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Mimicry: Gut bacteria metabolites copy human signalling molecules

By Emma Jane Cash , 07-Sep-2017

Mimicry: Gut bacteria metabolites copy human signalling molecules

New gut-mediated therapies could be on the horizon, according to new research that finds GPCR (G-protein-coupled receptor) ligands, formed by gut bacteria, mimic human signalling molecules.

The findings, published this week in Nature, come from The Rockefeller University’s Laboratory of Genetically Encoded Small Molecules and the Icahn School of Medicine at Mt. Sinai.

Despite being very different, gut bacteria and human cells have been shown to speak the same chemical language, using molecules called ligands, that researchers call mimicry.

Furthermore, the researchers, led by Sean Brady and Louis Cohen, have found a way to genetically engineer gut bacteria to produce molecules that can fight diseases by speaking to and altering the human metabolism. 

Talking bacteria

Gut bacteria, which make up the microbiome, have been extensively researched recently due to the many health benefits associated with bacterial diversity. There is also a range of research which links brain function to gut bacteria.

This new research found that modified bacteria can exchange important chemical information with cells to help them fight against disease.

“The bacterial effectors that we have identified provide mechanistic insights into potential functions of the human microbiome and suggest that these GPCR-active small molecules and their associated microbial biosynthetic genes have the potential to regulate the human physiology,” said the researchers.

As GPCRs have previously been shown to play roles in diseases including colitis, obesity, diabetes, autoimmunity and atherosclerosis, Brady and Cohen believe that altering these receptors could lead to new treatments.

GCPRs are common targets of drug therapy and are found in the gastrointestinal tract alongside the gut bacteria.

Brady and Cohen say the modified bacteria could be used to reduce blood-glucose levels and concentrations of insulin.

“Bacteria engineered to deliver bioactive small molecules produced by the human microbiota have the potential to help address diseases of the microbiome by modulating the native distribution and abundance of these metabolites,” the researchers said.

The chemical language is made of the presence of ligands, organic molecules which bind to receptors on the membranes of human cells.

Brady and Cohen’s new method uses artificial ligands, called N-acyl amides, which react with cell membranes in the same way as organic ligands but carry a different chemical message for the regulation of glucose and appetite.

“The biggest change is thought in this field over the last 20 years is that our relationship with these bacterial isn’t antagonistic,” he said.

“They are a part our physiology. What we’re doing is tapping into the native system and manipulating it to our advantage.”

It was also found that host-microbial interactions heavily rely on common lipids, sugars and peptides that are used in human signalling systems.

Therefore, the researchers believe that there are structural and functional similarities between bacterial and human bioactive lipids.

Brady argues that although the ligands are created in a lab, they are not foreign.

The study

Researchers introduced the genetically modified bacteria into mice and found that blood-glucose and insulin levels were reduced.

By using the Human Microbiome Project (HMP) sequence data, Brady and Cohen identified 143 unique human microbial N-acyl synthase genes (hm-NAS genes).

Forty-four of these hm-NAS genes were used for the study.

The researchers concluded that further studies will be needed to better define the role of the genes throughout the gastrointestinal tract and the language they use.

Source: Nature
Published online 30/08/2017 doi:10.1038/nature23874
“Commensal bacteria make GPCR ligands that mimic human signalling molecules”
Authors: Louis J. Cohen, et al

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