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
Abstract
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.