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Excess dietary sugar directly alters epithelial metabolism and macrophage polarization resulting in lethal colitis

Burr, Ansen (2022) Excess dietary sugar directly alters epithelial metabolism and macrophage polarization resulting in lethal colitis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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
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
CreatorsEmailPitt UsernameORCID
Burr, Ansenahb49@pitt.eduahb490000-0003-2524-897X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorHand, Timothyhandt@pitt.eduhandt
Committee ChairKaplan, Dandankaplan@pitt.edudankaplan
Committee MemberPiganelli, Jonjdp51@pitt.edujdp51
Committee MemberGottschalk, Rachelrachel.gottschalk@pitt.edurachel.gottschalk
Committee MemberMonga, Paulsmonga@pitt.edusmonga
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 2023 05:15


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