Select microbial metabolites promote tau aggregation in a murine tauopathy model

Description

The gut microbiome is emerging as a modifier of risk for neurodegenerative diseases, but underlying mechanisms remain poorly understood. Here, we show that the hTau.P301S mouse model for progressive tauopathy develops alterations in the composition and function of the gut microbiome that are not recapitulated in amyloid-based 5xFAD or 3xTg models for Alzheimer’s disease. Disrupting the gut microbiome via chronic antibiotic treatment exacerbates cognitive deficits and tau pathology in hTau.P301S mice, demonstrating a causal influence of the microbiome on tau-driven disease progression. This corresponds with widespread alterations in microbiome-dependent metabolites in the sera and brains of hTau.P301S mice, including subsets that correlate with the severity of tau pathology. By screening against tau biosensor cells, we identify select microbial metabolites—trimethylamine-N-oxide, 3-indoxyl sulfate, phenol sulfate, thymidine, and 2’deoxyuridine—that directly promote tau seeding and aggregation. Systemic administration of these metabolites worsens cognitive impairment and tau pathology in hTau.P301S mice. These findings establish a mechanistic link between the gut microbiome, serum and brain metabolites, and tau aggregation, and suggest that select microbial metabolites could serve as potential targets of therapeutic interventions for tau-driven disease. Files below contain untargeted metabolomics data from: -mouse brains collected from 6 month old C57B6J wild-type mice after antibiotic (ABX) or vehicle treatment (SPF) or hTau.P301S mice after antibiotic (ABX) or vehicle treatment (SPF) -mouse sera collected from 6 month old C57B6J wild-type mice after antibiotic (ABX) or vehicle treatment (SPF) or hTau.P301S mice after antibiotic (ABX) or vehicle treatment (SPF)

Institutions

• University of California Los Angeles

  CA, Los Angeles

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