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 (HRSD₁₇) 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 (log₂ fold difference (LFD) = −0.48; p = 0.021) and highly anxious (LFD = −0.43; p = 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]; p's range = [6.85E-6, 1.86E-2]). The interaction analysis of HRSD₁₇ 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, p = 0.0009), isoLCA (LFD = −1.08, p = 0.016) and several BA ratios (LFD's range [0.46, 1.66], p'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.

肠道微生物组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发挥作用。胆汁酸 (BA) 是类固醇酸，由胆固醇在肝脏中合成，并由肠道细菌酶进一步加工，因此在代谢过程中需要人类和肠道微生物组的酶促过程。BAs 参与一系列重要的宿主功能，例如脂质转运和代谢、细胞信号传导和能量稳态调节。BAs 最近与阿尔茨海默氏症和其他几种神经精神疾病的病理生理学有关，但这些肠道微生物组相关代谢物在抑郁症和焦虑症病理生理学中的生化基础仍然很大程度上未知。

使用靶向代谢组学，我们对 208 名未经治疗的 MDD 门诊患者的基线血清样本中的初级和次级 BAs 进行了分析。我们评估了 BA 浓度与抑郁和焦虑症状严重程度的关系，分别由 17 项汉密尔顿抑郁评定量表 (HRSD ₁₇ ) 和 14 项汉密尔顿焦虑评定量表 (HRSA-Total) 定义。我们还评估了 BA 的基线代谢谱是否可以告知治疗结果。

在基线时，严重抑郁症患者的初级 BA 鹅去氧胆酸 (CDCA) 浓度显着降低（log ₂倍差 (LFD) = -0.48；p= 0.021) 和高度焦虑 (LFD = -0.43;p= 0.021) 参与者与症状较轻的参与者相比。由 CDCA 产生的肠道细菌衍生的次级 BAs，如石胆酸 (LCA) 及其几种代谢物，以及它们与初级 BAs 的比率，在更焦虑的参与者中显着更高（LFD 的范围 = [0.23, 1.36]；p的范围 = [6.85E-6, 1.86E-2])。_{HRSD 17}和 HRSA-Total的交互作用分析表明，与抑郁症相比，BA 浓度差异与焦虑症状的相关性更强。基线 CDCA 的显着差异（LFD = -0.87，p= 0.0009), isoLCA (LFD = -1.08,p= 0.016）和几个 BA 比率（LFD 的范围 [0.46, 1.66]，p的范围 [0.0003, 0.049]) 将治疗失败与汇款人区分开来。

在患有 MDD 的患者中，代表肠道微生物组成分变化的 BA 谱与更高水平的焦虑和增加的一线治疗失败的可能性有关。如果得到证实，这些发现表明有可能开发针对以肠道生态失调为特征的 MDD 的肠道微生物组疗法。