How one gut bacterium influences immunity

From immunity to metabolism to mental health, it seems like the gut microbiome has been linked to every aspect of human health and disease.

But with hundreds of bacterial species populating our gastrointestinal tract, it’s a daunting task to pinpoint which molecules made by which bacteria affect which biological processes—and how they do so.

“Microbiome studies need to move from making associations to determining function and causation,” said the senior author.

Such knowledge is essential for learning how to manipulate gut bacteria to treat or prevent illness.

A team of researchers has just accomplished the rare feat of connecting those dots for one important gut bacterium.

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

The researchers focused on Akkermansia muciniphila, a species that accounts for an impressive 3 percent of the gut microbiome. It gets its name from the intestinal mucus it breaks down.

Study after study had suggested that A. muciniphila plays a key role in maintaining healthy immune processes, seeming to protect against diseases such as type 2 diabetes and inflammatory bowel disease and make cancer cells more responsive to immune checkpoint therapies

Until the current work, though, no one could confirm the connection by showing how.

The researchers show in a report published in Nature that the links begin with a lipid—a fat—in A. muciniphila’s cell membrane.

“That discovery was quite surprising. The usual suspects for triggering an immune response would be a protein or a sugar,” said the author.

After discovering the molecular structure of the lipid, 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 and toll-like receptor 1, detect bacteria and help the immune system determine whether they’re friend or foe. In this case, versions of TLR2 and TLR1 bound together in a way scientists hadn’t seen before.

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

They also confirmed that the lipid helps maintain immune homeostasis. They found that low doses of the lipid act like a leash, preventing the immune system from reacting to a potentially harmful molecule until that molecule reaches significant levels. On the other end, they saw that high doses of the lipid don’t stimulate an immune response much more than low or medium doses, keeping a healthy ceiling on inflammation.

The work introduces new possibilities for developing drugs that piggyback on A. muciniphila’s ability to manipulate the immune system and fight disease. Members of the lab have made that job easier by revealing the molecular structure of the lipid and figuring out how scientists can make it and similar ones easily in the lab.

The study also provides a model for pinpointing how other members of the gut microbiome act on the body.

“You can change the bacterium and apply the same set of tests,” said the author. 

The researchers showed that, contrary to the expectations of many people in the field, such work doesn’t require fancy techniques. They used traditional methods called spectroscopic analysis and chemical synthesis to find and understand the lipid molecule. 

In fact, despite its “remarkable activity,” the lipid has a “generic structure” that would have flown under the radar of more advanced genomic or metabolomic analyses, the author said.

“The gut microbiome and the immune system are very complicated, which makes you expect that answers will be complicated too,” the author said. “But sometimes complicated things are just lots of simple things.”