Palepu Mani Surya Kumar, Bhalerao Harshada Anil, Sonti Rajesh, Dandekar Manoj P
Department of Biological Sciences, Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
Eur J Pharmacol. 2024 Nov 15;983:176960. doi: 10.1016/j.ejphar.2024.176960. Epub 2024 Aug 29.
Alterations in commensal gut microbiota, such as butyrate-producing bacteria and its metabolites, have been linked to stress-related brain disorders, including depression. Herein, we investigated the effect of Faecalibacterium prausnitzii (ATCC-27766) administered along with fructooligosaccharides (FOS) and galactooligosaccharides (GOS) in a rat model of treatment-resistant depression (TRD). The behavioral changes related to anxiety-, anhedonia- and despair-like phenotypes were recorded employing elevated plus maze, sucrose-preference test, and forced-swim test, respectively. Rats exposed to unpredictable chronic mild-stress (UCMS) and adrenocorticotropic hormone (ACTH) injections exhibited a TRD-like phenotype. Six-week administration of F. prausnitzii and FOS + GOS ameliorated TRD-like conditions in rats. This synbiotic treatment also restored the decreased levels of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate in the fecal samples of TRD rats. Synbiotic-recipient TRD rats displayed an increased abundance of Lactobacillus helveticus, Lactobacillus hamsteri, and Ruminococcus flavefaciens. Moreover, more mucus-producing goblet cells were seen in the colon of synbiotic-treated rats, suggesting improved gut health. The synbiotic treatment effectively modulated neuroinflammation by reducing proinflammatory cytokines (IFN-γ, TNF-α, CRP, and IL-6). It normalized the altered levels of key neurotransmitters such as serotonin, gamma-aminobutyric acid, noradrenaline, and dopamine in the hippocampus and/or frontal cortex. The enhanced expression of brain-derived neurotrophic factor, tryptophan hydroxylase 1, and serotonin transporter-3 (SERT-3), and reduced levels of indoleamine 2,3-dioxygenase 1 (IDO-1) and kynurenine metabolite were observed in the synbiotic-treated group. We suggest that F. prausnitzii and FOS + GOS-loaded synbiotic may reverse the TRD-like symptoms in rats by positively impacting gut health, neuroinflammation, neurotransmitters, and gut microbial composition.
共生肠道微生物群的改变，如产生丁酸盐的细菌及其代谢产物，已与包括抑郁症在内的应激相关脑疾病有关。在此，我们研究了在难治性抑郁症（TRD）大鼠模型中，将普拉梭菌（ATCC-27766）与低聚果糖（FOS）和低聚半乳糖（GOS）一起给药的效果。分别采用高架十字迷宫、蔗糖偏好试验和强迫游泳试验记录与焦虑、快感缺失和绝望样表型相关的行为变化。暴露于不可预测的慢性轻度应激（UCMS）和促肾上腺皮质激素（ACTH）注射的大鼠表现出TRD样表型。对大鼠进行为期六周的普拉梭菌和FOS + GOS给药改善了TRD样状况。这种合生元治疗还恢复了TRD大鼠粪便样本中乙酸盐、丙酸盐和丁酸盐等短链脂肪酸（SCFA）水平的降低。接受合生元的TRD大鼠中瑞士乳杆菌、仓鼠乳杆菌和黄褐瘤胃球菌的丰度增加。此外，在接受合生元治疗的大鼠结肠中可见更多产生黏液的杯状细胞，表明肠道健康得到改善。合生元治疗通过减少促炎细胞因子（IFN-γ、TNF-α、CRP和IL-6）有效调节神经炎症。它使海马体和/或额叶皮质中血清素、γ-氨基丁酸、去甲肾上腺素和多巴胺等关键神经递质的改变水平恢复正常。在合生元治疗组中观察到脑源性神经营养因子、色氨酸羟化酶1和血清素转运体-3（SERT-3）的表达增强，以及吲哚胺2,3-双加氧酶1（IDO-1）和犬尿氨酸代谢产物水平降低。我们认为，装载普拉梭菌和FOS + GOS的合生元可能通过对肠道健康、神经炎症、神经递质和肠道微生物组成产生积极影响来逆转大鼠的TRD样症状。
