The therapeutic effects of probiotic supplementation in a mouse model of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, which is associated with impaired cognition. The pathophysiology of AD is not fully understood, but the accumulated amyloid beta (Aβ) has been known as an early sign of AD and neuroinflammation has been suggested as a contributor in the pathogenesis of AD. In the past decade, the understandings of the commensal microbiota in human have been expanded rapidly, and their roles in neuropsychiatric disorders have been investigated. Studies in germ-free animals and animals exposed to pathogenic microbial infections, antibiotics, probiotics, or fecal microbiota transplantation proposed a role of the gut microbiota in AD pathogenesis. However, there is a lack of studies that confirm the effects of specific strains of probiotics on the brain of AD. Therefore, I sought to examine the effects of selected probiotics on the neuropathologic progression in the brain of AD model. 5XFAD transgenic mice was used as an animal model of AD. At the age of five weeks, eight groups of mice (n=8~13 animals for each group), including six probiotic-fed groups of 5XFAD mice and two vehicle-fed groups of 5XFAD and wild type, were made and daily oral administration of probiotics or vehicle was maintained for 16 weeks. I sacrificed the

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mice and harvested the brain followed by the dissection of three brain regions (cortex, hippocampus, and brainstem). The amount of soluble and insoluble amyloid-β 42 (Aβ42), were quantified by enzyme-linked immunosorbent assay (ELISA). The plasma levels of pro- and anti-inflammatory cytokines were assayed using ELISA. Metagenomic and metabolomic analyses were done with feces and serum, respectively. Among the six probiotic groups, L. reuteri, L. bulgaricus, and S. thermophilus groups showed a decreased level of soluble Aβ42 in the cortex and B. lactis group did in the hippocampus and brainstem. The levels of soluble Aβ42 of the three species groups were similar to that of the wild type group. Especially, L. reuteri group also showed decreased level of insoluble Aβ42 in the brainstem. However, in contrast, B. lactis group showed an increased level of insoluble Aβ42 in the cortex and hippocampus. In plasma samples, anti-inflammatory cytokines (IL4, IL6, IL10, G-CSF, GM-CSF) increased and pro-inflammatory ones (IL1α, IL1β, IL2, IL12, IL17, IFNɣ) decreased in the three groups with decreased Aβ42 in the cortex. In the plasma metabolome of mice, the levels of Indole lactic acid, Tryptophan and rac-α methylkynurenine is higher in the groups with decreased Aβ which are L. reuteri, L. bulgaricus, and S. thermophilus than WT group.In summary, I found that probiotic supplementation for four months in 5XFAD can induce changes in the Aβ of the brain, plasma cytokines, and metabolites. In details, groups fed with S. thermophilus, L. reuteri, and L. bulgaricus showed decreased Aβ42 in the brain, increased anti-inflammatory and decreased pro-inflammatory cytokines, and metabolites alternation. These results suggest that probiotic supplementation might alter the natural deterioration processes of AD and have a therapeutic potential in AD.