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<p>The gut–brain axis is increasingly recognised as a modulator of Alzheimer’s disease progression. Diet-induced obesity alters gut microbial composition and host metabolism, but its interaction with early tau pathology remains insufficiently understood. Here, we investigated sex-specific alterations in urinary and fecal untargeted LC–MS metabolomic profiles and gut microbiome composition in the THY-Tau22 mouse model, which develops tau pathology without motor deficits. Male and female transgenic and wild-type mice were maintained on either standard chow or a high-fat diet, and fecal microbiota were characterised by 16&#xa0;S rRNA gene sequencing. High-fat diet was the dominant source of metabolomic and microbial variation, particularly in males, and was associated with elevated urinary acylcarnitines and increased fecal amino acids linked to obesity and insulin resistance. Genotype-associated differences were more subtle and depended on sex and dietary context. Genus-level analysis identified significant differences in unclassified <i>Erysipelotrichaceae</i>, <i>Prevotellaceae</i> UCG-001 and <i>Ruminococcus</i> in males, whereas no genus remained significant in females after false-discovery-rate correction. FDR-corrected integrative analyses linked selected bacterial families and fecal metabolites primarily to body weight and identified positive associations of <i>Lactobacillaceae</i> with Iba1 in the hippocampus and cortex. No association with the available Y-maze novel-zone visit ratio remained significant after correction. These findings show that diet and sex strongly shape peripheral metabolomic and gut microbial profiles in THY-Tau22 mice. The study identifies candidate tau-associated features for further validation while demonstrating that dietary effects must be explicitly separated from genotype effects in gut–brain-axis studies.</p>

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Sex differences in fecal and urinary metabolome and gut microbiome in a tauopathy mouse model of Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Doris Janoušová,
  • Petra Tomášová,
  • Miroslava Kacířová,
  • Lenka Maletínská,
  • Helena Marešová,
  • Blanka Šedivá,
  • Marie Heczková,
  • Nikola Ďásková,
  • Ištván Modos,
  • Monika Cahová,
  • Helena Pelantová,
  • Andrea Palyzová,
  • Jana Michailidu,
  • Olga Maťátková,
  • Marek Kuzma,
  • Irena Jarošová Kolouchová

摘要

The gut–brain axis is increasingly recognised as a modulator of Alzheimer’s disease progression. Diet-induced obesity alters gut microbial composition and host metabolism, but its interaction with early tau pathology remains insufficiently understood. Here, we investigated sex-specific alterations in urinary and fecal untargeted LC–MS metabolomic profiles and gut microbiome composition in the THY-Tau22 mouse model, which develops tau pathology without motor deficits. Male and female transgenic and wild-type mice were maintained on either standard chow or a high-fat diet, and fecal microbiota were characterised by 16 S rRNA gene sequencing. High-fat diet was the dominant source of metabolomic and microbial variation, particularly in males, and was associated with elevated urinary acylcarnitines and increased fecal amino acids linked to obesity and insulin resistance. Genotype-associated differences were more subtle and depended on sex and dietary context. Genus-level analysis identified significant differences in unclassified Erysipelotrichaceae, Prevotellaceae UCG-001 and Ruminococcus in males, whereas no genus remained significant in females after false-discovery-rate correction. FDR-corrected integrative analyses linked selected bacterial families and fecal metabolites primarily to body weight and identified positive associations of Lactobacillaceae with Iba1 in the hippocampus and cortex. No association with the available Y-maze novel-zone visit ratio remained significant after correction. These findings show that diet and sex strongly shape peripheral metabolomic and gut microbial profiles in THY-Tau22 mice. The study identifies candidate tau-associated features for further validation while demonstrating that dietary effects must be explicitly separated from genotype effects in gut–brain-axis studies.