| BackgroundDementia has emerged as a major global health challenge in the 21st century.Alzheimer’s disease(AD)is the most prevalent form of dementia,and 90%of AD patients experience behavioral and psychological symptoms during the course of the disease,including apathy,depression,anxiety,and agitation.Agitation,in particular,is a common behavioral and psychological symptom in AD and has a significantly negative impact on the quality of life for both patients and caregivers.The pathology of agitation remains unclear,and clinical drug interventions carry a high risk of adverse effects,while non-pharmacological interventions impose heavy caregiving burdens.In recent years,the association between-the-gut-microbiota and neurologic disorders has garnered significant attention.Research has indicated that the gut microbiota can communicate with the host’s physiological and psychological wellbeing through the gut-brain axis,particularly in terms of social and emotional behavior regulation.However,it remains unknown whether there is a correlation between the gut microbiota and agitation in Alzheimer’s disease,and if so,whether there is a causal relationship.Currently,no publicly available studies have reported on this subject matter.Methods:Section 1:This experiment aimed to explore the relationship between different levels of agitation and the gut microbiota in APP/PS1 mice,as well as the impact of agitation severity on cognitive decline.Using a resident-intruder paradigm,mice were divided into high agitation and low agitation groups,and their behavior was assessed through behavioral experiments.Fecal samples were collected for 16S rRNA sequencing and gut microbiota analysis.Section 2:Building upon Section 1,mice with similar agitation levels were randomly assigned to two groups and orally gavaged with fecal microbiota from mice with high agitation or low agitation.The differences in aggression,locomotor activity,and cognitive performance between the two groups of transplanted mice were observed,along with the examination of gut microbiota composition and neurotransmitter levels in the brain.Section 3:This experiment aimed to investigate the influence of Escherichia coli(E.coli)in the differential microbiota of mice with high and low agitation on mouse behavior.Mice were randomly assigned to either the control group(receiving PBS)or the E.coli gavage group.The differences in aggression,locomotor activity,and cognitive performance were observed after single-bacterium intervention.Results:In the APP/PS1 mouse model,significant differences in the gut microbiota were observed between mice with high agitation and those with low agitation,despite their similar baseline cognitive levels.Longitudinal observations revealed a faster cognitive decline and elevated levels of excitatory neurotransmitters in the brains of mice with higher agitation levels.Fecal microbiota transplantation induced changes in the level of agitation in mice.Analysis of neurotransmitter levels in the brain confirmed that transplanted mice exhibited alterations in excitatory neurotransmitter levels similar to those of the donor mice,suggesting that fecal microbiota transplantation may influence agitation levels in mice by modulating neurotransmitter levels in the brain.E.coli gavage intervention affected the level of agitation in mice.Following single-bacterium intervention,changes in the gut microbiota structure,aggravated agitation levels in mice,and increased levels of neuroinflammatory factors were observed.Conclusion:There exists a bidirectional relationship between the gut microbiota and agitation in Alzheimer’s disease,with mutual influence.In the APP/PS1 mouse model,significant associations were found between the severity of agitation and the dysbiosis of the gut microbiota,suggesting a causal relationship.Additionally,monoassociation with E.coli in the gut microbiota exacerbated agitation in mice with Alzheimer’s disease,indicating that it may be one of the key dysregulated bacteria contributing to the condition. |
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