How does the Brain-Gut-Axis really work?

Understanding Neuropods as a key sensory component of the brain-gut-axis.

"Does it make sense in your brain, feel right in your heart and gut?"

Rather than being just a colloquial saying, there is so much wisdom in this statement. All three areas are deeply impacted by the sensory nervous system's assessment of danger and safety.

My fascination with these connections has ultimately led me to my work with polyvagal theory and the Safe and Sound Protocol. Moreover, it has led me to another fascination of mine: studying the microbiota-brain-gut axis.

Early in my career, describing the microbiota-brain-gut-axis felt a lot like hand-waving.  But now we have an understanding of some of the key anatomical and physiologic pathways that connect this axis.

One key component of this axis are Neuropods.

Before I go to discuss Neuropods, please take a moment to sign up for my Microbiota-Brain-Gut-Axis webinar that I will be giving on August 22, 2024 at 6:00 pm. For those of you who pre-enrolled thank you.  The webinar is now $7. Paid members of my Substack will be emailed a free enrollment.

Now onto neuropods:

What are Neuropods?

Neuropods are specialized extensions of enteroendocrine cells in the mucosa of the small intestine and colon.

Neuropods can release neurotransmitters which signal afferent vagal fibers that transduce signals (such as pain and satiety) to the brain.

This signal is coordinated through the peripheral nervous system's vagal afferent pathways to the nodose ganglia, which then relays the information to the nucleus tractus solitarius (NTS) in the brainstem.

The NTS is a sensory processing center in the brain that provides feedback to the autonomic nervous system. Using neurotransmitters such as glutamate, the signal is reached to the brain in milliseconds. (Kaelberer et al., 2020)

Figure 1: A neuropod from intestinal cell of mouse expressing neuropeptide PYY from Liddle. 2019

Neuropod receptor system:

Neuropods contain receptors embedded within the sensory system. These receptors function to signal an autocrine response involving release of gastro-transmitters and peptides that influence functions such as motility and satiety. 

There are two receptors that are commonly discussed. First is the G-protein coupled receptor (GPCR) and another common receptor is the Toll-Like Receptor (TLR). 

GPCRs are involved in receiving signals from inputs such as nutrients, including short-chain fatty acids. These receptors play roles in gut-brain signaling and can influence immune responses.

TLRs are known to recognize microbial components such as flagellin, peptidoglycan, CpG DNA, and lipopolysaccharides (LPS). Activation of TLRs promotes immune responses. In enteroendocrine cells, activation of TLRs can lead to increased release of cholecystokinin (CCK), and pro-inflammatory cytokines like NF-κB, TNF-alpha, and TGF-alpha.

In addition, neuropods contain nutrient sensors that release glutamate in response to sugar stimuli, affecting insulin release, satiety, and motility. Mechanoreceptors in neuropods detect volume, gas, and stretch in the intestine, influencing feeding behavior. Peptide receptors like those for CCK and PYY respond to the consumption of fats and proteins, further affecting feeding behavior and motility. Chemoreceptors in neuropods detect noxious chemicals, which helps in identifying food poisons and related compounds.

From (Liddle, 2019)

Clinically, this has significant implications. Conditions such as intestinal permeability, dysbiosis, and SIBO all likely interface with neuropods. The binding of receptors and the subsequent upregulation of the microbiota-brain-gut axis can influence motility issues, brain function, and visceral pain.

Conversely, the downregulation of the microbiota-brain-gut axis with a balanced gut and intact intestinal barrier may promote CNS stability.

Eating Behavior and Neuropods:

If you have been following the world of weight loss and diabetes, you are likely familiar with GLP-1 agonist medications like Tirzepatide and Semaglutide. These medications bind to GLP-1 receptors in the body, influencing insulin release, controlling glucagon release, affecting motility, and regulating eating behavior.

It turns out neuropods play a role in the release of GLP-1 from enteroendocrine cells in response to nutrient intake, such as fats and carbohydrates. Once released, GLP-1 acts on receptors located on vagal afferent neurons, which project to the nucleus tractus solitarius (NTS) in the brainstem, influencing feeding behavior. Neurons in the nodose ganglia, where the cell bodies of these vagal afferents are located, have receptors for GLP-1. These vagal afferent cell bodies in the nodose ganglia project to the NTS in the brainstem, a region that influences eating behavior.

It has been found that ATP is required for optimal signaling, as it can act as a co-transmitter. Enteroendocrine cells, including those with neuropods, can release both GLP-1 and ATP, thereby influencing the activity of vagal afferent neurons and ultimately affecting eating behavior.

While we know of smaller and subtler ways to influence GLP-1 in the gut, such as through Akkermansia muciniphilia (a probiotic) prebiotics, and herbal medicines (berberine, curcumin, these interventions are not as robust and powerful as the medications currently available.

Take home message

The sensory system that his happening behind the scenes in our gut is a regulator of moods, appetite, pain perception, and behavior.  The gut interfaces with the brain via the vagal nerve system and this relationship explains a lot of imbalances in both gut health and metabolism. This understanding will help us develop better strategies and interventions to modify digestive dysfunction, mood changes, blood sugar dysregulation, metabolism and more. This makes sense to me in by brain, heart, and gut .

References:
Kaelberer, M. M., Rupprecht, L. E., Liu, W. W., Weng, P., & Bohorquez, D. V. (2020). Neuropod Cells: The Emerging Biology of Gut-Brain Sensory Transduction. In Annual Review of Neuroscience (Vol. 43, pp. 337–353). Annual Reviews Inc. https://doi.org/10.1146/annurev-neuro-091619-022657

Liddle, R. A. (2019). Neuropods. In CMGH (Vol. 7, Issue 4, pp. 739–747). Elsevier Inc. https://doi.org/10.1016/j.jcmgh.2019.01.006