AB1108 TOTAL GLUCOSIDES OF PAEONY ALLEVIATE DEPRESSIVE-LIKE BEHAVIORS IN LUPUS-PRONE MRL/lpr MICE BY MODULATING GUT MICROBIOTA AND METABOLITES
Authors: M. Yang, J. Qin, Y. Feng, P. Wang, Y. Lai, Q. Huang, J. Li
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Neuropsychiatric lupus erythematosus (NPSLE) has a range of clinical manifestations, among which mood disorders are one of the common subtypes. These mood disorders, particularly depression, significantly impact the quality of life for SLE patients and may even lead to suicidal thoughts or behaviors. Currently, the pathogenesis of lupus-related depression is unknown, and clinical intervention measures are limited. Total glucosides of paeony (TGP), a Chinese patent medicine primarily composed of paeoniflorin, has been shown to possess anti-inflammatory and immunomodulatory effects as well as potential antidepressant properties. Regulating intestinal metabolic disorders by improving the structure of intestinal flora is a new target of antidepressants in recent years. <h3>Objectives:</h3> This study aims to investigate the regulatory effects of TGP on intestinal flora and metabolites in lupus mice, and to clarify the metabolic pathway of TGP in the treatment of lupus-related depression. <h3>Methods:</h3> 30 female MRL/lpr mice were randomly divided into 3 groups with 10 mice in each group. Additionally, 10 age-matched MRL/MPJ mice were subjected to adaptive feeding for one week followed by 4 consecutive weeks of treatment with TGP at different doses: LPR group (MRL/lpr mice + saline), LTGP group (MRL/lpr mice + 100mg/kg TGP), HTGP group (MRL/lpr mice + 200mg/kg TGP), and MPJ group (MRL/MPJ mice + saline). Then we conducted behavioral tests, renal function assessment, spleen and lymph node index determination, and measurements of relative levels of proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) in peripheral blood. The fecal samples from each group were analyzed using 16S rRNA sequencing and metabolomics techniques to examine changes in gut flora composition and metabolite profiles. Furthermore, correlation analysis was performed among differential bacterial genera, metabolites and indicators. <h3>Results:</h3> Compared with the LPR group, the TGP groups showed significant relief in renal injury, spleen and lymph node enlargement, as well as improvement in depressive-like behavior. The TGP groups also showed relief in intestinal permeability and inflammation. Additionally, in TGP groups, the levels of proinflammatory cytokines in peripheral blood and brain regions were decreased, and the level of BDNF in the brain was increased. Compared with MPJ group, the abundance of Bacteroidetes was decreased, the abundance of Firmicutes was increased, and the ratio of Firmicutes to Bacteroidetes (F/B) was decreased in LPR group, while the composition of intestinal microorganisms in LTGP and HTGP groups was improved to varying degrees. Furthermore, we analyzed the differential metabolites and related metabolic pathways between LPR group and MPJ group, and between LPR group and HTGP group. The results showed that the differential pathways were primarily associated with depression. Specifically, the metabolites of the tryptophan pathway, including L-Tryptophan, Serotonin, L-Kynurenine, and Melatonin, showed significant differences between the LPR and MPJ groups. In LPR group and HTGP group, the metabolites of Serotonin, L-Kynurenine, and 6-Hydroxymelatonin showed significant differences. Correlation analysis showed that the abundance of Parabacteroides was positively correlated with inflammatory indicators, and negatively correlated with BDNF expression level. In the metabolites related to tryptophan pathway, the expression level of BDNF in the prefrontal cortex and hippocampus was negatively correlated with the contents of DL-Tryptophan, L-Tryptophan, Serotonin, and L-Kynurenine, and positively correlated with the contents of Melatonin and 6-Hydroxymelatonin. <h3>Conclusion:</h3> TGP can improve the lupus-like behavior of MRL/lpr mice. The relief of depression-like behavior in mice may be related to the regulation of intestinal microbiota and metabolites. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>