Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, M.S., 441 002, India.
Government College of Pharmacy, Kathora Naka, VMV Road, Amravati, M.S., 44604, India.
Eur J Pharmacol. 2024 Oct 15;981:176884. doi: 10.1016/j.ejphar.2024.176884. Epub 2024 Aug 10.
Depression is a global health concern affecting nearly 280 million individuals. It not only imposes a significant burden on economies and healthcare systems but also manifests complex physiological connections and consequences. Agmatine, a putative neuromodulator derived primarily from beneficial gut microbes specially Lactobacillus, has emerged as a potential therapeutic agent for mental health. The microbiota-gut-brain axis is involved in the development of depression through the peripheral nervous system, endocrine system, and immune system and may be a key factor in the effect of agmatine. Therefore, this study aimed to investigate the potential mechanism of agmatine in antibiotic-induced dysbiosis and depression-like behavior in rats, focusing on its modulation of the gut-brain axis. Depression-like behavior associated with dysbiosis was induced through a seven-day regimen of the broad-spectrum antibiotic, comprising ampicillin and metronidazole and validated through microbial, biochemical, and behavioral alterations. On day 8, antibiotic-treated rats exhibited loose fecal consistency, altered fecal microbiota, and depression-like behavior in forced swim test. Pro-inflammatory cytokines were elevated, while agmatine and monoamine levels decreased in the hippocampus and prefrontal cortex. Antibiotic administration disrupted tight junction proteins in the ileum, affecting gut architecture. Oral administration of agmatine alone or combined with probiotics significantly reversed antibiotic-induced dysbiosis, restoring gut microbiota and mitigating depression-like behaviors. This intervention also restored neuro-inflammatory markers, increased agmatine and monoamine levels, and preserved gut integrity. The study highlights the regulatory role of endogenous agmatine in the gut-brain axis in broad-spectrum antibiotic induced dysbiosis and associated depression-like behavior.
抑郁症是一种全球性的健康问题，影响着近 2.8 亿人。它不仅给经济和医疗系统带来了巨大负担，还表现出复杂的生理联系和后果。胍丁胺，一种主要来源于有益肠道微生物（特别是乳杆菌）的假定神经调节剂，已成为治疗心理健康的潜在药物。微生物群-肠道-大脑轴通过外周神经系统、内分泌系统和免疫系统参与抑郁症的发展，可能是胍丁胺作用的关键因素。因此，本研究旨在探讨胍丁胺在抗生素诱导的肠道菌群失调和大鼠抑郁样行为中的潜在机制，重点研究其对肠道-大脑轴的调节作用。通过为期七天的广谱抗生素（包括氨苄西林和甲硝唑）方案诱导与肠道菌群失调相关的抑郁样行为，并通过微生物、生化和行为改变进行验证。在第 8 天，抗生素处理的大鼠表现出粪便松软、粪便微生物群改变和强迫游泳试验中的抑郁样行为。促炎细胞因子升高，而海马体和前额叶皮质中的胍丁胺和单胺水平下降。抗生素给药破坏了回肠中的紧密连接蛋白，影响了肠道结构。胍丁胺单独或与益生菌联合口服给药可显著逆转抗生素诱导的肠道菌群失调，恢复肠道微生物群并减轻抑郁样行为。这种干预还恢复了神经炎症标志物，增加了胍丁胺和单胺水平，并保持了肠道完整性。该研究强调了内源性胍丁胺在广谱抗生素诱导的肠道菌群失调和相关抑郁样行为中的肠道-大脑轴的调节作用。
