ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo

Schulz-Kuhnt A, Rühle K, Javidmehr A, Döbrönti M, Biwank J, Knittel S, Neidlinger P, Leupold J, Liu L, Dedden M, Taudte RV, Geßner A, Fromm M, Mielenz D, Kreiß L, Waldner M, Schürmann S, Friedrich O, Dietel-Schor B, Lopez Posadas R, Plattner C, Zundler S, Becker C, Atreya R, Neurath M, Atreya I (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Gut BMJ Publishing Group

Pages Range: gutjnl-2023-330543

DOI: 10.1136/gutjnl-2023-330543

Abstract

Objective Mucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD.


Design ACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models.


Results ACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4+ and to a lesser extent in CD8+ T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4+ T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLYhigh CD4+ T cells and ameliorated chronic colitis.


Conclusion ACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation.

Authors with CRIS profile

Anja Schulz-Kuhnt Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Katharina Rühle Lehrstuhl für Innere Medizin I (Medizin 1) Asal Javidmehr Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Jana Biwank Lehrstuhl für Innere Medizin I (Medizin 1) Selina Knittel Lehrstuhl für Innere Medizin I (Medizin 1) Peter Neidlinger Lehrstuhl für Innere Medizin I (Medizin 1) Jannik Leupold Lehrstuhl für Innere Medizin I (Medizin 1) Lijuan Liu Lehrstuhl für Innere Medizin I (Medizin 1) Mark Dedden Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Arne Geßner Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Martin Fromm Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Dirk Mielenz Lehrstuhl für Innere Medizin III Lucas Kreiß Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Maximilian Waldner Lehrstuhl für Innere Medizin I (Medizin 1) Sebastian Schürmann Lehrstuhl für Medizinische Biotechnologie (MBT) Oliver Friedrich Lehrstuhl für Medizinische Biotechnologie (MBT) Rocío Lopez Posadas Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Sebastian Zundler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1) Imke Atreya Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF) FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

Related research project(s)

D037: ACLY as a therapeutic target to promote T cell-driven antitumor immune response in IBD-associated colon cancer April 1, 2023 - Sept. 30, 2025

Involved external institutions

Medizinische Universität Innsbruck AT Austria (AT)

How to cite

APA:

Schulz-Kuhnt, A., Rühle, K., Javidmehr, A., Döbrönti, M., Biwank, J., Knittel, S.,... Atreya, I. (2024). ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo. Gut, gutjnl-2023-330543. https://doi.org/10.1136/gutjnl-2023-330543

MLA:

Schulz-Kuhnt, Anja, et al. "ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo." Gut (2024): gutjnl-2023-330543.

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