Antibiotic treatment that changed the lung microbiome affected the activity of microglia, the brain-specific version of macrophages, and could prevent the development of the multiple sclerosis (MS) model experimental autoimmune encephalitis (EAE) in mice.

The experiments, which were published in the February 23, 2022, advance online edition of Nature, used EAE as a model of autoimmune disease. But co-corresponding author Alexander Flugel told BioWorld Science that the findings likely have implications for any brain diseases where microglial activation plays a role, and added "I don't know any [brain] disease that microglia are not involved in."

Previous work has suggested a role for microglia in neurodegenerative as well as autoimmune diseases.

The lung also plays a role in the pathogenesis of MS, with smoking and upper airway infections both increasing the risk of developing MS.

But the nature of the connection has been unknown to date.

In fact, how exactly MS starts is still unclear, but that start appears to occur somewhere in the periphery, because "T cells have to be stimulated at the beginning – non-primed T cells do not enter the brain," Flugel said.

There is a well-established role of the microbiome in signaling to the brain from the gut, which is another major interface between the body and the environment.

The gut was considered a prime suspect for harboring the cause of that activation – "there are a lot of factors that could prime T cells," he added. But although manipulations of the gut microbiome did have an effect on the development of EAE, they have to be "massive," said Flugel who is director of the Institute for Neuroimmunology and Multiple Sclerosis Research at University Medical Center Gottingen.

Compared to the gut, the lung was long considered "more or less sterile," Flugel said.

Recent studies have corrected that perception, although the microbiome of the lung is much less densely populated than that of the gut. But the lung does have one of the largest environmental interfaces of any organ – perhaps even the largest.

In a 2020 paper in the American Journal of Respiratory and Critical Care Medicine, researchers from the University of Michigan Medical School urged their readers to "ignore the protestations of our colleagues in gastroenterology: when it comes to surface area, the lungs beat the gut... brave heretics recently used modern morphometric methods to show that prior estimates [of gut lumen surface area] were greatly exaggerated," leading them to conclude that the lungs have roughly twice the surface area of the gut.

Flugel and his team specifically manipulated the lung microbiome by local administration of antibiotics, and found that "modifying a tiny population in the lung completely changes the reactivity of microglia in the brain," he said.

The team plans to study the path from the lung microbiome to brain microglia in greater detail. But roughly, it appears that antibiotic treatment caused lipopolysaccharide (LPS) levels to rise in the lung, which affected T-cell physiology.

When those T cells entered the central nervous system (CNS) and interacted with microglia there, "these microglial cells in the CNS assumed a type I interferon response, as if they had seen type I IFN. And type I IFN ... is typical for an antiviral response," while autoimmune reactions are linked to type II response, Flugel said.

See something, say something

Why microglia should be so highly responsive to changes in the lung microbiome is an open question. In a press release from the University of Gottingen, co-corresponding author Francesca Odoardi, Heisenberg Professor at the Institute for Neuroimmunology and Multiple Sclerosis Research, surmised that "the lung microbiome can be seen as an early warning system for the sensitive brain tissue."

Leon Hosang, postdoc and Klaus Faber Fellow at the institute, added that "microglia adapt their immunological response capacity according to microbial signals and can therefore react quickly to impending threats."

In future research, Flugel, Odoardi and their teams "would like to know what [environmental] stimuli can change the lung microbiome," he said, and whether there are other factors beyond LPS that play a role.

As for the translational potential of the work, for the time being, Flugel was cautious.

In principle, "If you understand in which stage of the disease microglia should be shifted in one way or the other, you could do it without injecting something into the brain," delivering therapeutics to the more accessible lung instead.

But much is still unknown about the link his team has uncovered, and "we don't know in which state you want to have an IFN response or not," he said. In the chronic phase of MS, "it could make things worse."