate early genes (IEGs) activating the ATF4-ATF3 stress response pathway. Notably, changes in serotonin dynamics, including increased levels and serotonylation, were observed, suggesting that serotonylation may regulate cellular stress responses and contribute to cell proliferation during inflammatory conditions.
Collectively, these findings illuminate the complex interplay of genetic, environmental, and dietary factors in modulating inflammatory responses in the colon, highlighting the significant roles of intestinal secretory cell lineages in orchestrating these responses through novel signaling pathways and interactions. The thesis shed light on potential therapeutic targets and suggests novel interventions, including the use of biologics and small molecule drugs, to modulate or ameliorate colon inflammation processes. Future research directions include pharmacological targeting of the L1CAM and NR4A nuclear receptor on certain epithelial cell types and exploring epigenetic regulation mechanisms such as serotonylation for therapeutic intervention treating either acute or chronic colitis.
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