The Effect And Mechanism Of Probiotics Against The Learning And Memory Damage Induced By Lead Exposure

Purposes:Chronic lead exposure is associated with the development of neurodegenerative diseases,featuring the long-term memory decline.Children are especially susceptible to lead exposure.The high blood-lead level can lead to a slow intelligence development of children.Probiotics,which have a wide application in making functional food and fermentative dairy beverage,have a notable effect on human's health.Some reports have claimed that probiotics can treat neurogenic disease by improving intestinal flora.Hence,the purpose of this paper is to investigate whether the learning and memory damage induced by lead could be prevented through adjusting gut microbiota,as well as the roles of cerebral epigenetics in such a process.Methods:Rats were randomly divided into four groups:control group,lead exposure group,lead exposure and probiotics treatment group,and probiotic treatment group.Here,pregnant SD rats and their female offspring were treated separately with low-level lead?125 ppm?or the extra probiotics(10¹⁰ organisms/rat/day)till adulthood?PND 68?.When the modeling was completed,Spatial memory was assessed through the behavioral and morphological tests.Gut microbial composition was profiled through16S rRNA sequencing.The existing levels of H3K27me3?methylation at Lys27 of histone H3?and IL-6?Interleukin 6?were assessed by Western blotting and ELISA,respectively,with genetic and pharmacological intervention utilized to examine their respective modulatory roles.Results:1)The memory dysfunction was considerably alleviated by the treatment of multispecies probiotics.Meanwhile,the structure of gut microbiota was partially normalized against lead-exposed at rats'both early developmental stage and adult,as manifested by the species diversity as well as the abundance of Firmicutes,Bacteroidetes and their relative ratio.Probiotics helped maintaining the relative homeostasis of the gut microbiota,and made the colony structure more similar to the control group.The results show that probiotics help rats get a higher score in the behavior test against the damage of spatial memory as well as working memory due to chronic lead exposure.The morphology detection of neuron dendritic spine in hippocampus supports the results of behavior test;2)EZH2-H3K27me3 as an epigenetics switch plays an important role in the process of repairing neuron damage.The decreased level of H3K27me3 in the adult hippocampus was restored with probiotic intervention,an epigenetic event mediated by the corresponding changes of EZH2?Enhancer of zeste homolog 2?.Using genetic perturbation in a neural cellular model,overexpression of EZH2 showed the similar rescue effect of probiotics,whereas its blockade led to the reproduced neural damages;3)Inflammatory factor?interleukin 6?IL-6 establishes the communication between intestinal microbiota and neuron damage.The abundance of IL-6 was aberrantly increased by lead and resumed by the treatment of probiotics.Intraperitoneal injection of tocilizumab,an IL-6 receptor antagonist,significantly upregulated the hippocampal EZH2 level and consequently alleviated the memory injuries induced by lead.Conclusions:Reshaping gut microbiota is a new strategy to mitigate memory dysfunction caused by chronic lead exposure,wherein the inflammation-hippocampal epigenetic pathway of IL-6-EZH2-H3K27me3,was proposed to mediate the studied gut-brain communication.These findings provided insight with epigenetic changes underlying a specific gut-brain interaction,shedding light on the safe and non-invasive therapeutics of neurodegenerative disorders with environmental etiology.