Chang Ting-Ting, Chen Jaw-Wen
Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
J Inflamm Res. 2021 Nov 27;14:6237-6250. doi: 10.2147/JIR.S343491. eCollection 2021.
Modulation of the gut microbiota may lead to changes in pathological conditions. C-C chemokine motif ligand (CCL) 4 was upregulated in diabetes mellitus (DM) and was shown to play a significant role in pancreatic inflammation and glucose metabolism. The detailed in vivo mechanisms have not been well explored. This study aimed to investigate the hypothesis that direct CCL4 inhibition could modify gut microbiota and systemic metabolism in diet-induced DM mice.
C57BL/6 mice fed a high-fat diet (HFD) were used as a diet-induced DM model. CCL4 inhibition was conducted by anti-CCL4 neutralizing monoclonal antibodies. The gut microbiota was analyzed by high-throughput sequencing of the 16S rRNA. Fecal microbiota transplantation (FMT) was used to verify the effect of CCL4 deficiency on gut microbiota and the linkage between CCL4-modulated gut microbiota and HFD-induced DM.
CCL4 inhibition stabilized glucose homeostasis, modulated lipid parameter, and decreased inflammatory markers in HFD-induced DM mice. Moreover, CCL4 inhibition reversed HFD-induced gut dysbiosis, evidenced by the decreased abundance of family Muribaculaceae and increased abundance of family Atopobiaceae when CCL4 antibodies were administrated. CCL4 inhibition led to a decrease in circulating trimethylamine N-oxide levels, a proinflammatory metabolite from gut microbiota. Taken together, CCL4 inhibition could modify gut microbiota profiles, suppress proinflammatory metabolites, reduce systemic inflammation, improve insulin resistance, and retard the progression of hyperglycemia in HFD-induced DM. Furthermore, FMT from CCL4 knockout mice rescued the glucose homeostasis in HFD-induced DM mice.
Our findings may not only provide a novel rationale to in vivo CCL4-based therapeutic approach in diet-induced DM but also indicate the significance of gut microbiota profile including the family Muribaculaceae and the family Atopobiaceae as a potential modifiable target for systemic metabolism.
调节肠道微生物群可能会导致病理状况的改变。C-C趋化因子基序配体（CCL）4在糖尿病（DM）中上调，并被证明在胰腺炎症和葡萄糖代谢中起重要作用。其详细的体内机制尚未得到充分研究。本研究旨在探讨直接抑制CCL4可改变饮食诱导的糖尿病小鼠肠道微生物群和全身代谢这一假说。
将喂食高脂饮食（HFD）的C57BL/6小鼠用作饮食诱导的糖尿病模型。通过抗CCL4中和单克隆抗体抑制CCL4。通过16S rRNA高通量测序分析肠道微生物群。采用粪便微生物群移植（FMT）来验证CCL4缺乏对肠道微生物群的影响以及CCL4调节的肠道微生物群与HFD诱导的糖尿病之间的联系。
抑制CCL4可稳定饮食诱导的糖尿病小鼠的葡萄糖稳态，调节脂质参数，并降低炎症标志物水平。此外，抑制CCL4可逆转HFD诱导的肠道生态失调，当给予CCL4抗体时，毛螺菌科丰度降低，阿托波氏菌科丰度增加可证明这一点。抑制CCL4导致循环中的氧化三甲胺水平降低，氧化三甲胺是一种来自肠道微生物群的促炎代谢产物。综上所述，抑制CCL4可改变肠道微生物群谱，抑制促炎代谢产物，减轻全身炎症，改善胰岛素抵抗，并延缓饮食诱导的糖尿病小鼠高血糖的进展。此外，来自CCL4基因敲除小鼠的FMT挽救了饮食诱导的糖尿病小鼠的葡萄糖稳态。
我们的研究结果不仅可为饮食诱导的糖尿病中基于CCL4的体内治疗方法提供新的理论依据，还表明包括毛螺菌科和阿托波氏菌科在内的肠道微生物群谱作为全身代谢潜在可调节靶点的重要性。
