A discovery that could change what we test next in ALS
- Richard Moore
- Feb 19
- 9 min read
If you or someone you love is living with motor neurone disease (MND), also called ALS, you’ll know how hard it is to live with the unknowns. We still don’t fully understand what starts the illness, or what keeps it getting worse once it begins.
For years, most research has focused on the brain and spinal cord, because that’s where the nerve cells are clearly being damaged. But what if one important part of the “spark” is happening somewhere else, like in the gut? The gut lining is one of the main places your immune system is constantly checking what’s safe, what’s harmful, and what it should ignore.
A new study published in Cell Reports looked at this in mice (McCourt et al., 2026). The researchers found something striking: mice with a high-risk ALS gene (C90FR72) had far less inflammation when they had no gut bacteria. When certain bacteria were added back, inflammation came back too. The team then focused on one thing these bacteria produce, a stored form of sugar called glycogen. When they helped break this down in the gut using an enzyme called alpha-amylase, the mice lived longer and signs of brain inflammation reduced (McCourt et al., 2026).
This is not a human treatment trial, and it doesn’t mean people with ALS should start taking enzyme supplements. But it is a rare example of a microbiome study that points to a specific “trigger” and a clear next step for researchers to test.
What makes this study stand out is that it goes beyond “the gut microbiome might matter.” It identifies a particular bacterial substance, explains how it may switch on the immune system, and shows a measurable signal that could be studied further (McCourt et al., 2026).
Quick explainer: what is C9ORF72, and why does it matter here?
C9ORF72 is the most common inherited genetic mutation linked to ALS and ALS–frontotemporal dementia (FTD), accounting for roughly 10% of ALS cases (Majounie et al., 2012).
The important point for this paper is that C9ORF72 does not just matter in nerve cells. It also helps regulate how certain immune cells respond to microbes (Burberry et al., 2020; McCourt et al., 2026).
A simple way to picture it is as a volume dial for immune reactions. When C9ORF72 is working well, immune cells can detect microbial signals without over-amplifying the response. When C9ORF72 function is reduced, the same microbial signal can be “turned up too loud”, so inflammation is easier to trigger and harder to settle (Burberry et al., 2020; McCourt et al., 2026).
This is why the gut becomes relevant: a microbial signal that might be “tolerated noise” for many people could become a bigger inflammatory problem when this immune control system is weaker.
Why would the gut matter in a brain and nerve disease?
If you’re new to the gut–brain conversation, it can sound like a stretch. But the gut and brain communicate constantly through immune signalling, microbial metabolites, and nerve pathways. A useful mental model is a two-way motorway: signals travel from gut to brain, and the brain sends signals back that influence gut movement, digestion, and stress responses.
In ALS, multiple studies report differences in gut microbial communities compared with healthy controls, although the exact patterns vary between cohorts, which is common in microbiome research (Nicholson et al., 2021). There is also early evidence of gut inflammation and dysbiosis in some people with MND/ALS, though this comes from small case series and does not prove the gut is the cause (Rowin et al., 2017).
So the gut is not a guaranteed “origin story”. But it is a plausible amplifier of immune and inflammatory tone, and that matters in a disease where immune activation repeatedly appears in the biology.
The cleanest experiment: germ-free mice
The most striking finding in this paper comes before the molecule itself.
The researchers used mice with reduced C9ORF72 function and raised them in a completely germ-free environment, meaning they had no gut bacteria at all. Despite carrying the same genetic vulnerability, these mice developed almost no systemic or neural inflammation.
Then the team added bacteria back, step by step. A low-inflammation bacterial community kept the mice relatively stable. A high-inflammation community triggered blood–brain barrier disruption, inflammatory cytokine accumulation in the brain, and immune cell infiltration into the spinal cord (McCourt et al., 2026).
The genetics were the same. The housing was the same. The difference was what was living in the gut.
One bacterium tips the balance
The study goes further. The researchers introduced a single human-derived bacterium, Parabacteroides merdae, into germ-free mice with reduced C9ORF72 function, either alone or alongside an otherwise low-inflammation gut community.
When P. merdae was added to that otherwise benign community, the mice developed a severe inflammatory phenotype: enlarged spleens, anaemia, elevated monocytes in the blood, T cells infiltrating the spinal cord, and immunoglobulin leaking into the brain. With C9ORF72 intact, the same exposure caused far less damage (McCourt et al., 2026).
That escalation makes gene-by-microbe interaction tangible. P. merdae is not “universally harmful”. In the wrong immune context, a normally tolerated organism can become inflammatory load.
The unexpected suspect: bacterial glycogen, and why its shape matters
So what is P. merdae producing that causes this?
You may already know glycogen as stored glucose in your liver and muscles. Gut bacteria can store glycogen too. The surprise in this paper is that bacterial glycogen is not one uniform thing. Its structure can differ, and those differences change how strongly immune cells react (McCourt et al., 2026).
Imagine two balls of string that weigh the same. One is loosely wound and easy to unravel. The other is tightly knotted into a dense tangle. In this study, the “tight knot” version of glycogen, meaning more compact and highly branched with shorter chain lengths, was more likely to trigger inflammatory signalling (McCourt et al., 2026).
Mechanistically, the authors show that microbial glycogen activates TLR2, one of the immune system’s pattern sensors for microbial signals. When C9ORF72 function was reduced in macrophages, those cells released significantly more TNF-α in response to this glycogen. With normal C9ORF72 function, the response was kept in check (McCourt et al., 2026).
This is a major shift in microbiome thinking. Many discussions get stuck on which bacteria are present. This study pushes us toward what bacteria are producing, and how the immune system interprets it.
What makes bacteria store “inflammatory” glycogen?
Bacteria store glycogen as a survival strategy, and compact glycogen structures have been linked to durability under stress and starvation (Wang & Wise, 2011). In this paper’s culture experiments, changing nutrient conditions shifted inflammatory signalling from some bacterial species but not others, reinforcing a key point: the same broad bacterial group can behave differently depending on its environment (McCourt et al., 2026).
This is exactly where the internet tends to over-simplify biology into rigid food rules. This paper does not justify that.
A cautious, clinically realistic interpretation is that gut ecosystem stressors, including erratic carbohydrate availability and low microbial diversity, might influence bacterial behaviour. Stable, varied feeding patterns and a broad range of dietary fibre could support a more resilient ecosystem. But in ALS, any dietary strategy has to protect the non-negotiables: adequate intake, stable weight, and practicality.
The gut lining: where this becomes clinically interesting
When people say “the gut”, what they often mean, without realising it, is the gut lining, especially the mucosa. This is the interface between the outside world (gut contents) and the inside world (tissues and bloodstream). It absorbs nutrients while keeping bacteria and bacterial products where they belong.
A practical image: the mucosa is the club door, and immune cells are the bouncers. Most nights, they handle the queue calmly. But if something keeps showing up that looks suspicious or is hard to process, the bouncers stay activated, and the whole venue gets chaotic.
In the mouse model, immune cells in the lamina propria (the immune-dense layer just beneath the gut surface) accumulated polysaccharide material in a C9ORF72-dependent way. This accumulation was reduced in germ-free mice, confirming the signal is coming from microbes rather than the body itself (McCourt et al., 2026).
The point is not a simplistic story of glycogen “leaking into the blood”. Immune activation can begin at the mucosal interface and then ripple outward, eventually affecting the nervous system’s immune environment.
The experiment that turns heads: breaking down glycogen changed outcomes in mice
This is the moment many readers jump to “should we all be taking enzymes?” The study does not support that leap, and it’s important to understand why.
The researchers took mice with reduced C9ORF72 function that were already showing signs of inflammatory disease (including reduced motor performance, elevated inflammatory blood markers, and enlarged spleens) and gave them daily oral alpha-amylase, an enzyme that breaks down glycogen. Over ten weeks, treated mice showed improved survival versus controls. Their spleens were smaller. Single-cell RNA sequencing suggested that microglia shifted away from inflammatory gene programmes linked to immune cell recruitment and toward more restorative patterns (McCourt et al., 2026).
Here is the translational nuance, in the right place. Humans already produce alpha-amylase in saliva and from the pancreas. So the question is not “do we have this enzyme?” It is whether microbial glycogen is accessible in the relevant gut compartments, whether it is protected inside bacterial cells or biofilms, and whether changing that immune trigger meaningfully shifts inflammation in people with ALS. The paper does not answer those questions yet (McCourt et al., 2026).
The most accurate takeaway is this: the paper strengthens the case that the gut can be a therapeutic entry point for neuroinflammation in a C9ORF72 context, and it identifies a specific target worth testing in humans.
What about humans with ALS?
The authors tested stool samples from 22 people with ALS, 1 person with C9ORF72-related FTD, and 12 healthy controls using a functional question: does alpha-amylase reduce inflammatory signalling when immune cells are exposed to that stool in the lab?
Alpha-amylase-sensitive inflammatory glycogen activity was present in stool from 15 out of 22 people with ALS, the 1 person with FTD, and 4 out of 12 healthy controls. When analysed in aggregate, the signal was enriched in ALS/FTD samples but not in controls (McCourt et al., 2026). The signal also appeared in stool from the two patients with the fastest rate of motor decline, and in 8 out of 9 samples collected within the first 18 months of disease (McCourt et al., 2026).
This is promising, but the sample is modest (35 people), and a proportion of healthy controls also showed the signal. It is also worth noting a methodological detail: the functional assay used mouse macrophages, not human immune cells, so the inflammatory response measured may not perfectly mirror how the human immune system would react to the same material. Replication in larger, more diverse cohorts, ideally using human immune cell assays, is needed.
What we know now, and what needs to happen next
So far, the evidence supports this chain: certain gut microbial communities can generate glycogen structures that trigger inflammatory signalling, and reduced C9ORF72 function makes immune cells more reactive to that signal. In mice, targeting that signal changed immune readouts in the brain and improved survival. In a small human cohort, a related functional signal was more common in ALS/FTD stool than in controls (McCourt et al., 2026; Burberry et al., 2020).
What we do not yet know is whether this mechanism defines a broad ALS pathway or a biologically distinct subgroup, whether diet can meaningfully alter this in humans without unintended consequences, and whether enzyme-based approaches translate to clinical benefit, and for whom (McCourt et al., 2026).
What should happen next is clear: larger multi-site studies, longitudinal sampling to see whether inflammatory glycogen appears early and tracks with progression, and carefully designed human trials testing whether modifying microbial glycogen activity shifts inflammatory biomarkers and outcomes while protecting nutrition and weight stability (McCourt et al., 2026).
The practical bottom line for people living with ALS, and carers
This research does not say “the gut causes ALS”. It says something more useful: in some ALS-related biology, the gut may supply immune triggers that the body struggles to handle calmly, and that immune overreaction may contribute to neuroinflammation (McCourt et al., 2026; Burberry et al., 2020).
That is not a cure. But it is progress, because it gives researchers a measurable target, and it strengthens the rationale for taking gut health seriously as part of comprehensive ALS support. In practice, that means working with a clinician who understands both the science and the realities of ALS nutrition: protecting calorie intake and weight while supporting a gut environment that minimises unnecessary inflammatory load.
How You Nutrition Clinic can help
At You Nutrition Clinic, we focus on gut health in neurological and neurodegenerative conditions because the gut is one of the most modifiable systems linking diet, immunity, inflammation, and resilience.
If you want support building a gut-informed nutrition plan that protects the ALS non-negotiables, including adequate calories, stable weight, and practical symptom management, we can help you do it in a way that is personalised, realistic, and aligned with evolving science.
Email us at admin@younutritionclinic.com for a free introductory chat and we’ll talk through what’s relevant for your situation, what’s plausible but not yet proven, and what might be worth measuring.
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Disclaimer: This article is for informational and educational purposes only and does not constitute medical advice. Always consult with a qualified, registered medical doctor (MD) for diagnosis and treatment decisions.
References
Burberry, A., Wells, M. F., Limone, F., et al. (2020). C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature, 582(7810), 89–94. https://doi.org/10.1038/s41586-020-2288-7
Majounie, E., Renton, A. E., Mok, K., et al. (2012). Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study. The Lancet Neurology, 11(4), 323–330. https://doi.org/10.1016/S1474-4422(12)70043-1
McCourt, B., Lemr, K., Chakrabarti, S., et al. (2026). C9orf72 in myeloid cells prevents an inflammatory response to microbial glycogen. Cell Reports, 45(2), 116906. https://doi.org/10.1016/j.celrep.2025.116906
Nicholson, K., Bjornevik, K., Abu-Ali, G., et al. (2021). The human gut microbiota in people with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal
Degeneration, 22(3–4), 186–194. https://doi.org/10.1080/21678421.2020.1828475
Rowin, J., Xia, Y., Jung, B., & Sun, J. (2017). Gut inflammation and dysbiosis in human motor neuron disease. Physiological Reports, 5(18), e13443. https://doi.org/10.14814/phy2.13443
Wang, L., & Wise, M. J. (2011). Glycogen with short average chain length enhances bacterial durability. Naturwissenschaften, 98, 719–729. https://doi.org/10.1007/s00114-011-0832-x
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