Severe Cognitive Decline in Long-term Care Is Related to Gut Microbiome Production of Metabolites Involved in Neurotransmission, Immunomodulation, and Autophagy

Abstract Aging-associated cognitive decline affects more than half of those in long-term residential aged care. Emerging evidence suggests that gut microbiome–host interactions influence the effects of modifiable risk factors. We investigated the relationship between gut microbiome characteristics and severity of cognitive impairment (CI) in 159 residents of long-term aged care. Severe CI was associated with a significantly increased abundance of proinflammatory bacterial species, including Methanobrevibacter smithii and Alistipes finegoldii, and decreased relative abundance of beneficial bacterial clades. Severe CI was associated with increased microbial capacity for methanogenesis, and reduced capacity for synthesis of short-chain fatty acids, neurotransmitters glutamate and gamma-aminobutyric acid, and amino acids required for neuroprotective lysosomal activity. These relationships were independent of age, sex, antibiotic exposure, and diet. Our findings implicate multiple gut microbiome–brain pathways in aging-associated cognitive decline, including inflammation, neurotransmission, and autophagy, and highlight the potential to predict and prevent cognitive decline through microbiome-targeted strategies.

• Publication year

  2025

• Venue

  The journals of gerontology. Series A, Biological sciences and medical sciences

• Publication date

  2025-03-28

• Fields of study

  Medicine, Environmental Science

• Identifiers
  DOI 10.1093/gerona/glaf053PMID 40166866PMCID 12168445
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2020influential reference
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  2020cited by this paper
• GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition

  2020cited by this paper
• The Microbiota-Gut-Brain Axis.

  2019cited by this paper
• The microbiota–gut–brain axis

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  2019cited by this paper
• Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health

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• Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

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• D-glutamate, D-serine, and D-alanine differ in their roles in cognitive decline in patients with Alzheimer's disease or mild cognitive impairment.

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• Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism

  2018cited by this paper
• Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson's disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway.

  2018cited by this paper
• ApoE facilitates the microglial response to amyloid plaque pathology

  2018cited by this paper
• Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure.

  2018cited by this paper
• Inflammation in CNS neurodegenerative diseases

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• Microglial Activation After Systemic Stimulation With Lipopolysaccharide and Escherichia coli

  2018cited by this paper
• Cognitive function trajectories and their determinants in older people: 8 years of follow-up in the English Longitudinal Study of Ageing

  2018cited by this paper
• Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation

  2018cited by this paper
• Association Between Autophagy and Neurodegenerative Diseases

  2018cited by this paper
• APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types.

  2018cited by this paper
• Neurotransmitter modulation by the gut microbiota.

  2018cited by this paper
• Inflammaging: a new immune–metabolic viewpoint for age-related diseases

  2018cited by this paper
• Genetic variation within endolysosomal system is associated with late-onset Alzheimer’s disease

  2018cited by this paper
• Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline

  2018cited by this paper
• A gut-brain neural circuit for nutrient sensory transduction

  2018cited by this paper
• Converging pathways in neurodegeneration, from genetics to mechanisms

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• Autophagy maintains tumor growth through circulating arginine

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• An Investigation Into Physical Frailty as a Link Between the Gut Microbiome and Cognitive Health

  2018cited by this paper
• APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types.

  2018cited by this paper
• Gut microbiome alterations in Alzheimer’s disease

  2017cited by this paper
• ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

  2017cited by this paper
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• ApoE4 Accelerates Early Seeding of Amyloid Pathology.

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• Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs

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• Plasma α-synuclein predicts cognitive decline in Parkinson’s disease

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• Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice

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• Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods123

  2016cited by this paper
• The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior

  2016cited by this paper
• The Central Nervous System and the Gut Microbiome.

  2016cited by this paper
• Regulation of immune cell function by short-chain fatty acids

  2016cited by this paper
• Signatures of early frailty in the gut microbiota

  2016cited by this paper
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• From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

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  2016cited by this paper
• Host microbiota constantly control maturation and function of microglia in the CNS

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• Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour.

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• Systemic Inflammation and the Brain: Novel Roles of Genetic, Molecular, and Environmental Cues as Drivers of Neurodegeneration

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• Effects of amyloid and vascular markers on cognitive decline in subcortical vascular dementia

  2015cited by this paper
• Trimmomatic: a flexible trimmer for Illumina sequence data

  2014influential reference
• Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.

  2014cited by this paper
• The role of autophagy in neurodegenerative disease

  2013cited by this paper
• Alzheimer’s disease: amino acid levels and brain metabolic status

  2013cited by this paper
• Normal cognitive aging.

  2013cited by this paper
• Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice.

  2013cited by this paper
• Fast gapped-read alignment with Bowtie 2

  2012influential reference
• Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer's disease

  2012cited by this paper
• GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology

  2012cited by this paper
• Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers

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• Composition, variability, and temporal stability of the intestinal microbiota of the elderly

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• Characterization of the sickness response in young and aging rats following E. coli infection.

  2009cited by this paper
• Induction of autophagy by spermidine promotes longevity

  2009cited by this paper
• A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease

  2008cited by this paper

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