Thibaut Morgane M, Sboarina Martina, Roumain Martin, Pötgens Sarah A, Neyrinck Audrey M, Destrée Florence, Gillard Justine, Leclercq Isabelle A, Dachy Guillaume, Demoulin Jean-Baptiste, Tailleux Anne, Lestavel Sophie, Rastelli Marialetizia, Everard Amandine, Cani Patrice D, Porporato Paolo E, Loumaye Audrey, Thissen Jean-Paul, Muccioli Giulio G, Delzenne Nathalie M, Bindels Laure B
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.
Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.
J Cachexia Sarcopenia Muscle. 2021 Feb;12(1):70-90. doi: 10.1002/jcsm.12652. Epub 2020 Dec 22.
Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia.
We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51).
In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of -1.97, -2.16, and -1.34, respectively; all Padj < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor α signalling via NFκB and inflammatory response pathways, normalized enrichment scores of -1.44 and -1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non-cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 μM, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C-reactive protein: ρ = 0.36, Padj = 0.017).
We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia.
癌症恶病质是一种导致机体衰弱的代谢综合征，是癌症死亡的一个原因。除肌肉外的其他器官可能参与癌症恶病质的发病机制。本研究探索癌症恶病质中肝脏改变的新机制。
我们利用转录组学揭示结肠癌26恶病质小鼠模型中的肝脏基因表达谱。我们进行了胆汁酸、组织mRNA、组织学、生化及蛋白质印迹分析。使用中和性白细胞介素6抗体和胆汁酸螯合剂考来烯胺进行了两项干预研究。我们的研究结果在94例有或无恶病质的结直肠癌患者队列（43/51）中进行了评估。
在结肠癌26恶病质小鼠中，我们发现五条炎症通路以及其他通路发生改变。这些通路包括胆汁酸代谢、脂肪酸代谢和外源性物质代谢（标准化富集分数分别为-1.97、-2.16和-1.34；所有Padj<0.05）。恶病质小鼠的肝胆转运系统严重受损，导致全身和肝脏胆汁酸水平升高（+1512±511.6 pmol/mg，P=0.01），恶病质小鼠肝脏炎症细胞因子增加，中性粒细胞向肝脏募集增多（每平方毫米+43.36±16.01个中性粒细胞，P=0.001）。通过抑制胆汁酸合成和增强基底外侧胆汁酸外排的替代途径，建立了适应性机制来抵消这种胆汁酸积累。使用考来烯胺靶向胆汁酸可减轻肝脏炎症，但不影响肝胆转运体（例如肿瘤坏死因子α通过NFκB的信号传导和炎症反应通路，标准化富集分数为-1.44和-1.36，所有Padj<0.05）。降低白细胞介素6水平可抵消参与肝胆转运、胆汁酸合成和炎症的基因表达变化。恶病质癌症患者的血清胆汁酸水平高于非恶病质癌症患者（例如总胆汁酸，+5.409±1.834 μM，P=0.026），且与全身炎症密切相关（牛磺鹅去氧胆酸和C反应蛋白：ρ=0.36，Padj=0.017）。
我们发现癌症恶病质中胆汁酸代谢和肝胆分泌发生改变。在此背景下，我们证明全身炎症对肝胆转运系统损伤的作用以及胆汁酸在肝脏炎症中的作用。这项工作为更好地理解肝脏在癌症恶病质中的作用铺平了道路。
