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The community of microbes living on the folds of the lung’s alveoli doesn’t attract the same scientific fascination as its neighbor, the gut microbiome. But new research in rats suggests it exerts significant influence over the immune system, just like gut microbes can.

Scientists from University Medical Center Göttingen demonstrated that perturbing the rat lung microbiome—a bacterial community that was long thought to not exist—can regulate autoimmunity in the central nervous system, according to research published last month (February 23) in Nature. Specifically, the scientists found that certain microbial treatments could alter the behavior of microglial cells in the animals’ brains—cells that typically maintain the central nervous system by clearing dead or damaged cells—influencing the development of symptoms in a rat model of multiple sclerosis (MS). “We could increase or decrease the ability to develop an autoimmunity response in the [central nervous system],” study author Alexander Flügel, a neuroimmunologist at University Medical Center Göttingen in Germany, tells The Scientist.

The study is the first demonstration of a lung-brain axis, experts tell The Scientist, and it offers a glimpse of what they describe as an exciting potential delivery mechanism for new medical treatments. Seeing lung microbes impact an organ as distant from the lungs as the brain came as a “major surprise,” Chengcheng Jin, a University of Pennsylvania biologist who didn’t work on the paper but studies the lung microbiome in the context of cancer, tells The Scientist.

Flügel explains that his team was inspired by prior research showing that some cells in the gut microbiome express proteins that resemble those found in the central nervous system. Those proteins seem to give gut microbes sway in the brain, so he says he became curious whether lung microbes could similarly impact the central nervous system, especially in light of other research that found certain environments in the lung can favor autoimmunity.

Specifically, the researchers gave rats a variety of treatments meant to alter their lung microbiomes and measured how they affected the animals’ autoimmune responses to lung experimental autoimmune encephalomyelitis (lung EAE), a common animal model of MS. In it, an accelerated MS-like condition is induced by transferring autoreactive inflammatory T cells into healthy rats.

The microglia cells sense continuously these signals coming from the microbiome of the lung.

—Alexander Flügel, University Medical Center Göttingen

Prior to lung EAE induction, the rats were treated with specific antibiotics every day for a week. Some of the rats received the antibiotic neomycin, while others received polymyxin B, which targets different microbes. In addition to monitoring the rats’ health, researchers extracted cells from the spinal cord every day to monitor changes in the central nervous system. Six days after treatment, the researchers observed that microglia in the samples from the neomycin group entered an anti-inflammatory state, counteracting the inflammation triggered by the introduced T cells. This ultimately resulted in the rats showing fewer symptoms. Flügel associates that protective effect with the neomycin shifting the lung microbiome toward lipopolysaccharide-producing taxa that seem to “influence the microglia in a protective way,” he says.

Conversely, treatment with the antibiotic polymyxin B steered the lung microbiome in the opposite direction, suppressing taxa that produce lipopolysaccharides, priming microglia to enter a pro-inflammatory state, and worsening lung EAE outcomes.

The researchers found that treating the polymyxin B group with either lipopolysaccharides or taxa of bacteria that produce them alleviated the animals’ symptoms, indicating that the bacteria play an active role in modulating the autoimmune response and determining disease outcomes. As Flügel explains, “there seems to be continuous relation” between lung bacteria and brain microglia. “The microglia cells sense continuously these signals coming from the microbiome of the lung.” 

See “Some Antibiotics Rev Up Host Immune Response to Viruses”

The study didn’t offer a complete explanation as to why or how changes in the lung microbiome resulted in changes in the central nervous system—figuring that out will require further study, Flügel says. Jin explains that the lung microbiome is a “very under-investigated area,” with progress happening only recently due to the emergence of new sequencing technologies. But experts tell The Scientist that the phenomenon does make sense based on what is known about the organ’s microbial residents. While lung bacteria are vastly outnumbered and outmassed by those in the gut, they have far better access to the bloodstream and, by extension, the rest of the body.

With the gut microbiome, “all of the blood from the gut, all the metabolites, go through three pounds of liver,” Imperial College London genomic medicine researcher William Cookson tells The Scientist. “A lot of stuff is taken out and modified. In the airways, you’ve got close association between bugs and a very, very porous mucus membrane, and [microbial products can go] directly to the general circulation. So it’s much closer to other organs such as the brain.”

Cookson adds that the paper represents an important part of scientists’ brand-new “recognition that the lung microbiome is very, very close to the immune system,” and that as a result “there’s the same opportunity in the airways” for all the known impacts and influences that the gut microbiome exerts throughout the body.

See “Disturbed Microbes Contribute to Lung Damage from Oxygen Treatment”

Still, questions remain. Chief among them is determining what, exactly, is transported from the lung to the brain in order to induce the microglial changes. Cookson speculates that the bacteria release antigens similar to those released by human cells.

When the gut microbiome influences the immune system, Flügel explains, it does so by triggering the activation and subsequent migration of T cells. But the mechanism triggered by the lung microbiome, whatever it may be, seems to differ. Flügel says that the team didn’t observe any indications of T cell activation in the lungs, nor did they observe any T cell migration. They also didn’t observe a concentrated autoimmune effect at the periphery of the brain, where the T cells from the lungs would have primarily entered and influenced the central nervous system—a finding that matches a decade-old Nature paper by the same team. Something else must be happening—he suspects some signaling molecule is released—to activate the microglia.

The fact that antibiotic treatments in the lung activated cells in the central nervous system but not immune cells in the lungs was a surprise to Jin, she says. “The findings are super exciting; they open up more questions for the future.”

As for the possibility of lung microbiome–related treatments in humans, there’s a long way to go, experts agree. But if treating neurological conditions via the lung microbiome becomes possible, though, Flügel says it should become “at least as attractive” as gut microbe manipulations in the eyes of clinicians and pharmaceutical researchers, because the smaller bacterial population in the lung and lack of filtering through the liver mean that manipulations could be gentler than what’s necessary to significantly alter the gut.

Cookson calls the idea “very exciting,” especially given the lungs’ proximity to the bloodstream. “The ability to manipulate things in airway bugs is, I believe, going to become very important,” he says. “I think there’s a huge potential here.”