Shijie Cao, Erica Budina, Michal M. Raczy, Ani Solanki, Mindy Nguyen, Taryn N. Beckman, Joseph W. Reda, Kevin Hultgren, Phillip S. Ang, Anna J. Slezak, Lauren A. Hesser, Aaron T. Alpar, Kirsten C. Refvik, Lucas S. Shores, Ishita Pillai, Rachel P. Wallace, Arjun Dhar, Elyse A. Watkins, Jeffrey A. Hubbell
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引用次数: 0
摘要
丁酸盐是一种由共生细菌产生的代谢产物,因其对免疫细胞(包括调节性 T 细胞、巨噬细胞和树突状细胞)的免疫调节作用而被广泛研究。然而,由于丁酸盐在肠道中的代谢速度快、效力低(因此必须加大剂量)以及气味和味道难闻,丁酸盐的口服生物利用度较低,这阻碍了丁酸盐作为药物的开发。我们在此报告,通过将丁酸酯酯化为丝氨酸,可以提高丁酸酯的口服生物利用度。丝氨酸是一种氨基酸转运体,可以帮助产生的无味无臭原药(O-丁酰-L-丝氨酸,我们将其命名为 SerBut)从肠道中排出,从而提高其全身吸收率。在胶原抗体诱导的关节炎(类风湿性关节炎的一种模型)和实验性自身免疫性脑脊髓炎(多发性硬化症的一种模型)小鼠中,我们发现 SerBut 能显著改善疾病的严重程度,调节全身和疾病相关组织中的关键免疫细胞群,并在不影响疫苗接种的整体免疫反应的情况下减少炎症反应。SerBut可能成为治疗自身免疫性疾病和炎症性疾病的一种有前途的疗法。
A serine-conjugated butyrate prodrug with high oral bioavailability suppresses autoimmune arthritis and neuroinflammation in mice
Butyrate—a metabolite produced by commensal bacteria—has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate’s poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-l-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases. The esterification of butyrate to serine makes for an odourless and tasteless oral prodrug that ameliorated disease severity and reduced inflammatory responses in mouse models of rheumatoid arthritis and multiple sclerosis.
期刊介绍:
Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.