Gut microbiota dysbiosis promotes early AD pathogenesis by dysregulating the microglial TREM2/SYK/NF-κB pathway, thereby driving neuroinflammation and synaptic dysfunction, and targeting this microbiota-signaling axis may offer novel therapeutic strategies.
Key Findings
Results
APP/PS1 AD mice exhibited reduced gut microbial diversity compared to wild-type mice, characterized by decreased Bacteroidetes and Lactobacillus.
Six-month-old APP/PS1 mice were used as the AD model, representing early AD pathogenesis.
Gut microbiota composition was assessed using 16S rRNA sequencing.
Specific reductions were observed in Bacteroidetes at the phylum level and Lactobacillus at the genus level.
Reduced microbial diversity was a distinguishing feature of the AD microbiota profile.
Results
AD mice showed altered circulating metabolites, including decreased butyrate and elevated lipopolysaccharide (LPS) levels.
Serum metabolites were assessed to characterize the metabolic consequences of gut dysbiosis.
Butyrate, a short-chain fatty acid with anti-inflammatory properties, was decreased in AD mice.
LPS, a pro-inflammatory bacterial product, was elevated in AD mice.
These metabolic changes were identified as potential mediators linking gut dysbiosis to neuroinflammation.
Results
AD mice exhibited heightened hippocampal glial activation and elevated pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6.
Hippocampal neuroinflammation was assessed at the molecular and cellular level.
Microglia showed a shift toward pro-inflammatory activation (M1-associated markers).
Pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were all elevated in hippocampal tissue.
Glial activation was accompanied by synaptic protein loss in AD hippocampi.
Results
TREM2 expression was downregulated while SYK phosphorylation and NF-κB activation were enhanced in the hippocampi of AD mice.
TREM2 downregulation and SYK/NF-κB upregulation occurred concomitantly with synaptic protein loss.
Enhanced SYK phosphorylation indicates increased activity of this kinase in the AD microglial signaling context.
NF-κB activation is consistent with the observed pro-inflammatory cytokine elevation.
These molecular changes define the TREM2/SYK/NF-κB signaling axis as central to microglial dysfunction in early AD.
Results
Fecal microbiota transplantation (FMT) from healthy donors reversed cognitive decline, neuroinflammatory abnormalities, and TREM2/SYK/NF-κB dysregulation in AD mice.
FMT was performed between AD (APP/PS1) and wild-type mice bidirectionally.
Healthy donor FMT into AD mice reversed reduced microbial diversity, elevated pro-inflammatory cytokines, microglial M1 polarization, and TREM2/SYK/NF-κB pathway abnormalities.
Cognitive function was improved following healthy FMT into AD mice.
Synaptic protein loss was also reversed by healthy donor FMT, supporting a causal role of gut microbiota in AD pathology.
Results
Transplantation of AD microbiota into wild-type mice induced mild AD-like pathology including neuroinflammation and microglial dysregulation.
Wild-type mice receiving AD fecal microbiota developed mild but detectable AD-like pathological features.
This finding provides causal evidence that gut dysbiosis, not just disease state, drives neuroinflammatory changes.
Pathology in wild-type recipients included changes consistent with microglial activation and TREM2/SYK/NF-κB pathway modulation.
The bidirectional FMT design strengthens the causal interpretation of gut microbiota's role in AD.
Results
In vitro, TREM2 activation or SYK inhibition attenuated Aβ oligomer-induced M1 microglial polarization and cytokine release in BV2 cells.
BV2 microglial cells were treated with Aβ oligomers to model AD-related microglial activation.
A TREM2 agonist was used to pharmacologically activate TREM2 signaling.
A SYK inhibitor was used to block SYK kinase activity downstream of TREM2.
Both TREM2 activation and SYK inhibition reduced pro-inflammatory M1 polarization markers and cytokine release, mechanistically validating the TREM2/SYK axis.
What This Means
This research suggests that an imbalance in the bacteria living in the gut (called gut microbiota dysbiosis) plays a causal role in the early stages of Alzheimer's disease (AD) by triggering harmful inflammation in the brain. The study found that AD mice had fewer beneficial gut bacteria, lower levels of a protective compound called butyrate, and higher levels of a bacterial toxin called LPS in their blood. These changes were linked to overactivation of brain immune cells (microglia) in a way that damages neurons and disrupts a key molecular pathway involving proteins called TREM2, SYK, and NF-κB — ultimately leading to memory and cognitive problems.
Critically, when researchers transplanted gut bacteria from healthy mice into AD mice (a technique called fecal microbiota transplantation, or FMT), it reversed many of these harmful changes — reducing brain inflammation, restoring molecular balance, and improving cognitive function. Conversely, when healthy mice received gut bacteria from AD mice, they developed mild AD-like brain changes. Laboratory experiments on brain immune cells confirmed that either activating TREM2 or blocking SYK could reduce the inflammation triggered by Alzheimer's-related proteins.
This research suggests that the gut microbiome is not just a bystander in Alzheimer's disease but may actively drive early brain pathology through a specific immune signaling pathway in microglia. These findings open the door to potential new therapeutic strategies targeting the gut-brain connection, such as microbiota-based interventions or drugs that modulate the TREM2/SYK/NF-κB pathway, as ways to slow or prevent the early progression of Alzheimer's disease.
Tian M, Wang D, Zhang C, Fan J, Li W, Liu X, et al.. (2026). Gut Microbiota Dysbiosis Drives Early Alzheimer's Pathogenesis via Microglial TREM2/SYK/NF-κB Signaling Axis.. ACS chemical neuroscience. https://doi.org/10.1021/acschemneuro.6c00173