Study Links Gut Bacteria to Molecular Changes in the Brain

A new study by researchers at the European Molecular Biology Laboratory (EMBL) Heidelberg in Germany has uncovered a significant link between gut bacteria and molecular changes in the brain. Published in Nature Structural and Molecular Biology, the study is the first to demonstrate that gut bacteria can influence how proteins in the brain are modified by carbohydrates, a process known as glycosylation.

The investigation was conducted using a method developed by the researchers called DQGlyco, which enables the study of glycosylation on a much larger scale and with greater resolution than previously possible.

 “Glycosylation can affect how cells attach to each other (adhesion), how they move (motility), and even how they talk to one another (communication),” explained Clément Potel, PhD, first author of the study and Savitski Team Research Scientist. “It is involved in the pathogenesis of several diseases, including cancer and neuronal disorders.”

Despite its importance, glycosylation has been notoriously difficult to study due to the small proportion of glycosylated proteins in cells and the challenges of concentrating them for analysis. “So far, it's not been possible to do such studies on a systematic scale, in a quantitative fashion, and with high reproducibility,” said Mikhail Savitski, PhD, Team Leader, Senior Scientist, and Head of the Proteomics Core Facility at EMBL Heidelberg.

According to the study, the new DQGlyco method overcomes these obstacles by using readily available, cost-effective laboratory materials to selectively enrich glycosylated proteins from biological samples, which can then be identified and measured with precision.

Applying this technique to brain tissue samples from mice, the researchers identified over 150,000 glycosylated protein forms (‘proteoforms’), marking a more than 25-fold increase compared to previous studies. The method’s quantitative capabilities also allow scientists to compare and measure differences across various tissue samples, species, and cell lines, facilitating the study of ‘microheterogeneity’—a phenomenon where different sugar groups modify the same protein segment in multiple ways, the study explained.

Given the high precision of the DQGlyco method, the researchers sought to investigate whether gut microbiomes influence glycosylation patterns in the brain. In collaboration with Michael Zimmermann’s group at EMBL, they analyzed brain samples from mice with and without gut bacteria. “It is known that gut microbiomes can affect neural functions, but the molecular details are largely unknown,” said Dr. Potel. “Glycosylation is implicated in many processes, such as neurotransmission and axon guidance, so we wanted to test if this was a mechanism by which gut bacteria influenced molecular pathways in the brain.”

Their findings showed that mice with gut bacteria exhibited distinct glycosylation patterns in neural proteins, particularly those associated with cognitive processing and axon growth, compared to germ-free mice raised in sterile conditions. These datasets have been made openly available through a dedicated app, enabling further research.

The team is also investigating whether their data can help predict glycosylation sites across different species using machine learning approaches such as AlphaFold, the AI-driven tool for protein structure prediction that earned the 2024 Nobel Prize in Chemistry. “By training the models on mouse data, we can start predicting what could be the variability of glycosylation sites in humans, for example,” said Martin Garrido, PhD, a researcher at Savitski and Saez-Rodriguez groups at EMBL and another first author of the study. “It could be very useful for people studying other organisms to help them identify glycosylation sites in their proteins of interest.”

Looking ahead, the researchers said they plan to apply the DQGlyco method to further fundamental biological questions and to gain deeper insights into the role of glycosylation in cellular function.