August 13, 2022

Lipid in cell membrane of gut bacteria linked to effects on immunity

Researchers from Harvard Medical School and the Broad Institute have shown that the lipid communicates with two receptors found on the surface of many immune cells, namely toll-like receptors 1 and 2 (TLR1 and TLR2). Activation of the receptors by fat triggered the release of certain cytokines, immune proteins that play a role in inflammation. Researchers have also shown that the lipid helps maintain immune homeostasis.


The study, details of which were published July 27 in Nature, marks a breakthrough in work to understand how the gut microbiome affects host physiology. There was already plenty of evidence for links between bacteria, including A. muciniphila and human processes such as metabolism and immunity, but there was a lack of knowledge about the mechanisms that drive the effects.


“The real significance of this work was to connect a bacterium, the molecule it makes, the pathway by which it operates, and the biological outcome. That’s very rare,” said Jon Clardy, PhD, co-lead author of the study and Hsien Wu and Daisy Yen Wu, professor of biological chemistry and molecular pharmacology at Harvard Medical School’s Blavatnik Institute, said in A declaration.


To identify and understand the lipid, Clardy and his collaborators relied on traditional methods, rather than the genomic and metabolomic analyzes that are at the forefront of microbiome studies. Specifically, the team used spectroscopic analysis and chemical synthesis, techniques better suited than more modern approaches to identify the lipid and its generic structure.


The researchers examined the ability of A. muciniphila cultures to induce cytokine release, causing them to focus on a single active lipid moiety that produced robust induction of tumor necrosis factor A. Mass spectroscopic analysis revealed the molecular formula, indicating the presence of a phospholipid, and nuclear magnetic resonance analysis identified a phosphatidylethanolamine (PE). PE is the dominant membrane phospholipid in most bacteria.


After discovering the structure of the lipid, the researchers sought to show how it interacts with the immune system. The work revealed that the lipid helps maintain immune homeostasis. Low doses of lipids prevent the immune system from reacting to potentially harmful molecules until they reach significant levels.


The study highlights opportunities for drug development. By describing the molecular mechanism of a drug pathway, researchers have suggested ways to piggyback on the bacteria’s ability to modulate the immune system to treat disease. The work also provides a blueprint for how to study interactions between other bacteria and host physiology.


At the same time, the study authors noted that “the data underlying the model comes from in vitro studies and in vivo studies will be needed to fully validate it.”


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