Gut Microbiota Alteration and Its Time Course in a Tauopathy Mouse Model

Abstract

Emerging evidence suggests that gut microbiota dysbiosis plays a role in neurodegenerative disorders. However, whether the composition and diversity of the gut microbiota are altered in tauopathies remains largely unknown. This study was aimed to examine the diversity and composition of the gut microbiota in tauopathies, as well as the correlation with pathological changes in the brain. We collected fecal samples from 32 P301L tau transgenic mice and 32 age-and gendermatched littermate mice at different ages. The 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. Brain tau pathology levels were measured by immunohistochemistry. The diversity and composition of the gut microbiota significantly changed with aging. At the phylum level, the relative abundance of Bacteroidetes was increased, while Firmicutes were decreased in P301L mice compared with that in Wt mice after 3 months of age. In addition, Actinobacteria was decreased in P301L mice at 3 and 6 months of age, meanwhile Tenericutes was decreased in P301L mice at 10 months of age. Moreover, several specific macrobiota were highly associated with the levels of AT8-tau or pT231-tau protein in the brain. Our findings suggest that gut microbiota changed with aging, as well as in the tauopathy mice model. Modulation of the gut microbiota may be a potential strategy for treatment of tauopathy.

Spatial Memory and Gut Microbiota Alterations Are Already Present in Early Adulthood in a Pre-clinical Transgenic Model of Alzheimer’s Disease

“…Our results agree with those reported by Bonfili et al (2017) , where they show no differences in alpha diversity in 3xTg-AD mice at 2, 3, 4.5, and 6 months old. This same effect was observed in P301L tau transgenic mice at 1, 3, and 6 months old ( Sun et al, 2019 ). However, it has been demonstrated that 9 months old 3xTg-AD mice showed lower alpha diversity than NoTg mice ( Syeda et al, 2018 ).…”

“…Furthermore, we observed a decrease in the relative abundance of TM7 in female and male 3xTg-AD mice at 3 and 5 months old in comparison to NoTg mice, while an increase was found in the relative abundance of Fusobacteria and Cyanobacteria in female and male 3xTg-AD mice at 5 months old in comparison to NoTg mice. This effect has been also reported in P301L mice, a tauopathy model at 3 and 6 months old ( Sun et al, 2019 ), and in AD patients ( Vogt et al, 2017 ). Also, a decrease in relative abundance in both TM7 and Cyanobacteria has been documented in female 3xTg-AD mice at 9 months old ( Syeda et al, 2018 ).…”

“…Bifidobacterium is a principal bacterium of Actinobacteria phylum that participates in intestinal homeostasis, and the gut–brain axis modulates the GABAergic system in the intestine ( Binda et al, 2018 ). A decrease in Actinobacteria contributes to tau pathogenesis and cognitive decline ( Sun et al, 2019 ). This loss in the relative abundance of Actinobacteria could be related to the memory retention deficit of NOL observed in this study.…”

Roles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease

“…Wang et al (2015) demonstrated that exposure to Helicobacter pylori filtrate induces Alzheimer-like tau hyperphosphorylation by activating glycogen synthase kinase-3β (GSK-3β). Sun et al (2019a) also found that decrease in abundance of gut bacteria such as Marvinbryantia, Lactobacillus, Streptococcus, unclassified_Erysipelotrichaceae, and Eubacterium_brachy_group were negatively correlated with tau pathology in the brain in a tauopathy model, suggesting that the decrease in these microbiota may be closely related to the severity of tauopathies. Recently, Wei et al (2020) found that outer membrane vesicles, produced by the gut microbiota, increase the permeability of the BBB and promote the activation of astrocytes and microglia, inducing an inflammatory response and tau hyperphosphorylation by activating the GSK-3β pathway, ultimately leading to cognitive impairment.…”

Contribution of Gut Microbiota to Immunological Changes in Alzheimer’s Disease

“…Both higher ( 44 , 49 , 52 ) and lower ( 45 , 51 ) abundance was reported of the phylum Firmicutes in AD mouse models. Families and genera that contain butyrate-producing species like the family Lachnospiraceae ( 49 , 51 , 52 ) and the genus Roseburia ( 50 – 52 ) were also both increased and reduced in AD mice compared to WT. Notably, the butyrate-producing genus Ruminococcus was either unchanged or decreased ( 46 , 47 , 49 ).…”