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Late Breaking/Rapid Science Poster Session 2

(LB03-17-24) Patient-Derived Colon Organoids Reveal a Lipid-dependent Modulation of Epithelial Metabolism and Inflammation in Pediatric Ulcerative Colitis

Sunday, June 30, 2024
4:00 PM – 5:30 PM CT
Location: W185A-C - Poster Board 16
Disclosure(s):
Babajide A. Ojo, MS, PhD: No relevant financial relationship(s) with ineligible companies to disclose.


Objectives: Patient-derived organoids recapitulate several complexities of the parent tissue; however, it is unclear if and how they can model the metabolic impairments observed in the ulcerative colitis (UC) epithelium. This study aims to identify functional metabolic derangements unique to the pediatric UC epithelium and their link to inflammation using patient-derived colon organoids (colonoids).

Methods: We generated epithelial spheroids from rectal biopsies obtained from pediatric patients with endoscopically active UC (aUC) and non-IBD controls (C) [n=8/grp, median age 14.5 yrs]. Cryopreserved spheroids were thawed, passaged, and differentiated into colonoids for 3-5 days. We analyzed the bioenergetics of intact colonoids using Seahorse extracellular flux. We used gene expression analysis, imaging, flow cytometric, and spectrometric assays to assess nutrient usage and chemokine expression.

Results: We observed a profound increase in basal O2 consumption in aUC colonoids compared to C (120% increase, p = 0.0019) with no proportional increase in ATP. Accordingly, we found a 75% increase in proton leak (p = 0.036) in aUC compared to C. This hypermetabolic state in aUC was associated with chemokine overexpression (CXCL1, CCL2, CCL28, and CXCL11), impaired colonoid morphology, and reduced differentiation markers. Compared to C, we found enhanced lipid droplet accumulation in aUC colonoids (32% increase, p = 0.011), which supported their hyperactive OXPHOS. Palmitic acid exposure in C colonoids sufficiently impaired their morphology and upregulated CXCL1 expression in all patient colonoid lines, with personalized responses in other chemokines. Through transcriptomic and mechanistic assays, we found that the PPARA network contributes to lipid-dependent hypermetabolic phenotypes in aUC colonoids. Pharmacological inhibition of PPARA in aUC colonoids suppressed lipid accumulation leading to reduced hypermetabolic phenotypes, alleviated CXCL1 secretion, and improved differentiation markers.

Conclusions: Epithelial colonoids derived from patients with UC exhibited hypermetabolism supported by the metabolic oversupply of lipids during differentiation. Colonoids may serve as a preclinical human model for testing dietary or therapeutic approaches against epithelial metabolic dysfunction.

Funding Sources: Grant #R21DK123691 from the NIH