title: Halofuginone reduces the inflammatory responses of DSS-induced colitis through metabolic reprogramming.
abstract: Hypoxia and inflammation have been identified as the hallmarks of colitis, intertwined with metabolism. Here, we report that halofuginone (HF), an antiparasitic drug, attenuates dextran sulfate sodium (DSS)-induced colitis in mice, as represented by attenuating the disease activity index, inhibiting colonic shortening, ameliorating colonic lesions and histological signs of damage, reducing colonic myeloperoxidase activity, and suppressing the production of pro-inflammatory cytokines in colon tissue. Intriguingly, the hypoxia-inducible factor 1alpha (HIF-1α) and tumor necrosis factor alpha were also suppressed by HF treatment in colon tissues, exhibiting a tissue-specific effect. To further reveal the metabolic signatures upon HF treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in liver, spleen and colon tissues was performed. As a result, we found that HF treatment counteracted the levels of acylcarnitines, including palmitoyl-l-carnitine, isobutyrylcarnitine, vaccenylcarnitine, and myristoylcarnitine, in colon tissues with DSS induction, but no significant change in the levels of acylcarnitines was observed in liver or spleen tissues. The metabolic signatures may indicate that incomplete fatty acid oxidation (FAO) in the colon could be restored upon HF treatment as the tissue-specific metabolic characterization. Taken together, our findings uncovered that the HF potentiated anti-inflammatory effect in DSS-induced colitis in mice and its underlying mechanisms could be associated with the inhibition of HIF-1α and reduced levels of acylcarnitines, suggesting that both the inhibition of HIF-1α and the counteraction of incomplete FAO might be useful in the prevention and treatment of inflammatory bowel disease.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. lsswdm@mail.sysu.edu.cn and School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. bzxiang@hkbu.edu.hk.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. bzxiang@hkbu.edu.hk and School of Pharmacy, Guizhou Medicial University, Guiyang 550025, China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Xiao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. lsswdm@mail.sysu.edu.cn.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. bzxiang@hkbu.edu.hk.
authors.forename: Huai-Xue
authors.initials: HX
authors.lastname: Mu
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. bzxiang@hkbu.edu.hk.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. lsswdm@mail.sysu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. lsswdm@mail.sysu.edu.cn.
authors.forename: Depo
authors.initials: D
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. lsswdm@mail.sysu.edu.cn.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. bzxiang@hkbu.edu.hk.
authors.forename: Zhao-Xiang
authors.initials: ZX
authors.lastname: Bian
authors.affiliation: School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China. bzxiang@hkbu.edu.hk and Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China. slin@shsmu.edu.cn.
authors.forename: Shu-Hai
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015415:Biomarkers; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D010641:Phenotype; D010880:Piperidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D016207:Cytokines; D005227:Fatty Acids; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D010880:Piperidines; D052999:Quinazolinones; D012333:RNA, Messenger; D016264:Dextran Sulfate; D009195:Peroxidase; C010176:halofuginone