背景:弓形虫感染影响了全球很大一部分人口,导致严重的弓形虫病,在免疫功能低下的患者中,甚至死亡。在弓形虫感染期间,肠道微生物群的破坏进一步加剧了对肠道和大脑屏障的损害。因此,在感染过程中识别不平衡的益生菌并恢复其平衡可以调节肠道微生物群代谢产物的平衡,从而减轻组织损伤。
方法:采用波形蛋白基因敲除(vim-/-)小鼠作为免疫受损模型,评估弓形虫感染期间宿主免疫反应对肠道菌群平衡的影响。进行行为实验以评估慢性感染的vim-/-和野生型(WT)小鼠之间的认知水平和抑郁倾向的变化。对粪便样品进行16S核糖体RNA(rRNA)测序,和血清代谢产物进行分析,以确定潜在的肠道益生菌及其代谢产物用于治疗弓形虫感染。
结果:与具有免疫能力的WTsv129小鼠相比,在慢性感染期间,免疫功能低下的小鼠表现出较低水平的神经元凋亡和较少的神经行为异常。16SrRNA测序显示益生菌的丰度显着下降,包括几种乳酸菌,在WT小鼠中。通过施用鼠乳杆菌和加氏乳杆菌来恢复这种平衡显着抑制了肠道中的弓形虫负担,肝脏,和大脑。此外,这两种乳酸菌的移植。显著改善肠屏障损伤,减轻中枢神经系统炎症反应和神经元凋亡。代谢物检测研究表明,各种乳酸菌相关代谢物的水平,包括血清中的吲哚-3-乳酸(ILA),弓形虫感染后显著下降。我们证实gasseri乳杆菌比murinus乳杆菌分泌更多的ILA。值得注意的是,ILA可激活肠上皮细胞芳香烃受体信号通路,促进CD8+T细胞的激活和干扰素-γ的分泌。
结论:我们的研究表明,宿主针对弓形虫感染的免疫反应严重破坏了肠道菌群的平衡,导致肠道和脑损伤。乳杆菌属。在免疫调节中起着至关重要的作用,和代谢物ILA是有效和安全治疗弓形虫感染的有前途的治疗化合物。
BACKGROUND: Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death. During T. gondii infection, disruption of gut microbiota further exacerbates the damage to intestinal and brain barriers. Therefore, identifying imbalanced probiotics during infection and restoring their equilibrium can regulate the balance of gut microbiota metabolites, thereby alleviating tissue damage.
METHODS: Vimentin gene knockout (vim-/-) mice were employed as an immunocompromised model to evaluate the influence of host immune responses on gut microbiota balance during T. gondii infection. Behavioral experiments were performed to assess changes in cognitive levels and depressive tendencies between chronically infected vim-/- and wild-type (WT) mice. Fecal samples were subjected to 16S ribosomal RNA (rRNA) sequencing, and serum metabolites were analyzed to identify potential gut probiotics and their metabolites for the treatment of T. gondii infection.
RESULTS: Compared to the immunocompetent WT sv129 mice, the immunocompromised mice exhibited lower levels of neuronal apoptosis and fewer neurobehavioral abnormalities during chronic infection. 16S rRNA sequencing revealed a significant decrease in the abundance of probiotics, including several species of Lactobacillus, in WT mice. Restoring this balance through the administration of Lactobacillus murinus and Lactobacillus gasseri significantly suppressed the T. gondii burden in the intestine, liver, and brain. Moreover, transplantation of these two Lactobacillus spp. significantly improved intestinal barrier damage and alleviated inflammation and neuronal apoptosis in the central nervous system. Metabolite detection studies revealed that the levels of various Lactobacillus-related metabolites, including indole-3-lactic acid (ILA) in serum, decreased significantly after T. gondii infection. We confirmed that L. gasseri secreted much more ILA than L. murinus. Notably, ILA can activate the aromatic hydrocarbon receptor signaling pathway in intestinal epithelial cells, promoting the activation of CD8+ T cells and the secretion of interferon-gamma.
CONCLUSIONS: Our study revealed that host immune responses against T. gondii infection severely disrupted the balance of gut microbiota, resulting in intestinal and brain damage. Lactobacillus spp. play a crucial role in immune regulation, and the metabolite ILA is a promising therapeutic compound for efficient and safe treatment of T. gondii infection.