乳酸片球菌(Pediococcus acidilactici)是一类高产乳酸的益生菌,该文旨在探究乳酸片球菌CCFM6432对小鼠抑郁症状的缓解作用及其作用机制。该研究通过为期4周的慢性不可预知温和刺激建立抑郁小鼠模型,并给予小鼠益生菌(乳酸片球菌CCFM6432和对照菌株FXJKS25M4)干预治疗。肠道菌群和代谢物分析结果显示,相比于模型组和对照组,CCFM6432干预后能显著调节肠道代谢物乳酸、鸟嘌呤和腺嘌呤等的含量,降低肠道致病菌的丰度,并提高了短链脂肪酸合成菌属毛螺菌科(Lachnospiraceae)的丰度,有助于恢复肠道屏障损伤,逆转血清中脂多糖(lipopolysaccharide, LPS)异常升高。此外,CCFM6432还能下调脑部TLR4/NF-kB信号通路的受体蛋白和促炎因子的异常表达,从而抑制海马中小胶质细胞的过度活化。该研究揭示了CCFM6432通过调节特定肠道代谢物来抑制肠道致病菌的生长,从而缓解神经炎症导致的抑郁症状,并为抑郁症治疗方法以及肠-脑轴信号通路探索提供新的见解。
Pediococcus acidilactici is a group of probiotics known for its high lactate production.This study aims to investigate the alleviation of depressive symptoms in mice by P.acidilactici CCFM6432 and its underlying mechanisms.A Chronic Unpredictable Mild Stress (CUMS) model in mice was established for 4 weeks, followed by probiotic interventions with Lactobacillus strains (CCFM6432 and control strain FXJKS25M4).Results from the analysis of gut microbiota and metabolites revealed that, compared to both the model and control groups, CCFM6432 intervention significantly regulated the levels of gut metabolites such as lactate, uracil, and adenine.This intervention reduced the abundance of pathogenic gut bacteria and increased the abundance of Lachnospiraceae, a family associated with short-chain fatty acid synthesis, thereby assisting in the restoration of intestinal barrier integrity and the normalization of elevated lipopolysaccharide (LPS) levels in the serum.Additionally, CCFM6432 downregulated the expression of receptor proteins and pro-inflammatory factors involved in the TLR4/NF-kB signaling pathway in the brain.This inhibition contributed to the suppression of excessive microglial cell activation in the hippocampus.This study elucidates how CCFM6432 alleviates depressive symptoms by regulating specific gut metabolites to inhibit the growth of pathogenic gut bacteria, shedding light on novel insights for the treatment of depression and the exploration of the gut-brain axis signaling pathways.
[1] MURRAY E, SHARMA R, SMITH K B, et al.Probiotic consumption during puberty mitigates LPS-induced immune responses and protects against stress-induced depression- and anxiety-like behaviors in adulthood in a sex-specific manner[J].Brain, Behavior, and Immunity, 2019, 81:198-212.
[2] LIU L X, WANG H Y, CHEN X Y, et al.Gut microbiota and its metabolites in depression:From pathogenesis to treatment[J].EBioMedicine, 2023, 90:104527.
[3] 田培郡. 具有缓解抑郁功能的短双歧杆菌CCFM1025的研究[D].无锡:江南大学, 2021.
TIAN P J.Research on Bifidobacterium breve CCFM1025 with the antidepressant-like effect[D].Wuxi:Jiangnan University, 2021.
[4] CRYAN J F, DINAN T G.Mind-altering microorganisms:The impact of the gut microbiota on brain and behaviour[J].Nature Reviews.Neuroscience, 2012, 13(10):701-712.
[5] BARANDOUZI Z A, STARKWEATHER A R, HENDERSON W A, et al.Altered composition of gut microbiota in depression:A systematic review[J].Frontiers in Psychiatry, 2020, 11:541.
[6] ZHENG P, ZENG B, ZHOU C, et al.Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism[J].Molecular Psychiatry, 2016, 21(6):786-796.
[7] NIKOLOVA V L, CLEARE A J, YOUNG A H, et al.Acceptability, tolerability, and estimates of putative treatment effects of probiotics as adjunctive treatment in patients with depression:A randomized clinical trial[J].JAMA Psychiatry, 2023, 80(8):842-847.
[8] 邹仁英, 朱慧越, 许梦舒, 等.“精神益生菌” 对慢性应激诱导的抑郁和便秘症状的缓解及机制研究[J].食品与发酵工业, 2021, 47(3):1-9.
ZOU R Y, ZHU H Y, XU M S, et al.Effect and mechanism of psychobiotics in regulating chronic stress induced depression and constipation[J].Food and Fermentation Industries, 2021, 47(3):1-9.
[9] HUANG Y, WU J, ZHANG H P, et al.The gut microbiome modulates the transformation of microglial subtypes[J].Molecular Psychiatry, 2023, 28(4):1611-1621.
[10] LOGAN R W, EDGAR N, GILLMAN A G, et al.Chronic stress induces brain region-specific alterations of molecular rhythms that correlate with depression-like behavior in mice[J].Biological Psychiatry, 2015, 78(4):249-258.
[11] TIAN P J, O'RIORDAN K J, LEE Y K, et al.Towards a psychobiotic therapy for depression:Bifidobacterium breve CCFM1025 reverses chronic stress-induced depressive symptoms and gut microbial abnormalities in mice[J].Neurobiology of Stress, 2020, 12:100216.
[12] YU Z L, CHEN W J, ZHANG L B, et al.Gut-derived bacterial LPS attenuates incubation of methamphetamine craving via modulating microglia[J].Brain, Behavior, and Immunity, 2023, 111:101-115.
[13] LIANG J J, ZHAO Y M, XI Y, et al.Association between depression, anxiety symptoms and gut microbiota in Chinese elderly with functional constipation[J].Nutrients, 2022, 14(23):5013.
[14] BALLOU S, KATON J, SINGH P, et al.Chronic diarrhea and constipation are more common in depressed individuals[J].Clinical Gastroenterology and Hepatology:the Official Clinical Practice Journal of the American Gastroenterological Association, 2019, 17(13):2696-2703.
[15] 邹仁英. 复合益生菌缓解抑郁的功效评价及机制探究[D].无锡:江南大学, 2021.
ZOU R Y.Founction evaluation and mechanism investigation of compound probiotics on alleviating depression[D].Wuxi:Jiangnan University, 2021.
[16] LIU L X, WANG H Y, ZHANG H P, et al.Toward a deeper understanding of gut microbiome in depression:The promise of clinical applicability[J].Advanced Science, 2022, 9(35):2203707.
[17] GUO H, CHOU W C, LAI Y J, et al.Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites[J].Science, 2020, 370(6516):eaay9097.
[18] TIAN P J, CHEN Y, QIAN X, et al.Pediococcus acidilactici CCFM6432 mitigates chronic stress-induced anxiety and gut microbial abnormalities[J].Food & Function, 2021, 12(22):11241-11249.
[19] GROSHEVA I, ZHENG D P, LEVY M, et al.High-throughput screen identifies host and microbiota regulators of intestinal barrier function[J].Gastroenterology, 2020, 159(5):1807-1823.
[20] KÖHLER C A, MAES M, SLYEPCHENKO A, et al.The gut-brain axis, including the microbiome, leaky gut and bacterial translocation:Mechanisms and pathophysiological role in Alzheimer's disease[J].Current Pharmaceutical Design, 2016, 22(40):6152-6166.
[21] CIESIELSKA A, MATYJEK M, KWIATKOWSKA K.TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling[J].Cellular and Molecular Life Sciences:CMLS, 2021, 78(4):1233-1261.
[22] LONG H Z, ZHOU Z W, CHENG Y, et al.The role of microglia in Alzheimer's disease from the perspective of immune inflammation and iron metabolism[J].Frontiers in Aging Neuroscience, 2022, 14:888989.
[23] MA C M, LI S, HU Y C, et al.AIM2 controls microglial inflammation to prevent experimental autoimmune encephalomyelitis[J].The Journal of Experimental Medicine, 2021, 218(5):e20201796.
