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.

丁酸盐是一种由共生细菌产生的代谢物，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，丁酸盐作为药物的发展一直受到丁酸盐口服生物利用度差的阻碍，因为丁酸盐在肠道中代谢迅速、效力低（因此需要高剂量）以及恶臭和味道。在这里，我们报告说，通过将丁酸酯化为丝氨酸，可以提高丁酸的口服生物利用度，丝氨酸是一种氨基酸转运蛋白，有助于生成的无臭无味的前药（O-丁酰-l-丝氨酸，我们将其命名为 SerBut）从肠道逃逸，增强其全身吸收。在患有胶原蛋白抗体诱导的关节炎（类风湿性关节炎模型）和实验性自身免疫性脑脊髓炎（多发性硬化症模型）的小鼠中，我们发现 SerBut 显着改善了疾病的严重程度，系统地调节了系统和疾病相关组织中的关键免疫细胞群，并减少炎症反应而不损害对疫苗接种的整体免疫反应。 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治疗方法。