Uno Kinuko, Sekiguchi Keita, Suzuki-Kemuriyama Noriko, Ohta Takeshi, Miyajima Katsuhiro
Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University.
Department of Nutritional Science and Food Safety, Faculty of Applied Biosciences, Tokyo University of Agriculture.
J Toxicol Sci. 2025;50(7):343-350. doi: 10.2131/jts.50.343.
Nonalcoholic fatty liver disease (NAFLD) is a lifestyle-related disease. A gut-liver axis is involved in the progression of NAFLD. Disruption of the intestinal barrier function is an exacerbating factor of NAFLD. In this study, we have investigated the interaction between colitis and NAFLD in mouse models of dextran sodium sulfate (DSS)-induced colitis and diet-induced NAFLD-like lesions. Male C57BL/6J mice were provided with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and 1.25% DSS water for 3 weeks. The DSS water was administered intermittently. In the large intestine, the DSS-treated groups clearly demonstrated inflammation. Dilation of crypt and goblet cells was observed in the DSS + CDAHFD group. The expression of minor inflammation-related genes was increased in the CDAHFD group. In the liver, the CDAHFD group demonstrated non-alcoholic steatohepatitis (NASH)-like lesions. The number of C-X-C motif chemokine ligand 16 (CXCL16)-positive cells increased in the CDAHFD group and tended to increase in the DSS + CDAHFD group. Toll-like receptor 4 (TLR4)-positive cells were observed mainly in gallbladder epithelial cells in all groups and were more pronounced in the DSS-administered groups. Inflammation-related genes were upregulated in the DSS group. The expression of fibrosis-related genes increased in the DSS + CDAHFD group. DSS-induced colitis and CDAHFD-induced NASH interacted with each other. NAFLD lesions were induced by CDAHFD and exacerbated by TLR4 and CXCL16 in DSS-induced colitis. Colitis is induced by DSS and exacerbated by changes in the intestinal environment due to liver injury. This combined model was useful in analyzing early lesions of liver-gut axis for NAFLD.
非酒精性脂肪性肝病（NAFLD）是一种与生活方式相关的疾病。肠-肝轴参与了NAFLD的进展。肠道屏障功能的破坏是NAFLD的一个加重因素。在本研究中，我们在葡聚糖硫酸钠（DSS）诱导的结肠炎和饮食诱导的NAFLD样病变的小鼠模型中，研究了结肠炎与NAFLD之间的相互作用。给雄性C57BL/6J小鼠喂食胆碱缺乏、L-氨基酸限定的高脂饮食（CDAHFD）并饮用1.25% DSS水，持续3周。DSS水间歇性给予。在大肠中，DSS处理组明显出现炎症。在DSS + CDAHFD组中观察到隐窝和杯状细胞扩张。CDAHFD组中与轻度炎症相关基因的表达增加。在肝脏中，CDAHFD组表现出非酒精性脂肪性肝炎（NASH）样病变。CDAHFD组中C-X-C基序趋化因子配体16（CXCL16）阳性细胞数量增加，DSS + CDAHFD组有增加趋势。在所有组中，Toll样受体4（TLR4）阳性细胞主要在胆囊上皮细胞中观察到，在给予DSS的组中更明显。DSS组中与炎症相关的基因上调。DSS + CDAHFD组中与纤维化相关的基因表达增加。DSS诱导的结肠炎和CDAHFD诱导的NASH相互作用。CDAHFD诱导NAFLD病变，并在DSS诱导的结肠炎中由TLR4和CXCL16加剧。结肠炎由DSS诱导，并因肝损伤导致的肠道环境变化而加剧。这种联合模型有助于分析NAFLD肝-肠轴的早期病变。
