MahmoudianDehkordi Siamak, Bhattacharyya Sudeepa, Brydges Christopher R, Jia Wei, Fiehn Oliver, Rush A John, Dunlop Boadie W, Kaddurah-Daouk Rima
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, United States.
Department of Biological Sciences, Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR, United States.
Front Neurosci. 2022 Jul 20;16:937906. doi: 10.3389/fnins.2022.937906. eCollection 2022.
The gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut-bacterial enzymes, thus requiring both human and gut microbiome enzymatic processes in their metabolism. BAs participate in a range of important host functions such as lipid transport and metabolism, cellular signaling and regulation of energy homeostasis. BAs have recently been implicated in the pathophysiology of Alzheimer's and several other neuropsychiatric diseases, but the biochemical underpinnings of these gut microbiome-linked metabolites in the pathophysiology of depression and anxiety remains largely unknown.
Using targeted metabolomics, we profiled primary and secondary BAs in the baseline serum samples of 208 untreated outpatients with MDD. We assessed the relationship of BA concentrations and the severity of depressive and anxiety symptoms as defined by the 17-item Hamilton Depression Rating Scale (HRSD) and the 14-item Hamilton Anxiety Rating Scale (HRSA-Total), respectively. We also evaluated whether the baseline metabolic profile of BA informs about treatment outcomes.
The concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log fold difference (LFD) = -0.48; = 0.021) and highly anxious (LFD = -0.43; = 0.021) participants compared to participants with less severe symptoms. The gut bacteria-derived secondary BAs produced from CDCA such as lithocholic acid (LCA) and several of its metabolites, and their ratios to primary BAs, were significantly higher in the more anxious participants (LFD's range = [0.23, 1.36]; 's range = [6.85E-6, 1.86E-2]). The interaction analysis of HRSD and HRSA-Total suggested that the BA concentration differences were more strongly correlated to the symptoms of anxiety than depression. Significant differences in baseline CDCA (LFD = -0.87, = 0.0009), isoLCA (LFD = -1.08, = 0.016) and several BA ratios (LFD's range [0.46, 1.66], 's range [0.0003, 0.049]) differentiated treatment failures from remitters.
In patients with MDD, BA profiles representing changes in gut microbiome compositions are associated with higher levels of anxiety and increased probability of first-line treatment failure. If confirmed, these findings suggest the possibility of developing gut microbiome-directed therapies for MDD characterized by gut dysbiosis.
肠道微生物群可能在包括重度抑郁症（MDD）在内的神经精神疾病的发病机制中起作用。胆汁酸（BAs）是由胆固醇在肝脏中合成并由肠道细菌酶进一步加工的类固醇酸，因此其代谢需要人类和肠道微生物群的酶促过程。胆汁酸参与一系列重要的宿主功能，如脂质运输和代谢、细胞信号传导以及能量稳态的调节。最近，胆汁酸与阿尔茨海默病和其他几种神经精神疾病有关，但这些与肠道微生物群相关的代谢产物在抑郁症和焦虑症病理生理学中的生化基础仍 largely unknown。
我们使用靶向代谢组学技术，对208名未接受治疗的MDD门诊患者的基线血清样本中的初级和次级胆汁酸进行了分析。我们分别评估了胆汁酸浓度与抑郁和焦虑症状严重程度之间的关系，抑郁症状严重程度由17项汉密尔顿抑郁量表（HRSD）定义，焦虑症状严重程度由14项汉密尔顿焦虑量表（HRSA - 总分）定义。我们还评估了胆汁酸的基线代谢谱是否能预测治疗结果。
与症状较轻的参与者相比，严重抑郁（对数倍差（LFD）=-0.48；=0.021）和高度焦虑（LFD=-0.43；=0.021）的参与者在基线时初级胆汁酸鹅去氧胆酸（CDCA）的浓度显著较低。在焦虑程度较高的参与者中，由CDCA产生的肠道细菌衍生的次级胆汁酸，如石胆酸（LCA）及其几种代谢产物，以及它们与初级胆汁酸的比率显著更高（LFD范围=[0.23, 1.36]；范围=[6.85E - 6, 1.86E - 2]）。HRSD和HRSA - 总分的交互分析表明，胆汁酸浓度差异与焦虑症状的相关性比与抑郁症状的相关性更强。基线CDCA（LFD=-0.87，=0.0009）、异LCA（LFD=-1.08，=0.016）和几种胆汁酸比率（LFD范围[0.46, 1.66]，范围[0.0003, 0.049]）的显著差异区分了治疗失败者和缓解者。
在MDD患者中，代表肠道微生物群组成变化的胆汁酸谱与更高水平的焦虑和一线治疗失败的可能性增加有关。如果得到证实，这些发现表明有可能开发针对以肠道微生物群失调为特征的MDD的肠道微生物群导向疗法。
