Wang Jun, Tan Huishi, Ye Ziwen, Weng Senhui, Shi Yanqiang, Xu Jiahui, Liu Hongbin, Li Jierui, Huang Linwen, Zhai Luyue, Luo Huishan, Lin Zelong, Zhong Cailing, Tang Jing, Wang Zezheng, Zhang Haiyan, Zhang Beiping, Huang Chongyang
Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.
Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment for Refractory Chronic Diseases.
Gut Microbes. 2025 Dec;17(1):2518338. doi: 10.1080/19490976.2025.2518338. Epub 2025 Jul 1.
Aging is associated with increased severity of inflammatory bowel disease (IBD). Gut senescence and altered environmental factors contribute to changes in the intestinal metabolome, particularly in frail older individuals. However, the role of age-associated dysbiosis, characterized by a decline in beneficial gut microbiota and their metabolites, in exacerbating IBD remains unclear.
To investigate the impact of aging-associated dysbiosis on colitis development, we employed fecal microbiota transplantation (FMT) in wild-type and IL-10-deficient mice. Aged mice were treated with gut microbiota from either young or aged mice and then subjected to dextran sulfate sodium (DSS) to induce experimental colitis. 16S rDNA sequencing and metabolomics were used to analyze microbial and metabolite profiles. Single-cell RNA sequencing (scRNA-seq) was performed to characterize lamina propria CD45 immune cell composition.
Aged mice receiving microbiota from young mice exhibited less severe colitis than those receiving microbiota from aged mice, as evidenced by reduced disease activity, weight loss, and colonic shortening. Besides, aged mice displayed a significant decrease in the population, accompanied by a reduction in Nordihydroguaiaretic acid (NDGA) levels. Decreased fecal NDGA levels were also observed in both IBD patients and elderly individuals. Administration of NDGA alleviated experimental colitis by downregulating the GSDMD/NR4A1/NLRP3 axis-mediated macrophage pyroptosis. Deletion of GSDMD in macrophages significantly diminished the protective effect of NDGA on colitis.
Our findings demonstrate that aging is associated with dysbiosis and reduced NDGA production, which increases susceptibility to intestinal inflammation. Gut microbial NDGA exhibits potential anti-inflammatory activity in colitis, suggesting a promising therapeutic target for aged-related IBD.
衰老与炎症性肠病（IBD）的严重程度增加有关。肠道衰老和环境因素的改变导致肠道代谢组的变化，尤其是在体弱的老年人中。然而，以有益肠道微生物群及其代谢产物减少为特征的年龄相关的生态失调在加重IBD方面的作用仍不清楚。
为了研究衰老相关的生态失调对结肠炎发展的影响，我们在野生型和白细胞介素-10缺陷型小鼠中采用了粪便微生物群移植（FMT）。用来自年轻或老年小鼠的肠道微生物群治疗老年小鼠，然后用葡聚糖硫酸钠（DSS）诱导实验性结肠炎。使用16S rDNA测序和代谢组学分析微生物和代谢产物谱。进行单细胞RNA测序（scRNA-seq）以表征固有层CD45免疫细胞组成。
接受年轻小鼠微生物群的老年小鼠比接受老年小鼠微生物群的小鼠表现出较轻的结肠炎，这通过疾病活动度降低、体重减轻和结肠缩短得到证明。此外，老年小鼠的 数量显著减少，同时去甲二氢愈创木酸（NDGA）水平降低。在IBD患者和老年人中也观察到粪便NDGA水平降低。给予NDGA通过下调GSDMD/NR4A1/NLRP3轴介导的巨噬细胞焦亡来减轻实验性结肠炎。巨噬细胞中GSDMD的缺失显著减弱了NDGA对结肠炎的保护作用。
我们的研究结果表明，衰老与生态失调和NDGA产生减少有关，这增加了肠道炎症的易感性。肠道微生物NDGA在结肠炎中表现出潜在的抗炎活性，这表明它是与年龄相关的IBD的一个有前景的治疗靶点。
