Setting the Speed on Sepsis

My inner light bulb 💡 switched on in 2023 when I learned about the lower neural pathways for vasovagal syncope. I quickly spread the word in the chronic illness community, but they were mostly nonplussed. And who can blame them: the brain has become largely synonymous with mental health in much of science media.

In 2024, the conversation changed after this breakthrough, also published in Nature. The phenomenon of a “cytokine storm” entered public consciousness during the height of the pandemic, unfortunately all too often: these storms preceded many of the millions of deaths. This study discovered something hardly anyone conceived during the pandemic: some cytokine levels are significantly controlled by the lower brain. 

This work came from the team of Charles Zuker, a pioneer in the sense of taste. For this study, his team turned its focus to internal sensing, aka interoception, of cytokines. They pinpointed specific neurons within the vagus nerve that responded to the injection of cytokines into the bloodstream. In fact, they found two distinct sets of neurons: one set responding to pro-inflammatory cytokines (IL-6, IL-1β, TNF) and another set responding to an anti-inflammatory cytokine (IL-10).

Excerpt of Figure 4 from A body–brain circuit that regulates body inflammatory responses | Nature, licensed under CC-BY. Shows that distinct vagal neurons respond to pro-inflammatory (top row) and anti-inflammatory (middle row) cytokines injected in the tail. These were distinct from another known set of vagal neurons that respond to glucose ingestion (bottom row).

Several neuroscience technologies were used: activity mapping, activity-based genetic labeling, chemogenetics, and live calcium imaging. Activity mapping, using a molecule called cFos that brightens with activity, is what first clued Zuker’s team into the role played by ascending body-to-brain vagal neurons. Whole-brain microscopy pinpointed a nucleus within a nucleus:  the caudal nucleus of the solitary tract nucleus (abbreviated cNTS due to Latin name), as the single most activated brain region following an artificial immune stimulus with lipopolysaccharides (LPS), a bacterial component known to trigger the innate immune system. NTS is the brainstem region where the vagus nerve enters the brain from the body. The authors further confirmed the cNTS brainstem activity arises from body to brain interoception, not LPS permeating the brain, by abolishing the activity through vagus nerve ablation.

Once this interoception pathway became clear, the authors wondered: does the cNTS itself exert influence back from brain to body? Today’s neuroscience allowed them to specifically “tag” the activated cNTS neurons with chemogenetic receptors for physiological testing. They found the answer to be Yes, with two key experiments:

• silencing the body-to-brain signaling led to runaway inflammation (Figure 2)

• activating cNTS suppressed/boosted pro-/anti-inflammatory cytokines (Figure 3)

From there, they proceed to what scientist-me considers the centerpiece: Figure 4, excerpted above, revealing specific cell types within the vagus nerve that sense the pro- and anti-inflammatory cytokines reaching the cNTS. This worked because the vagus nerve “balloons” at what’s called the nodose ganglion, making it accessible to today’s neuromicroscopy. They went further (Figure 5) to identify which molecules are differently expressed in those distinct vagal neurons, i.e., their respective molecular “barcodes”. 

Finally they reached what everyone-but-me would consider the centerpiece: a pathway to preventing LPS-induced sepsis! Chemogentically activating the now molecularly pinpointed anti-inflammatory pathway, either in the vagus nerve or the brainstem, could rescue mice from an otherwise lethal dose of LPS:

Excerpt of Figure 6 from A body–brain circuit that regulates body inflammatory responses | Nature, licensed under CC-BY. Shows that sepsis from a lethal dose of lipopolysaccharides (LPS) can be prevented by chemogentically activating (via the molecule CNO, clozapine-N-oxide) the molecularly-identified anti-inflammatory pathway in either the vagus nerve (top left) or brainstem (bottom left).

Overall, the lower nervous system appears to have evolved accelerator- and brake-like control over the “fuel” and “rubber” components of the immune system, with each pathway identifiable down to cells and molecules by using advanced neuroscience. This detailed understanding appears poised for clinical use, as neural interfaces could be used to “pump the brakes” to prevent fatalities from acute infections. While I’m no immunologist, a quick check shows the cytokine pathways in this study may be similar to those of the COVID-19 cytokine storms. Imagine - this bacteria model study could help limit casualties in a future viral pandemic!

Although focused on acute illness dynamics, this study notably opened up the chronic illness community to discussing the brain’s role more. But much of the chatter, and even Nature itself, drifted towards images and ideas of the brain being inflamed, sometimes under the broad banner of neuroinflammation. In fact, the brain was not directly affected by LPS in this study, even at lethal doses. That’s why Ansyme exists: to better communicate what today’s neuroscience is capable of and what the lower nervous system can do.