Gut bacterial metabolites reduce levels of toxic tau

IScientists are increasingly realizing how important our gut bacteria are to human health. The extent of our microbiome’s influence is Spreads to the brainSome evidence also suggests that it plays a role in neurodegenerative diseases.¹ Researchers have found that patients with Alzheimer’s disease (AD) Different gut bacteria than healthy people.² However, the mechanisms by which gut bacteria affect the brain are not fully understood.

Recent Cell Report studyThe researchers identified microbial molecules from bacteria that are common in healthy people but lacking in those with AD.³ The researchers then computationally modeled over one million interactions between these microbial metabolites and various neural receptors. Finally, they assessed the effects of these metabolites on neurons from cells of AD patients and found that they reduced levels of phosphorylated tau, a key factor in AD. This approach may help the researchers identify potential therapeutic targets for future disease-modifying treatments.

Study authors Cheng Fei-HsiungThe Cleveland Clinic systems biologist and his colleagues Gut microbial metabolites In human plasma.^Four They gathered again Existing data upon Genetic variations in neuroreceptorsSpecifically, those belonging to the G protein-coupled receptor (GPCR) family.^5,6 By considering which human donors across multiple datasets developed AD, the research team uncovered which of these metabolite and receptor mutations correlated with increased or decreased risk of AD.

To study possible interactions between receptors and metabolites relevant to AD, the team took advantage of existing 3D structural data on neuroreceptors. The models allowed them to work out how metabolites dock into different regions of each protein, like trying a key in a different lock. The simulations allowed them to identify so-called “orphan” GPCRs ( Unidentified ligand—Strongly binds to metabolites that are negatively correlated with AD risk.⁷ These findings have drawn attention to previously understudied GPCRs, suggesting that they may represent suitable targets for future drugs.

The researchers used neurons derived from induced pluripotent stem cells (iPSCs) from AD patients to explore the potential effects of predicted metabolite-receptor interactions.

They inoculated neurons with two metabolites linked to reduced Alzheimer’s risk, agmatine and phenethylamine, which bound tightly to GPCRs in a computer model. Agmatine binds to the complement component 3a receptor (C3AR), and Involved in inflammation On the other hand, phenethylamines bound to the orphan receptor. About GP153 Function unknown.^8,9 These two bacterial products attracted attention because AD patients often have deficiencies in certain bacterial species, including: Eubacterium rectal and Ruminococcusproducing large amounts of these metabolites.^10,11

The researchers added these metabolites to cells and measured their effect on levels of phosphorylated tau. Stabilizing the microtubule cytoskeleton These proteins hold cells together, but in AD they become irregularly phosphorylated and detach from microtubules.¹² As a result, neurons lose structure and separate from each other, inducing the disease. These metabolites reduce the amount of phosphorylated tau, suggesting that they may reduce the severity of the disease. “However, the exact mechanisms remain to be elucidated,” Chen said.

Currently, there are only two FDA-approved drugs that target AD-related proteins. Lecanemab and Donanemab There are antibody therapies that target beta-amyloid in the brain, but scientists have recently Questioned the validity Of previous drugs.^13-15 However, there are currently no approved therapies that target tau. Identifying metabolites and GPCRs that reduce the accumulation of phosphorylated tau may yield promising new treatments.

“There are some very simple things we can do to prevent or reduce the risk of Alzheimer’s,” Chen speculated. Specifically, eating a healthy diet that fosters a diversity of “good” gut bacteria. This might be an easier strategy than designing drugs to reach the brain, Chen reasoned.

While Chen and his team have experimentally validated two microbial molecules that limit levels of phosphorylated tau, future studies aim to investigate other receptor-metabolite interactions that may increase AD risk.

Microbiome investigations could also serve as an affordable diagnostic: “It can be easily assessed using a combination of blood-based biomarkers and simple stool samples, and may be very accessible in low- and middle-income countries,” he said. Beau Anse“Most of the clinical trials we’ve tried in Alzheimer’s have been done quite late in the disease progression, so they’ve really had little to no effect,” said Upton Wilson, a neurologist at Washington University in St. Louis who was not involved in the study. The research could also help detect the disease earlier, which could lead to improved treatment outcomes. “Most of the clinical trials we’ve tried in Alzheimer’s have been done quite late in the disease progression, so they’ve really had little to no effect at all,” he said. 99.6% of AD clinical trials failThis is probably in part because by the time patients are diagnosed, much of the damage has already occurred.¹⁶ Early intervention with new treatments could change the landscape of this disease.