Picture this: you're at a party and three different guests describe the same person as "tall with brown hair," "medium height with auburn hair," and "lanky with reddish hair." Are they describing the same human? Different people? Impossible to say.
That's basically what's happening in enteric neuroscience right now, except the party guests are research labs and the person they're describing is your gut's nervous system. A call to action in The EMBO Journal is sounding the alarm: the field desperately needs to get on the same page.
Your Gut: The Other Brain Nobody Talks About
Let's start with some numbers that should make you pause. Your enteric nervous system, the network of neurons embedded in your intestinal wall, contains somewhere between 200 and 600 million neurons. That's more than your spinal cord. It's enough to run a small country, neurologically speaking.
This "second brain" handles digestion, coordinates with your immune system, influences your mood, and does about a hundred other things we're still discovering. It's so independent that if you severed all connections to the central nervous system, your gut would keep on working. Not well, mind you, but it would try.
Given how important this system is, you'd think we'd have a pretty solid understanding of what kinds of neurons live there. You'd be wrong.
The Classification Catastrophe
Modern neuroscience loves single-cell transcriptomics. You take individual cells, sequence their RNA to see which genes are active, and then cluster similar cells together. In theory, this gives you a beautiful census of cell types.
In practice, when different labs do this to gut neurons, they keep coming up with different answers. Not slightly different. Substantially different. The authors of this paper compared multiple datasets and found discrepancies significant enough to make you wonder if everyone's looking at the same organ.
Lab A says there are 12 neuron types. Lab B says 15. Lab C says 9, but describes them with different markers. Nobody's classifications map cleanly onto anyone else's. It's neuroscience Babel.
Why Can't Scientists Agree?
Several factors are conspiring to create this mess.
First, different labs use different techniques. Different sequencing platforms, different tissue processing methods, different computational algorithms for clustering. Each choice introduces variability. It's like asking five chefs to make "basic tomato sauce" without sharing recipes. You'll get five different sauces.
Second, gene expression isn't stable. It varies by where in the gut you sample (the small intestine is different from the colon), how old the tissue is, what species you're working with, and probably what the animal ate for lunch. A neuron type that's obvious in mouse ileum might look completely different in human rectum.
Third, and this is the philosophical kicker: RNA expression doesn't tell you everything. It tells you which genes are turned on, but not how the resulting proteins behave, what electrical properties the neuron has, or who it talks to in the neural network. It's like judging a restaurant solely by reading its supply invoices without ever tasting the food. You're missing the point.
The One-Technique Trap
Here's where the paper gets pointed. The field has been leaning heavily on transcriptomics because it's powerful and relatively accessible. But treating transcriptomics as the definitive answer is a mistake.
Think about it: you're trying to understand a massively complex biological system using just one type of measurement. That's not how science usually works. When we study the brain in the skull, we combine genetics with imaging, electrophysiology, behavioral tests, anatomical tracing, and whatever else we can throw at the problem.
For some reason, when it comes to gut neurons, many labs have been content with transcriptomics alone. And then everyone's surprised when the results don't converge.
The Fix: Actually, Use More Than One Approach
The authors propose what they call a "unified and multimodal" approach. Translation: stop relying on transcriptomics alone.
Combine it with:
- Multiplexed imaging to see where different cell types actually sit in the tissue
- Electrophysiology to measure what these neurons actually do electrically
- Spatial transcriptomics to preserve location information that gets lost in single-cell sequencing
- Proteomics to see which proteins are actually being made
- Metabolomics to understand the chemical environment
Each technique has blind spots. The whole point is that different blind spots cover different things. Combine them, and you get a much clearer picture.
The paper also suggests that human stem cell-derived organoids could help. These are little gut-like structures grown in a dish from human cells. They give researchers gut neurons they can poke, prod, and characterize from every possible angle without relying on whatever tissue happened to be available from today's surgery.
Why Getting This Right Actually Matters
This isn't just academic fussiness about definitions. The enteric nervous system is implicated in a surprisingly long list of conditions.
Irritable bowel syndrome? Involves gut neurons. Inflammatory bowel disease? Involves gut neurons. Constipation, diarrhea, gastroparesis? Gut neurons. And then there's the weird stuff: Parkinson's disease often shows gut involvement years before motor symptoms appear. Autism spectrum disorders have GI components that may relate to enteric nervous system differences.
If we want to develop treatments for any of these conditions, we need to know what we're working with. We need to understand which neuron types exist, what they do, how they go wrong in disease, and how to target them specifically.
Right now, the field is trying to build that understanding on a foundation of conflicting classifications. It's like trying to diagnose a car problem when different mechanics can't agree on what the parts are called.
The Path Forward Requires Actual Collaboration
The paper ends with a call for collaboration and investment. Which sounds like the boilerplate ending of every academic paper ever written. But in this case, it's actually the point.
No single lab can afford to do transcriptomics AND proteomics AND electrophysiology AND spatial analysis AND organoid work. The field needs to share data, adopt common standards, and work together to build a classification system that actually holds up across techniques and labs.
This isn't glamorous work. It won't produce the splashy discovery that lands on the cover of Nature. But without it, all those splashy discoveries in enteric neuroscience are built on quicksand.
The Bottom Line
Your gut contains a second brain with hundreds of millions of neurons, and the scientific community can't agree on how to classify them. Different labs, different techniques, different results. It's a mess.
Fixing it requires moving beyond the single-technique approach and combining multiple methods to build a robust, reproducible understanding of what's actually in there. That's harder and more expensive, but it's the only way forward.
At least everyone agrees on that much.
Reference: Majd H, et al. (2025). A call for a unified and multimodal definition of cellular identity in the enteric nervous system. The EMBO Journal. doi: 10.1038/s44318-025-00559-1 | PMID: 40954253
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.