Burr, Ansen
(2022)
Excess dietary sugar directly alters epithelial metabolism and macrophage polarization resulting in lethal colitis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The intestinal barrier is exposed to trillions of bacteria and dietary metabolites every day, requiring both continuous renewal of the epithelium and surveillance by resident immune cells. As the first line of cellular defense, intestinal epithelium must regenerate every 3-5 days via intestinal stem cells (ISCs) to maintain barrier integrity, especially after inflammatory damage. Macrophages are critical first responders when the barrier is breached and must play a balancing act between eradicating threats to the host while also maintaining an environment that promotes healing. Recent studies have explored how diet can alter not only the microbiome and corresponding immune responses, but also have direct effects on host cells that influence proliferative and inflammatory responses. Given the significant increase in consumption of processed foods over the last two hundred years, we were interested in how excess dietary sugar affects mouse models of colitis.
We hypothesized that expansion of sucrose-consuming bacteria would drive a pro-inflammatory intestinal immune response, exacerbating disease. However, we found that sugar-induced exacerbation of colitis was lymphocyte-independent, rather, sugar reduced the number of M2 colonic macrophages and reduced the proliferative gene signature of ISCs. Using 3-dimensional colonoids, we demonstrated sugar directly inhibits colonoid development and alters metabolic pathways. Restoring metabolic flux of glycolytic metabolites by inhibiting pyruvate dehydrogenase kinase rescued sugar-impaired colonoid development. We validate these effects in
v
vivo using a mouse-model fed high-sucrose (HS) or high-fiber diets. Crypts isolated from HS-fed mice have an increased glycolytic response, yet also exhibit greater spare respiratory capacity, or unused oxidative potential, demonstrating inefficient glucose utilization for oxidative respiration. To recapitulate the rapid proliferative response of developing colonoids, we treated mice with dextran sodium sulfate (DSS) to induce colonic damage. Lineage tracing experiments showed reduced number and migration of daughter cells after DSS in mice fed HS. As a result, mice fed a HS diet failed to repair DSS-induced colonic damage, resulting in lethal intestinal pathology. Our results indicate that short-term, excess dietary sugar can directly inhibit epithelial proliferation in response to damage and may inform diets that better support the treatment of acute intestinal injury.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
4 November 2022 |
| Date Type: |
Publication |
| Defense Date: |
13 July 2022 |
| Approval Date: |
4 November 2022 |
| Submission Date: |
26 July 2022 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
214 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Mucosal Immunology, IBD, metabolism, regeneration |
| Date Deposited: |
04 Nov 2022 18:57 |
| Last Modified: |
04 Nov 2022 18:57 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43386 |
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