2. Academic Validation
  3. Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn's disease

Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn's disease

  • Cell Host Microbe. 2024 Nov 13;32(11):1927-1943.e9. doi: 10.1016/j.chom.2024.10.008.
Jinjie Wu 1,  Wanyi Zeng 2,  Hongyu Xie 3,  Mujia Cao 2,  Jingyi Yang 2,  Yanchun Xie 2,  Zhanhao Luo 2,  Zongjin Zhang 1,  Haoyang Xu 2,  Weidong Huang 4,  Tingyue Zhou 5,  Jinyu Tan 4,  Xiaomin Wu 4,  Zihuan Yang 2,  Shu Zhu 6,  Ren Mao 7,  Zhen He 8,  Ping Lan 9
Affiliations

Affiliations

  • 1 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China.
  • 3 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 5 Key Laboratory of immune response and immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 6 Key Laboratory of immune response and immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Electronic address: zhushu@ustc.edu.cn.
  • 7 Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: maor5@mail.sysu.edu.cn.
  • 8 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China. Electronic address: hezh5@mail.sysu.edu.cn.
  • 9 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; State Key Laboratory of Oncology in South China, Guangzhou, China. Electronic address: lanping@mail.sysu.edu.cn.
PMID: 39541945 DOI: 10.1016/j.chom.2024.10.008
Abstract

Hyperplasia of mesenteric tissues in Crohn's disease, called creeping fat (CrF), is associated with surgical recurrence. Although microbiota translocation and colonization have been found in CrF, convincing mouse phenotypes and the underlying mechanisms of CrF formation remain unclear. Utilizing single-nucleus RNA (snRNA) Sequencing of CrF and different mouse models, we demonstrate that the commensal Achromobacter pulmonis induces mesenteric adipogenesis through macrophage alteration. Targeted metabolome analysis reveals that L-kynurenine is the most enriched metabolite in CrF. Upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) enhances kynurenine metabolism and drives mesenteric adipogenesis. Leveraging single-cell RNA (scRNA) Sequencing of mouse mesenteric tissues and macrophage-specific IDO1 knockout mice, we verify the role of macrophage-sourced L-kynurenine in mesenteric adipogenesis. Mechanistically, L-kynurenine-induced adipogenesis is mediated by the aryl hydrocarbon receptors in adipocytes. Administration of an IDO1 Inhibitor or bacteria engineered to degrade L-kynurenine alleviates mesenteric adipogenesis in mice. Collectively, our study demonstrates that microbiota-induced modulation of macrophage metabolism potentiates CrF formation.

Keywords

Crohn’s disease; creeping fat; kynurenine; macrophages; microbiota.

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