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Comorbid Alzheimer's Disease and Type 2 Diabetes Microbiota Shape Age-Associated Gut-Brain Axis Profiles

Alessandro Atzeni1, Jonas Mingaila1, Gediminas Alzbutas2

  • 1Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania.

Aging Cell
|April 22, 2026
PubMed

Insights

Gut microbiota from elderly individuals with Alzheimer's disease and type 2 diabetes significantly alters the gut-brain axis in mice, impacting neurotrophic genes and behavior. Age-associated microbial changes may influence neurodegeneration.

Area of Science:

  • Neuroscience
  • Microbiology
  • Gerontology
  • Metabolic Disorders

Background:

  • Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share underlying metabolic and inflammatory pathways potentially influenced by gut microbiota.
  • The specific neurobiological effects of comorbid AD and T2DM microbiota, particularly from elderly donors, have not been previously investigated.

Purpose of the Study:

  • To explore the neurobiological impact of fecal microbiota transplantation (FMT) from elderly donors with healthy, AD, T2DM, or comorbid AD+T2DM conditions into mice.
  • To analyze the resulting changes in mouse behavior, blood profiles, hippocampal gene expression, and gut microbial composition and function.

Main Methods:

  • Fecal microbiota from elderly female donors (healthy, AD, T2DM, AD+T2DM) was transplanted into antibiotic-treated male mice.
  • Comprehensive analysis included behavioral testing, blood profiling, hippocampal neurotrophic gene expression analysis, and 16S rRNA sequencing for microbial profiling (taxonomic, functional, metabolic).

Main Results:

  • Microbiota from AD+T2DM donors induced the most significant gut dysbiosis in mice, characterized by increased pro-inflammatory bacteria, reduced butyrate producers, and diminished neuroprotective pathways.
  • FMT from AD+T2DM donors led to the greatest divergence in recipient gut microbiota composition compared to controls and healthy recipients.
  • Recipient hippocampal neurotrophic gene expression was most suppressed in the AD+T2DM group, correlating with specific microbial taxa and functions associated with disease and aging.
  • AD recipients exhibited impaired olfactory discrimination and increased daytime activity; metabolic analysis revealed depleted biosynthesis pathways for flavonoids, isoflavonoids, and lignans.

Conclusions:

  • Gut microbiota from elderly individuals with comorbid AD+T2DM can induce significant gut-brain axis alterations, linking aging, metabolic dysfunction, and neurodegeneration.
  • Age-associated gut microbial signatures play a crucial role in modulating neurobiological outcomes, highlighting potential therapeutic targets for neurodegenerative diseases.
Keywords:
Alzheimer's diseaseagingcomorbidityfecal microbiota transplantationgut microbiotagut–brain axistype 2 diabetes mellitus

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