Fatty Acid Oxidation Suppression Reprograms Fibroblasts in Fibrostenotic Crohns Disease

Jihad Aljabban, J.; Awad, A.; McMichael, B. D.; Gartner, V.; Thomas, V.; Huan, B.; Weaver, D.; Lian, G.; Beasley, C.; Lau, G. W.-J.; Silverstein, S.; Kapadia, M.; Salvador, A. C.; Rieder, F.; Thaxton, J. E.; Furey, T. S.; Bhatt, A. P.; Sheikh, S. Z.

doi:10.64898/2026.05.06.723289

bioRxiv · 10.64898/2026.05.06.723289

Fatty Acid Oxidation Suppression Reprograms Fibroblasts in Fibrostenotic Crohns Disease

Jihad Aljabban, J.·Awad, A.·McMichael, B. D.·Gartner, V.·Thomas, V.·Huan, B.·Weaver, D.·Lian, G.·Beasley, C.·Lau, G. W.-J.·Silverstein, S.·Kapadia, M.·Salvador, A. C.·Rieder, F.·Thaxton, J. E.·Furey, T. S.·Bhatt, A. P.·Sheikh, S. Z.

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Abstract

Fibrostenotic complications represent a major cause of morbidity in Crohns disease (CD), yet the cellular mechanisms that drive intestinal fibrosis independent of active inflammation remain poorly understood. Here, we identify impaired fatty acid oxidation (FAO) as a defining metabolic feature of fibroblasts in fibrostenotic CD. Untargeted lipidomics of non-inflamed colonic tissue from CD patients demonstrated enrichment of triacylglycerols and long-chain acylcarnitines, suggesting altered lipid utilization. Across three independent RNA-sequencing cohorts, including treatment-naive pediatric ileal biopsies, FAO genes (CPT1A, CPT2, SLC25A20) were selectively downregulated in patients with or destined to develop fibrostenotic disease. Single-cell RNA-sequencing localized these transcriptional alterations specifically to fibroblasts within strictured ileum. Primary fibroblasts derived from fibrostenotic CD exhibited increased neutral lipid accumulation, impaired mitochondrial fatty acid trafficking, and diminished responsiveness to PPAR{gamma}-mediated suppression of TGF{beta}-induced myofibroblast activation. Together, these findings demonstrate that FAO impairment is a conserved, fibroblast-specific metabolic program associated with intestinal fibrosis in CD and suggest that metabolic modulation of stromal cells represents a potential therapeutic strategy for fibrostenotic disease.

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Jihad Aljabban, J., Awad, A., McMichael, B. D., Gartner, V., Thomas, V., Huan, B., Weaver, D., Lian, G., Beasley, C., Lau, G. W.-J., Silverstein, S., Kapadia, M., Salvador, A. C., Rieder, F., Thaxton, J. E., Furey, T. S., Bhatt, A. P., Sheikh, S. Z.. 2026-05-10. Fatty Acid Oxidation Suppression Reprograms Fibroblasts in Fibrostenotic Crohns Disease. https://doi.org/10.64898/2026.05.06.723289

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