Fang Xiuyu, Liu Haiyang, Liu Junling, Du Yongqing, Chi Zihan, Bian Yiqi, Zhao Xuan, Teng Teng, Shi Baoming
College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, People's Republic of China.
Research (Wash D C). 2025 May 8;8:0673. doi: 10.34133/research.0673. eCollection 2025.
Supplementation with short-chain fatty acids (SCFAs) is a potential therapeutic approach for inflammatory bowel disease (IBD). However, the therapeutic effects and mechanisms of action of isobutyrate in IBD remain unclear. Clinical data indicate that the fecal levels of isobutyrate are markedly lower in patients with Crohn's disease than in healthy controls. Compared with healthy mice and healthy pigs, mice and pigs with colitis presented significantly lower isobutyrate levels. Furthermore, the level of isobutyrate in pigs was significantly negatively correlated with the disease activity index. We speculate that isobutyrate may play a crucial role in regulating host gut homeostasis. We established a model of dextran sulfate sodium-induced colitis in pigs, which have gastrointestinal structure and function similar to those of humans; we performed multiomic analysis to investigate the therapeutic effects and potential mechanisms of isobutyrate on IBD at both the animal and cellular levels and validated the results. Phenotypically, isobutyrate can significantly alleviate diarrhea, bloody stools, weight loss, and colon shortening caused by colitis in pigs. Mechanistically, isobutyrate can increase the relative abundance of , thereby increasing the production of indole-3-lactic acid, regulating aryl hydrocarbon receptor expression and downstream signaling pathways, and regulating Foxp3 CD4 T cell recruitment to alleviate colitis. Isobutyrate can directly activate G protein-coupled receptor 109A, promote the expression of Claudin-1, and improve intestinal barrier function. In addition, isobutyrate can increase the production of intestinal SCFAs and 3-hydroxybutyric acid and inhibit the TLR4/MyD88/NF-κB signaling pathway to suppress intestinal inflammation. In conclusion, our findings demonstrate that isobutyrate confers resistance to IBD through host-microbiota interactions, providing a theoretical basis for the use of isobutyrate in alleviating colitis.
补充短链脂肪酸（SCFAs）是治疗炎症性肠病（IBD）的一种潜在方法。然而，异丁酸在IBD中的治疗效果和作用机制仍不清楚。临床数据表明，克罗恩病患者粪便中的异丁酸水平明显低于健康对照者。与健康小鼠和健康猪相比，患有结肠炎的小鼠和猪的异丁酸水平显著降低。此外，猪体内异丁酸水平与疾病活动指数呈显著负相关。我们推测异丁酸可能在调节宿主肠道内环境稳定中起关键作用。我们建立了葡聚糖硫酸钠诱导的猪结肠炎模型，猪的胃肠道结构和功能与人类相似；我们进行了多组学分析，以研究异丁酸在动物和细胞水平上对IBD的治疗效果和潜在机制，并对结果进行了验证。从表型上看，异丁酸可以显著缓解猪结肠炎引起的腹泻、便血、体重减轻和结肠缩短。从机制上讲，异丁酸可以增加 的相对丰度，从而增加吲哚-3-乳酸的产生，调节芳烃受体表达和下游信号通路，并调节Foxp3 CD4 T细胞募集以减轻结肠炎。异丁酸可以直接激活G蛋白偶联受体109A，促进Claudin-1的表达，并改善肠道屏障功能。此外，异丁酸可以增加肠道SCFAs和3-羟基丁酸的产生，并抑制TLR4/MyD88/NF-κB信号通路以抑制肠道炎症。总之，我们的研究结果表明，异丁酸通过宿主-微生物群相互作用赋予对IBD的抗性，为使用异丁酸缓解结肠炎提供了理论依据。
