Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway Original paper

What was studied?

The focus keyphrase Alzheimer’s disease microbiome anchors this study, which investigated how the intestinal microbial ecosystem of elders with Alzheimer’s disease differs from that of elders without dementia or with other dementia types. The researchers used shotgun metagenomic sequencing and functional epithelial assays to examine whether the Alzheimer’s disease microbiome contributes to dysregulation of the anti-inflammatory P-glycoprotein (P-gp) pathway, a key regulator of intestinal homeostasis. They followed 108 nursing home residents for up to five months, collecting 300 longitudinal stool samples and pairing microbial community profiling with in vitro experiments to test whether stool-derived metabolites alter epithelial P-gp expression. This design allowed direct exploration of how specific microbial signatures relate to inflammation-associated dysfunction in epithelial barrier regulation, a hypothesized mechanistic link along the gut–brain axis.

Who was studied?

The cohort consisted of 108 nursing home elders: 51 without dementia, 24 with clinically diagnosed Alzheimer’s disease, and 33 with other dementia types. Participants were similar in age, sex, and comorbidity burden, though those with Alzheimer’s disease had higher frailty and malnutrition scores. Individuals with recent antimicrobial exposure or acute illness were excluded to avoid confounding effects on the microbiome. Monthly stool collections yielded up to four samples per participant, producing a robust longitudinal dataset. The study population reflects a high-risk demographic in which dementia, frailty, and polypharmacy frequently overlap, enabling detailed evaluation of how these clinical factors modify microbiome composition.

Most important findings

Elders with Alzheimer’s disease showed a distinct microbial signature characterized by reduced abundances of key butyrate-producing taxa (e.g., Eubacterium rectale, E. hallii, Faecalibacterium prausnitzii, Roseburia hominis, Butyrivibrio hungatei) and increased abundances of proinflammatory or neurologically associated species (Odoribacter splanchnicus, Bacteroides vulgatus, Eggerthella lenta, Klebsiella pneumoniae, Bacteroides fragilis). These differences persisted after adjusting for frailty, malnutrition, and medications. Machine-learning models integrating clinical and microbiome data accurately distinguished Alzheimer’s disease from non-dementia states, with microbial taxa often outperforming clinical variables. Functionally, stool supernatants from Alzheimer’s disease elders induced significantly lower epithelial P-gp expression and slightly elevated MRP2 expression, indicating a shift toward a more inflammatory epithelial phenotype. A subset of Alzheimer’s associated species also predicted P-gp suppression, linking microbial composition directly to functional impairment of the anti-inflammatory pathway.

Key implications

The Alzheimer’s disease microbiome appears to foster a proinflammatory intestinal environment characterized by reduced butyrate synthesis capacity and impaired P-gp-mediated epithelial regulation. These findings provide mechanistic support for the hypothesis that Alzheimer’s pathophysiology may involve gut-derived inflammatory signaling. By identifying microbial species and functional pathways that predict both dementia status and epithelial immune dysregulation, the study points toward microbiome-derived biomarkers and therapeutic targets. Such targets may include restoration of butyrate-producing taxa, modulation of inflammatory species, or interventions aimed at rebalancing P-gp/endocannabinoid signaling. This positions the gut microbiome not merely as a correlate of Alzheimer’s disease but as a potential contributor to its systemic inflammatory burden.

Citation

Haran JP, Bhattarai SK, Foley SE, Dutta P, Ward DV, Bucci V, McCormick BA. Alzheimer’s disease microbiome is associated with dysregulation of the anti-inflammatory P-glycoprotein pathway.mBio. 2019;10(3):e00632-19. doi:10.1128/mBio.00632-19