Redefining Our Body’s Internal Maps: New Discoveries in Body Axes
We’ve long known about the intricate connections within our body, like the brain-heart axis, which helps explain conditions such as “broken heart syndrome” (Takotsubo cardiomyopathy) triggered by intense emotional or stressful events. Recently, however, a flurry of reports has shed light on new body axes and expanded our understanding of known ones. This article summarizes these fascinating new discoveries on interconnected body axes and circadian clocks, highlighting the intricate circuits being revealed within our body.
The Body – Brain Axis of the Immune System
In a groundbreaking Nature paper, researchers from Columbia University have unraveled how immune activation in the body triggers responses in the brain. By injecting bacterial compounds into the abdomens of mice, they observed that a region in the brainstem was activated, as visualized through specialized imaging.
The vagus nerve connects to the caudate nucleus solitaris (cNST) in the brainstem, which, when activated, significantly reduces inflammation (by approximately 70%). Conversely, silencing these neurons unleashed the immune response, increasing inflammation mediators (interleukin-6, IL-1beta, IL-10) by 3 to 10 times. This circuit acts like a master dial for the immune system, finely tuning its response.
Single-cell sequencing revealed two distinct circuits within the vagus nerve, each responding to pro-inflammatory and anti-inflammatory molecules. In a mouse model of ulcerative colitis, manipulating this circuit either induced severe colitis or protected against inflammation.
The researchers were surprised to find that this body-brain circuit modulates both pro-inflammatory and anti-inflammatory responses, a discovery they termed a “black swan event.” This new understanding of the neuro-immune axis holds promise for better approaches to treating autoimmune diseases, Long COVID, and other conditions involving immune dysregulation.
The Gut – Sperm Axis
We know that our genome is transmitted from one generation to the next, but recent research reveals that our gut microbiome may also have an unexpected influence. A study published in Nature by the European Molecular Biology Laboratory (EMBL) led by Jamie Hackett demonstrated that disruptions to the gut microbiome in male mice—through antibiotics, diet, and laxatives—affected the microbiome of the testes and altered sperm RNA. These changes impacted the offspring, with some mice showing low birth weight and shortened lifespan.
Restoring the paternal gut microbiome reversed these effects. The use of IVF and microbiome transplantation indicated that these effects were mediated through sperm cells, not the paternal microbiome. While it’s unclear if this occurs in humans, the implications are potentially significant.
The Gut – Bone Marrow – Tumor Axis
A new paper in PNAS detailed how a high-fat diet promotes cancer spread. In mice, a high-fat diet increased leucine production from the gut microbiome, particularly from the Desulfovibrio species. This activated the mTOR pathway, leading to the differentiation of bone marrow suppressor white blood cells (PMN-polymorphonuclear) and tumor progression. Some findings were corroborated in breast cancer patients, highlighting the clinical relevance of this axis.
Brain – Muscle & Brain – Skin Circadian Circuits
Two collaborative studies from Barcelona, published in Science and Cell Stem Cell, explored the communication between the brain and peripheral tissues like muscle and skin. Nearly all body cells have circadian clocks, but the central clock in the brain—the suprachiasmatic nucleus (SCN)—serves as mission control.
In older mice, time-restricted eating helped restore SCN function and mitigated muscle loss. Surprisingly, the skin circadian clock also relied on signals from tissues other than the brain SCN and could even override the brain clock, emphasizing the importance of synchronizing brain and peripheral clocks to prevent aging.
The Vagus Nerve
A review in NEJM highlighted the critical role of the vagus nerve in taste and metabolism. It quickly conveys sugar-sensing information to the brain, affecting reward and appetite circuits.
Recent studies also suggest the vagus nerve also impacts hippocampal function and neuro-inflammation. A preprint published using exenatide, an early GLP-1 peptide, showed it could slow aging biomarkers in old mice, emphasizing the gut-brain axis’s role in brain health.
Summary
Advances in imaging and sequencing technique are revolutionizing our understanding of the body’s internal circuits. These recent discoveries underscore the interconnectedness of our bodily systems and their implications for treating major diseases, including autoimmune conditions, cancer, neurodegenerative diseases, and aging. Understanding these intricate circuits will be crucial for translating this knowledge into clinical benefits, promoting health, and preventing disease.
References
https://pubmed.ncbi.nlm.nih.gov/38692285/
https://pubmed.ncbi.nlm.nih.gov/38693261/
https://pubmed.ncbi.nlm.nih.gov/38709933/
https://pubmed.ncbi.nlm.nih.gov/38696572/
https://pubmed.ncbi.nlm.nih.gov/38701785/
https://pubmed.ncbi.nlm.nih.gov/38718360/
https://www.biorxiv.org/content/10.1101/2024.04.28.591513v1
