Researchers have found that a specific lipid in the membrane of a common gut microbe regulates human immune responses. In addition, they characterized the signaling pathway involved, providing a complete picture of how a specific molecule from a microbe influences a physiological process in its host.

The work was led by Jon Clardy, PhD, and Ramnik Xavier, MD, from Harvard Medical School and the Broad Institute. It was published in Nature (“Akkermansia muciniphila phospholipid induces homeostatic immune responses”).

“The real significance of this work was connecting a bacterium, the molecule it makes, the pathway it operates through, and the biological outcome,” Clardy said. “That’s very rare.”

Xavier agreed. “Microbiome studies need to move from making associations to determining function and causation,” he said.

 Multiple studies have suggested that A. muciniphila, which makes up 3% of the human gut microbiome, plays a key role in maintaining healthy immune processes, possibly protecting against type 2 diabetes and inflammatory bowel disease and making cancer cells more responsive to immune checkpoint therapies. But, until now, the link had not been confirmed and the mechanistic underpinnings had not been deciphered.

After discovering the molecular structure of the lipid, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), the team found that it communicates with a pair of receptors on the surface of many immune cells. These receptors, known as toll-like receptor 2 (TLR2) and toll-like receptor 1 (TLR1), detect bacteria and protect against invading pathogens. In this case, versions of TLR2 and TLR1 bound together in an unexpected way.

The researchers showed the activation of TLR2-TLR1 can trigger the release of certain cytokines—immune proteins involved in inflammation—while leaving other cytokines alone.

“The potency of TLR2 heterodimers is conventionally thought to be governed by a peptide, peptide-like, or (poly)saccharide moiety emerging from the dimer interface, and the absence of this chain in a15:0-i15:0 PE might be responsible for the molecule’s unusual immunomodulatory effects,” the researchers wrote in the article.

The team also confirmed that the lipid likely helps to maintain immune homeostasis. “Although there is still much to be learned about the pharmacology of a15:0-i15:0 PE, the existing data support a model in which repeated low-level stimulation of the TLR2–TLR1 signaling pathway resets the activation threshold so that weak signals are ignored and strong signals are moderated, thereby contributing to homeostatic immunity,” they wrote.

“It is also important to note that the data underlying the model are from in vitro studies and in vivo studies will be needed to fully validate it,” they added.

The work may lead to the development of drugs based on A. muciniphila’s ability to manipulate the immune system and fight disease. It also provides a model for how other gut microbes act on the body.

Working on a project that’s rooted in basic biochemistry and has immediate ties to human health “feels great,” said Clardy. “In principle, this kind of work is what we’re supposed to do, but it’s not always the way things work out.”

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