Increasingly, scientists recognize how fundamental gut bacteria are to human health. The microbiome’s radius of influence even extends as far as the brain, with some evidence suggesting that it plays a role in neurogenerative diseases.1 Researchers have found that people with Alzheimer’s disease (AD) harbor different gut microbes than healthy people.2 However, the mechanisms by which gut-resident bacteria may affect the brain are incompletely understood.
In a recent Cell Reports study, researchers identified microbial molecules from bacteria that are common in healthy people but missing in those with AD.3 Next, they computationally modelled more than one million possible interactions between these microbial metabolites and a variety of neural receptors. Finally, they assessed the effects of these metabolites on neurons derived from AD patient cells and found that they reduced levels of a key player in AD called phosphorylated tau. This approach could help researchers identify potential therapeutic targets for future disease-modifying treatments.
Study author Feixiong Cheng, a systems biologist at the Cleveland Clinic, and his colleagues sourced data from previous studies on gut microbial metabolites in human plasma.4 They also gathered existing data on genetic variation in neural receptors, specifically those that belong to the family of G protein coupled receptors (GPCR).5,6 By reviewing which human donors across the multiple datasets developed AD, the team worked out which of these metabolite and receptor variations were correlated with an increased or decreased risk of the disease.
To study possible interactions between receptors and metabolites linked to AD, the team harnessed existing three-dimensional structural data about the neural receptors. The models allowed them to work out how the metabolites dock at different regions on each protein, like testing out a key across different locks. Their simulations revealed that so-called “orphan” GPCR—receptors with unidentified ligands—bound strongly to metabolites negatively correlated with AD risk.7 These findings bring these underexplored GPCR into the spotlight, suggesting they could serve as suitable targets for future drugs.
Using neurons derived from induced pluripotent stem cells (iPSC) from AD patients, the researchers explored the effects that these predicted metabolite-receptor interactions would have.
They inoculated the neurons with two metabolites that they had linked to reduced AD risk: agmatine and phenethylamine. These molecules bound strongly to GPCR in their computer models. Agmatine bound to the complement component 3a receptor (C3AR), which is involved in inflammation whereas phenethylamine bound to the orphan receptor GPR153 with unknown functions.8,9 This duo of bacterial products also caught their attention because people with AD often lack certain bacterial species, such as Eubacterium rectale and Ruminococcus, that churn out these metabolites.10,11
Once they added these metabolites to the cells, researchers measured their effects on levels of phosphorylated tau. Normally, tau stabilizes the microtubule cytoskeleton that holds the cell together but in AD it undergoes irregular phosphorylation, causing it to dissociate from the microtubules.12 As a result, neurons lose their structures and disconnect from one another, precipitating the disease. These metabolites lowered the abundance of phosphorylated tau, suggesting they might reduce the severity of the condition. “But the exact mechanism we have to figure out in the future,” Cheng said.
Currently, there are only two FDA-approved drugs that target AD-associated proteins. Both lecanemab and donanemab are antibody therapies that target brain beta-amyloid, although scientists have recently called into question the efficacy of the former drug.13-15 There are currently no approved therapies that target tau, however. Identifying metabolites and GPCR that reduce the buildup of phosphorylated tau could provide promising new treatment avenues.
“We can do some very simple things to prevent or reduce our Alzheimer’s risk,” speculated Cheng, namely consuming a healthy diet that supports a diverse set of “good” gut bacteria. This may be a simpler strategy than designing a drug that reaches the brain, he supposed.
Though Cheng and his team experimentally validated two microbial molecules that limit levels of phosphorylated tau, they aim to explore other receptor-metabolite interactions that may increase AD risk in future work.
Surveying the microbiome could serve as an affordable diagnostic, too. “You could easily look at blood-based biomarkers in combination with doing a simple stool sample for evaluating, and that may be very accessible in low- and middle-income countries,” said Beau Ances, a neurologist at Washington University in St Louis who was not involved with the study. It might even aid with spotting the condition early, which could improve treatment outcomes. “Most of the clinical trials that we have been trying in Alzheimer’s disease have been very late in the disease process, and because of that, they really haven’t had a big effect, if any,” Up to 99.6 percent of AD clinical trials fail, perhaps partly because too much damage has already occurred by the time that patients are diagnosed.16 Earlier interventions with new therapeutics could change the game for this condition.
References
1. Cryan JF, et al. The microbiota-gut-brain axis. Phys Rev. 2019;99(4):1877-2013.
2. Li B, et al. Mild cognitive impairment has similar alterations as Alzheimer’s disease in gut microbiota. Alzheimers Dement. 2019;15(10):1357-1366.
3. Qiu Y, et al. Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer’s disease. Cell Rep. 2024;43(5):114128.
4. Chen Y, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet. 2023;55(1):44-53.
5. Sieberts SK, et al. Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions. Sci Data. 2020;7(1):340.
6. De Klein N, et al. Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases. Nat Genet. 2023;55(3):377-388.
7. Tang X, et al. Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. Acta Pharmacol Sin. 2012;33(3):363-371.
8. Litvinchuk A, et al. Complement C3aR inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer’s disease. Neuron. 2018;100(6):1337-1353.e5.
9. Gutiérrez-Ruiz JR, et al. Expression profiles of GPR21, GPR39, GPR135, and GPR153 orphan receptors in different cancers. Nucleos Nucleot Nucl. 2022;41(2):123-136.
10. Cattaneo A, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60-68.
11. Liu P, et al. Altered microbiomes distinguish Alzheimer’s disease from amnestic mild cognitive impairment and health in a Chinese cohort. Brain Behav Immun. 2019;80:633-643.
12. Rawat P, et al. Phosphorylated tau in Alzheimer’s disease and other tauopathies. IJMS. 2022;23(21):12841.
13. Schiller ER, et al. Profiling lecanemab as a treatment option for Alzheimer’s disease. Expert Rev Neurother. 2024;24(5):433-441.
14. Sims JR et al. Donanemab in early symptomatic Alzheimer disease: The TAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.
15. Kurkinen M. Lecanemab (Leqembi) is not the right drug for patients with Alzheimer’s disease. Adv Clin Exp Med. 2023;32(9):943-947.
16. Frausto DM, et al. Dietary regulation of gut-brain axis in Alzheimer’s disease: importance of microbiota metabolites. Front Neurosci. 2021;15:736814.
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