Wang Chen, Qiu Mei, Wang Shuo, Luo Jinjin, Huang Ling, Deng Qi, Fang Zhijia, Sun Lijun, Gooneratne Ravi
Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China.
College of Agriculture and Biotechnology, Sun Yat-sen University, Shenzhen 518107, China.
Int J Mol Sci. 2024 Dec 3;25(23):12998. doi: 10.3390/ijms252312998.
Intestinal mucosal barrier damage is regarded as the critical factor through which chronic unpredictable mild stress (CUMS) leads to a variety of physical and mental health problems. However, the exact mechanism by which CUMS induces intestinal mucosal barrier damage is unclear. In this study, 14, 28, and 42 d CUMS model mice were established. The indicators related to ileal mucosal barrier damage (IMBD), the composition of the ileal microbiota and its amino acid (AA) and short-chain fatty acid (SCFA) metabolic functions, and free amino acid (FAA) and SCFA levels in the ileal lumen were measured before and after each stress period. The correlations between them are analyzed to investigate how CUMS induces intestinal mucosal barrier damage in male C57BL/6 mice. With the progression of CUMS, butyric acid (BA) levels decreased (14 and 28 d) and then increased (42 d), and IMBD progressively increased. In the late CUMS stage (42 d), the degree of IMBD is most severe and positively correlated with significantly increased BA levels ( < 0.05) in the ileal lumen and negatively correlated with significantly decreased FAAs, such as aspartic, glutamic, alanine, and glycine levels ( < 0.05). In the ileal lumen, the abundance of BA-producing bacteria (, , and ) and the gene abundance of specific AA degradation and BA production pathways and their related enzymes are significantly increased ( < 0.05). In addition, there is a significant decrease ( < 0.05) in the abundance of core bacteria (, , , , and ) that rely on these specific AAs for growth and/or are sensitive to BA. These changes, in turn, promote further colonization of BA-producing bacteria, exacerbating the over-accumulation of BA in the ileal lumen. These results were validated by ileal microbiota in vitro culture experiments. In summary, in the late CUMS stages, IMBD is related to an excessive accumulation of BA caused by dysbiosis of the ileal microbiota and its overactive AA degradation.
肠黏膜屏障损伤被视为慢性不可预测轻度应激（CUMS）导致多种身心健康问题的关键因素。然而，CUMS诱导肠黏膜屏障损伤的确切机制尚不清楚。本研究建立了14天、28天和42天的CUMS模型小鼠。在每个应激期前后，测量与回肠黏膜屏障损伤（IMBD）相关的指标、回肠微生物群的组成及其氨基酸（AA）和短链脂肪酸（SCFA）代谢功能，以及回肠腔中的游离氨基酸（FAA）和SCFA水平。分析它们之间的相关性，以研究CUMS如何诱导雄性C57BL/6小鼠的肠黏膜屏障损伤。随着CUMS的进展，丁酸（BA）水平先降低（14天和28天），然后升高（42天），而IMBD则逐渐增加。在CUMS后期（42天），IMBD程度最为严重，与回肠腔中BA水平显著升高（<0.05）呈正相关，与天冬氨酸、谷氨酸、丙氨酸和甘氨酸等FAA水平显著降低（<0.05）呈负相关。在回肠腔中，产BA细菌（、和）的丰度以及特定AA降解和BA产生途径及其相关酶的基因丰度显著增加（<0.05）。此外，依赖这些特定AA生长和/或对BA敏感的核心细菌（、、、和）的丰度显著降低（<0.05）。这些变化反过来促进了产BA细菌的进一步定植，加剧了BA在回肠腔中的过度积累。这些结果通过回肠微生物群体外培养实验得到验证。总之，在CUMS后期，IMBD与回肠微生物群失调及其过度活跃的AA降解导致的BA过度积累有关。
