Correlation Between Gut Microbiota And Tauopathies

Background and objectiveTauopathies are progressive neurodegenerative disorders and the accumulation of pathological tau is the hallmark of these diseases and is closely correlated with cognitive decline.The comprehensive pathogenesis of tauopathies remains unclear.Moreover,thus far,no therapeutic interventions are currently available.Bidirectional communication between the brain and gut microbiota?GM?has long been recognized.The dyshomeostasis in the gut microbiota is proposed to be a crucial cause of central nervous system diseases.However,the alteration in gut microbial composition and diversity of tauopathies has not yet been clearly confirmed.In the present study,we analyzed the alteration of GM in P301 L transgenic mice mice and their sex-matched wild-type?Wt?littermates at different ages.The differences of GM between P301 L and Wt mice were compared;the correlation between GM and pathological tau protein levels in the brain of tau mice was also analyzed.Materials and methods1.We collected fecal samples from P301 L tau transgenic mice and age-and gender-matched littermate mice at 1,3,6 and 10 months of age.The DNA of gut microbiota was extracted by E.Z.N.A.? Stool DNA Kit.2.The 16 S ribosomal RNA sequencing technique?16S rRNA?was used to analyze the microbiota composition in feces.3.The differences of GM diversity were analyzed by R software and SPSS,as well as the differences between P301 L and Wt mice.4.Immunohistochemistry methods were used for phosphorylated tau immunohistochemical staining.The fraction of positive staining was quantified as the burden of tau pathological.The correlation between brain pathology and the abundance of microbiota were analyzed.Results1.Changes in ? and ? diversity of GM during aging: The ? divestity was higher in 3-month-old and 6 month-old Wt mice than in 1-month-old Wt mice.The relationships between the community structures were examined by PCoA.The community structures of the GM differed as a function of age in Wt mice.2.Changes in ? and ? diversity of GM during aging for tauopathies mouse model: No significant difference was observed in ? divestity between different months of age P301 L mice.The community structures of the GM examined by PCoA differed as a function of age in P301 L mice.For mice at different months of age,no significant difference was observed in PCoA btween P301 L and Wt mice in 1-month-old,wile significant difference were observed in PCoA btween P301 L and Wt mice from 3 months of age onward.3.Changes of GM composition in tauopathies mouse model.At the phylum level,no significant difference was observed in GM btween P301 L and Wt mice at 1 months of age.After 3 months of age,the relative abundance of Bacteroidetes was increased,while Firmicutes was decreased in P301 L mice compared with that in Wt mice.In addition,Actinobacteria was decreased in P301 L mice at 3 and 6 months of age.Tenericutes was decreased in P301 L mice at 10 months of age when compared with that in Wt mice.4.The correlation between GM and pathological tau protein levels in the brain of P301 L mice.PT231-positive staining was mainly observed in hippocampus and amygdala of p301 L mice as early as 1 month,while significant AT8-positive staining was observed until the animal reached 3 months,which mainly accumulated in the area of amygdala.Significant correlation was observed between GM and pathological tau protein levels in the brain of P301 L mice.At the genus level,Marvinbryantia was negatively correlated with pT231-tau levels in the brain of P301 L mice at 3 months of age.In P301 L mice at 6 months of age,Lactobacillus and Desulfovibrio were negatively correlated with pT231-tau levels,while Streptococcus,Anaerotruncus,Lactococcus,unclassified_fErysipelotrichaceae and Eubacterium_brachy_group were negatively correlated with AT8-tau levels in the brain.In P301 L mice at 10 months of age,Candidatus_Saccharimonas,Alistipes,Rikenella,Odoribacter,Blautia,Ruminococcaceae_UCG-014,Eubacterium_xylanophilum_group,Paraprevotella,Butyricicoccus,Ruminiclostridium₆ and Parvibacter were negatively correlated with pT231-tau levels,while Bacteroides,Parabacteroides,Escherichia-Shigella and Clostridium_innocuum_group were positively correlated with pT231-tau levels in the brain.ConclusionThe diversity of gut microbiota changed with aging in mice.Moreover,changes in gut microbiota composition are highly associated with pathological changes in the brain in tauopathies,suggesting gut microbiota may be involved in the occurrence and development of tauopathies.