Long-term probiotic intervention mitigates memory dysfunction through a novel H3K27me3-based mechanism in lead-exposed rats

Abstract

Chronic lead exposure is associated with the development of neurodegenerative diseases, characterized by the long-term memory decline. However, whether this pathogenesis could be prevented through adjusting gut microbiota is not yet understood. To address the issue, pregnant rats and their female offspring were treated with lead (125 ppm) or separately the extra probiotics (1010 organisms/rat/day) till adulthood. For results, memory dysfunction was alleviated by the treatment of multispecies probiotics. Meanwhile, the gut microbiota composition was partially normalized against lead-exposed rats, which in turn mediated the memory repairment via fecal transplantation trials. In the molecular aspect, the decreased H3K27me3 (trimethylation of histone H3 Lys 27) in the adult hippocampus was restored with probiotic intervention, an epigenetic event mediated by EZH2 (enhancer of zeste homolog 2) at early developmental stage. In a neural cellular model, EZH2 overexpression showed the similar rescue effect with probiotics, whereas its blockade led to the neural re-damages. Regarding the gut–brain inflammatory mediators, the disrupted IL-6 (interleukin 6) expression was resumed by probiotic treatment. Intraperitoneal injection of tocilizumab, an IL-6 receptor antagonist, upregulated the hippocampal EZH2 level and consequently alleviated the memory injuries. In conclusion, reshaping gut microbiota could mitigate memory dysfunction caused by chronic lead exposure, wherein the inflammation–hippocampal epigenetic pathway of IL-6-EZH2-H3K27me3, was first proposed to mediate the studied gut–brain communication. These findings provided insight with epigenetic mechanisms underlying a unique gut–brain interaction, shedding light on the safe and non-invasive treatment of neurodegenerative disorders with environmental etiology.

Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain

“…Pregnant rats and their female offspring exposed to lead resulted in the loss of dendritic spines in both CA1 and dentate gyrus (DG) regions irrespective of the developmental stages (PND 22 or PND 68). Long-term intervention with multispecies probiotic ( Bifidobacterium longum BL986, Lactobacillus acidophilus LA43, Lactobacillus fermentum LF26, Lactobacillus helveticus LH43, Lactobacillus paracasei LPC12, Lactobacillus rhamnosus LRH10, and Streptococcus therophilus ST30) restored the spine densities in both adolescence and adulthood [ 142 ].…”

Epigenetic Basis of Lead-Induced Neurological Disorders

“…Therefore, it is proposed that treatment strategies directed to the neuronal representations may be more effective in alleviating the lead-induced neurological damages [1]. In one of our previous publications [171], probiotic formulation effectively mitigated lead-led memory deficits by remodeling hippocampal histone modifications in SD rats, which demonstrated the feasibility of epigenetic manipulations in treating lead-led neuronal impairment.…”

Gut microbiome-mediated epigenetic regulation of brain disorder and application of machine learning for multi-omics data analysis

“…Gut microbiota dysbiosis has been shown to contribute to the development of AD or other cognition-related psychiatric disorders (Dickerson et al 2017;Hsiao et al 2013). In a recent study, manipulating the gut bacteria in animals using probiotics has been shown to restore the decreased H3K27me3 (trimethylation of histone H3 Lys 27) found in the adult hippocampus and partially prevented the memory dysfunction suggesting that the memory dysfunction could be ameliorated via epigenetic modulators or altering gut microbiota (Xiao et al 2020). miRNAs are a class of small, noncoding RNAs that epigenetically modulate gene expression.…”