3,3-二甲基-1-丁醇及其代谢物 3,3-二甲基丁酸酯可改善胶原蛋白诱发的关节炎,而与胆碱三甲胺溶酶活性无关。

IF 4.5 2区 医学 Q2 CELL BIOLOGY Inflammation Pub Date : 2024-08-17 DOI:10.1007/s10753-024-02126-y
Sabrina Fechtner, Brendan E Allen, Meagan E Chriswell, Widian K Jubair, Charles E Robertson, Jennifer N Kofonow, Daniel N Frank, V Michael Holers, Kristine A Kuhn
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引用次数: 0

摘要

在类风湿性关节炎和胶原诱导性关节炎(CIA)小鼠自身免疫性关节炎模型中,关于细菌肉碱和胆碱代谢成炎症产物三甲胺(TMA)的作用存在相互矛盾的数据,三甲胺在肝脏中被氧化成三甲胺-N-氧化物(TMAO)。利用两种已发表的细菌 TMA 裂解酶抑制剂--3,3-二甲基-1-丁醇(DMB)和氟甲基胆碱(FMC),我们测试了 TMA/TMAO 是否与 CIA 发病过程中的炎症有关。令人惊讶的是,与 FMC 和药物处理的小鼠相比,DMB 处理的小鼠关节炎严重程度降低了 50%,但疾病的改善与 TMA/TMAO 的产生无关。鉴于 DMB 不抑制 TMA 这一明显矛盾之处,我们随后研究了 DMB 的保护机制。在验证了 DMB 的作用与肠道微生物群无关之后,我们追踪了 DMB 在宿主体内的代谢过程,并发现了一种新的宿主来源的 DMB 代谢产物--3,3-二甲基-1-丁酸 (DMBut)。对使用 DMB 或 DMBut 治疗的小鼠进行的体内研究表明,这两种分子都能显著减少 CIA 中的疾病和促炎细胞因子,而体外研究表明,这些分子可能通过调节巨噬细胞分泌促炎细胞因子而发挥作用。总之,我们的研究表明,DMB 和/或其代谢物通过直接的免疫调节作用而不是抑制细菌 TMA 裂解酶对 CIA 具有保护作用。
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3,3-Dimethyl-1-Butanol and its Metabolite 3,3-Dimethylbutyrate Ameliorate Collagen-induced Arthritis Independent of Choline Trimethylamine Lyase Activity.

Conflicting data exist in rheumatoid arthritis and the collagen-induced arthritis (CIA) murine model of autoimmune arthritis regarding the role of bacterial carnitine and choline metabolism into the inflammatory product trimethylamine (TMA), which is oxidized in the liver to trimethylamine-N-oxide (TMAO). Using two published inhibitors of bacterial TMA lyase, 3,3-dimethyl-1-butanol (DMB) and fluoromethylcholine (FMC), we tested if TMA/TMAO were relevant to inflammation in the development of CIA. Surprisingly, DMB-treated mice demonstrated > 50% reduction in arthritis severity compared to FMC and vehicle-treated mice, but amelioration of disease was independent of TMA/TMAO production. Given the apparent contradiction that DMB did not inhibit TMA, we then investigated the mechanism of protection by DMB. After verifying that DMB acted independently of the intestinal microbiome, we traced the metabolism of DMB within the host and identified a novel host-derived metabolite of DMB, 3,3-dimethyl-1-butyric acid (DMBut). In vivo studies of mice treated with DMB or DMBut demonstrated efficacy of both molecules in significantly reducing disease and proinflammatory cytokines in CIA, while in vitro studies suggest these molecules may act by modulating secretion of proinflammatory cytokines from macrophages. Altogether, our study suggests that DMB and/or its metabolites are protective in CIA through direct immunomodulatory effects rather than inhibition of bacterial TMA lyases.

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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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