Yang Guiyan, Wan Yu-Jui Yvonne
College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
Department of Pathology and Laboratory Medicine, University of California, Davis, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, 95817, Sacramento, CA, USA.
Biomark Res. 2024 Nov 22;12(1):145. doi: 10.1186/s40364-024-00694-7.
Bile acid (BA) and its receptor FXR play crucial roles in metabolism, and dysregulated BA synthesis regulated by hepatic and bacterial enzymes causes metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Moreover, because ~ 75% of hepatic blood is from the gut, liver metabolism is influenced by intestinal bacteria and their metabolites. Thus, we used gut microbiota and metabolites from the urine and serum to uncover biomarkers for metabolic distress caused by Western diet (WD) intake, aging, and FXR inactivity. Hepatic transcriptomes were profiled to define liver phenotypes. There were 654 transcriptomes commonly altered by differential diet intake, ages, and FXR functional status, representing the signatures of liver dysfunction, and 76 of them were differentially expressed in healthy human livers and HCC. Machine learning approaches classified urine and serum metabolites for differential dietary intake and age difference. Additionally, the gut microbiota could predict FXR functional status. Furthermore, FXR was essential for differentiating dietary effects in colonizing age-related gut microbes. The integrated analysis established the relationships between the metabolites and gut microbiota correlated with hepatic transcripts commonly altered by diet, age, and FXR functionality. Remarkably, the changes in metabolites involved in the urea cycle, mitochondrial metabolism, and amino acid metabolism are associated with hepatic dysfunction (i.e. FXF deactivation). Taken together, noninvasive specimens and biomarkers are promising resources for identifying metabolic distress.
胆汁酸（BA）及其受体FXR在代谢中起关键作用，由肝脏和细菌酶调节的胆汁酸合成失调会导致代谢功能障碍相关脂肪性肝炎（MASH）和肝细胞癌（HCC）。此外，由于约75%的肝血来自肠道，肝脏代谢受肠道细菌及其代谢产物的影响。因此，我们利用肠道微生物群以及尿液和血清中的代谢产物来揭示由西方饮食（WD）摄入、衰老和FXR失活引起的代谢紊乱的生物标志物。对肝脏转录组进行分析以确定肝脏表型。共有654个转录组因不同的饮食摄入、年龄和FXR功能状态而发生改变，代表了肝功能障碍的特征，其中76个在健康人肝脏和HCC中差异表达。机器学习方法对尿液和血清代谢产物进行分类，以区分不同的饮食摄入和年龄差异。此外，肠道微生物群可以预测FXR功能状态。此外，FXR对于区分饮食对与年龄相关的肠道微生物定殖的影响至关重要。综合分析确定了与通常因饮食、年龄和FXR功能而改变的肝脏转录本相关的代谢产物和肠道微生物群之间的关系。值得注意的是，参与尿素循环、线粒体代谢和氨基酸代谢的代谢产物变化与肝功能障碍（即FXF失活）相关。综上所述，非侵入性标本和生物标志物是识别代谢紊乱的有前景的资源。
