ALS and the gut, part one: why a disease of the motor neurones may also begin in the belly

Richard Moore
May 9
14 min read

For most of the modern history of amyotrophic lateral sclerosis (ALS), the story has been told from the nerves outward. The motor neurones fail. The muscles weaken. Speech, swallowing, movement, and eventually breathing become harder. ALS is therefore usually described as a disease of the nervous system.

That description is true. But it may not be complete.

A growing body of research now suggests that ALS may also involve the gut, the immune system, the intestinal barrier, and the trillions of microbes living inside the bowel (Lee et al., 2024; Oriquat et al., 2026). This does not mean ALS is “caused by the gut”. It does not mean that probiotics, special diets, or gut protocols can reverse the disease. The evidence is not there for that.

But it does mean something important.

The gut may not simply be an innocent bystander. In some people, it may be part of the wider biological environment that shapes inflammation, energy metabolism, immune activity, and motor neurone vulnerability.

One way to picture this is to imagine ALS as a fire in the nervous system. The motor neurones are where the flames are most visible. But the gut may be part of the weather around the fire. It may influence how dry the forest is, how strong the wind becomes, and how easily inflammation spreads.

This first article explores that emerging science carefully. Part two will look at what, if anything, can be done with this information in practice.

The first warning may have come from below the diaphragm

A surprisingly common observation in ALS care is that digestive symptoms often appear early. Constipation, bloating, altered bowel habits, delayed gastric emptying, and changes in gut motility have all been reported in people with ALS (Lee et al., 2024).

In one Mexican cohort of 43 patients, more than 60% reported constipation, 57% reported a sensation of incomplete evacuation, and more than 55% reported persistently hard stools, with symptoms being more common in people with more advanced disease (Lee et al., 2024).

The obvious explanation is that ALS makes digestion harder because movement, chewing, swallowing, hydration, posture, and food intake all change as the disease progresses. That is clearly part of the picture.

But there is another possibility: the gut may be involved earlier than we once assumed.

Some studies suggest that gut changes can appear before obvious motor decline in ALS animal models. In mice carrying ALS-associated mutations, researchers have found changes in gut nerves, gut bacteria, intestinal permeability, and inflammatory signalling before the animals show clear weakness (Lee et al., 2024; Zhang et al., 2017).

In other words, the gut may not just be reacting to ALS. In some cases, it may be participating in the conversation.

The trillion-strong roommates who quietly run the house

To understand why the gut matters, we need to understand who lives there.

The gut microbiota is the community of bacteria, fungi, viruses, and other microorganisms that live mostly in the large intestine. The microbiome refers to their collective genetic material (Oriquat et al., 2026). These organisms are not passive passengers. They behave more like an invisible organ.

They help break down fibres that human enzymes cannot digest. They produce short-chain fatty acids, including butyrate, which help feed the cells lining the colon. They train the immune system. They influence bile acid metabolism. They help produce or regulate compounds involved in mood, sleep, inflammation, and brain signalling (Cusumano et al., 2025; Mudda et al., 2026; Oriquat et al., 2026).

A useful analogy is to think of the gut microbiome as the maintenance crew in a large building. When the crew is balanced and well supplied, the lights stay on, the heating works, the alarms are calibrated, and the walls are repaired. But if the wrong crew takes over, or the crew is starved of the materials it needs, small problems can become building-wide problems.

This imbalance is called dysbiosis. It does not mean “bad bacteria” alone. It means the whole ecosystem has shifted: fewer helpful species, more inflammatory signals, lower production of protective metabolites, or reduced resilience.

In ALS, researchers are now asking whether dysbiosis could alter the terrain in which motor neurones are trying to survive.

The gut–brain axis: not a one-way street

The gut and brain are connected through several overlapping routes.

The vagus nerve acts like a direct communication cable between the gut and the brainstem. Microbial metabolites can enter the bloodstream and reach distant organs. Immune cells activated in the gut can send inflammatory messages throughout the body. The brain also signals back to the gut through the autonomic nervous system, influencing gut motility, secretion, blood flow, and the types of microbes that can thrive there (Mudda et al., 2026; Oriquat et al., 2026).

This is called the gut–brain axis, but it may be better imagined as a roundabout rather than a straight road. Signals are constantly entering and leaving from several directions: microbes, immune cells, nerves, hormones, metabolites, diet, stress, medication, and disease activity.

In ALS, the key question is not whether the gut “causes” the disease. The better question is whether gut-derived signals can make the nervous system more inflamed, more metabolically stressed, or less able to repair itself.

The wall that quietly holds everything together

The intestinal barrier is one of the most important parts of this story.

The lining of the gut is only one cell thick. That sounds fragile, but in health it is remarkably well organised. The cells are joined together by tight junction proteins, including occludin, claudins, and zonula occludens-1. These act like the stitching between tiles in a bathroom wall. When the stitching is intact, water stays where it belongs. When it cracks, leakage begins.

On top of this cell layer sits mucus, which acts like a protective gel. Beneath it are immune cells, blood vessels, and the enteric nervous system, sometimes called the “second brain” because it contains a vast network of neurones controlling gut function (Cusumano et al., 2025; Lee et al., 2024).

When the gut barrier is working well, bacteria and bacterial fragments largely stay inside the gut, where they belong. If that barrier becomes more permeable, microbial products can cross into the bloodstream and interact with the immune system. This is often called “leaky gut”, although the more precise research term is intestinal hyperpermeability (Kalyan et al., 2022). The important question in ALS is not simply whether the gut barrier can become disrupted, but whether that disruption is enough to influence inflammation, metabolism, or motor neurone vulnerability in a meaningful way.

ALS mouse studies suggest it may matter.

In SOD1G93A mice, one of the most commonly used ALS models, researchers have reported disrupted tight junctions, increased gut permeability, and reduced abundance of butyrate-producing bacteria before overt motor symptoms appear (Lee et al., 2024; Oriquat et al., 2026; Zhang et al., 2017).

When these mice were given sodium butyrate, a microbial metabolite normally produced when gut bacteria ferment fibre, researchers reported improved gut barrier integrity, delayed weight loss, and extended survival (Zhang et al., 2017). This is not proof that butyrate will help humans with ALS. But it does suggest that gut barrier integrity is biologically relevant enough to study seriously.

When the fingerprints do not quite match

Some studies have reported shifts in major bacterial groups such as Firmicutes and Bacteroidetes. Others have reported different or even opposite patterns. One study found no major compositional differences between people with ALS and healthy controls, while another reported changes in several bacterial genera (Nicholson et al., 2021; Oriquat et al., 2026; Zeng et al., 2020).

The largest early human study compared 50 people with ALS with 50 healthy controls and found altered abundance of several microbial genera. The same research group also ran a 6-month probiotic intervention, but it did not produce a clear clinical benefit or reliably move the ALS microbiome closer to that of healthy controls (Di Gioia et al., 2020; Lee et al., 2024).

This is important. It means we should not jump from “the gut may matter” to “take this probiotic”.

There are several reasons human findings are inconsistent. ALS itself changes the gut environment. People may eat differently because of swallowing problems, fatigue, appetite loss, weight loss, or gastrostomy feeding. Mobility changes. Constipation becomes more common. Medications, antibiotics, supplements, and altered hydration all affect the microbiome (Oriquat et al., 2026).

The microbiome is like a crime scene after many people have walked through it. There may be real clues there, but it becomes hard to know which footprints came first.

That is why the most careful conclusion is this: gut microbial imbalance appears to be present in at least some people with ALS, but no single reproducible ALS microbiome signature has yet been established.

The mice that keep nudging us back

When researchers move from mice to people, the picture becomes harder to read. Human studies have produced important clues, but they do not yet tell a simple story.

Despite the mixed human data, the animal evidence keeps pulling researchers back to the gut.

A landmark study by Blacher and colleagues used shotgun metagenomic sequencing, which reads the broader genetic content of the microbiome rather than only identifying bacteria by a marker gene. In ALS-prone SOD1 mice, the researchers found that the gut microbiome influenced disease features (Blacher et al., 2019).

One bacterium, Akkermansia muciniphila, appeared protective in the ALS mouse model. Two others, Ruminococcus torques and Parabacteroides distasonis, appeared harmful. The protective effect of Akkermansia muciniphila was linked to nicotinamide, a form of vitamin B3 and a precursor for NAD+, a molecule central to cellular energy production and stress resilience (Blacher et al., 2019).

A simple way to understand NAD+ is to imagine it as part of the battery-exchange system inside cells. Motor neurones are extremely energy-hungry cells. They have long axons, high maintenance demands, and limited tolerance for metabolic disruption. If their energy systems are already strained, changes in microbial metabolites that influence mitochondrial function could plausibly matter.

The most interesting part of the Blacher study was that the researchers did not stop at mice. In people with ALS, they found lower bacterial gene content for nicotinamide synthesis, and lower nicotinamide levels in serum and cerebrospinal fluid compared with controls (Blacher et al., 2019).

This does not prove causation. The human findings were correlative. But the study is valuable because the microbe, metabolite, and mechanism lined up across animal and human observations.

The new 2026 clue: bacterial glycogen and C9ORF72

One of the most important recent additions to this story is the 2026 Cell Reports study by McCourt and colleagues (McCourt et al., 2026).

This study focused on C9ORF72, the most common genetic cause of familial ALS and frontotemporal dementia. C9ORF72 is involved in immune regulation and cellular waste-handling. When this pathway is impaired, immune cells may become more reactive to microbial signals.

McCourt et al. identified a specific gut-derived signal: inflammatory forms of bacterial glycogen. Glycogen is usually thought of as a storage form of glucose, like a compact energy reserve. But in this context, certain bacterial glycogen structures appeared to act less like stored fuel and more like a badly labelled parcel at airport security. The immune system sees it, mistrusts it, and overreacts.

In mouse models with C9orf72-related vulnerability, these bacterial glycogen signals triggered inflammatory responses. Importantly, degrading the microbial glycogen reduced inflammation and improved outcomes in the model (McCourt et al., 2026). The researchers also found inflammatory forms of glycogen in stool samples from 15 of 22 people with ALS, 1 person with C9ORF72-related frontotemporal dementia, and 4 of 12 healthy controls (McCourt et al., 2026).

This is early-stage research. It does not mean bacterial glycogen causes ALS. It does not yet provide a clinical treatment. But it does give the field something more specific than “the microbiome may be altered”. It identifies a microbial product, an immune pathway, a genetic susceptibility context, and a possible therapeutic target.

That is exactly the kind of mechanistic bridge ALS research needs.

The molecules that travel

If gut microbes influence ALS biology, they are likely doing so through molecules they produce or modify.

Some of these molecules may be protective.

Short-chain fatty acids, especially butyrate, are produced when fibre-degrading bacteria ferment plant fibres in the colon. Butyrate helps maintain the gut barrier, supports colon cells, influences gene expression through enzymes called histone deacetylases, and promotes regulatory T cells, which help restrain excessive inflammation (Mudda et al., 2026; Oriquat et al., 2026).

Histone deacetylases can sound painfully technical. Think of them as volume controls on gene activity. Butyrate can turn down certain inflammatory settings, helping the immune system respond without getting stuck in a permanently loud mode.

Nicotinamide, as discussed above, contributes to NAD+ biology, mitochondrial function, and cellular stress responses (Blacher et al., 2019).

Tryptophan-derived metabolites, including indoles, may signal through the aryl hydrocarbon receptor, a receptor involved in immune and barrier regulation. These pathways may influence astrocytes, the support cells in the brain and spinal cord that can either protect neurones or contribute to inflammation depending on context (Oriquat et al., 2026).

Other microbial molecules may be harmful when they escape the gut.

Lipopolysaccharide, LPS, is a component of the outer wall of Gram-negative bacteria. It is sometimes called endotoxin. If LPS crosses a weakened gut barrier and enters the bloodstream, it can activate immune sensors called toll-like receptors. This can trigger inflammatory cytokines, including tumour necrosis factor alpha and interleukin-1 beta (Kalyan et al., 2022).

One analogy is to imagine LPS as smoke from a fire alarm test. Inside the right place, it is manageable. But if it spreads through the whole building every day, the alarm system becomes exhausted and overreactive.

Some studies have reported elevated circulating endotoxin in sporadic ALS, with associations between endotoxin levels and immune activation (Zhang et al., 2009; Kalyan et al., 2022). This does not yet make LPS a reliable ALS biomarker, but it supports the broader idea that gut-derived inflammatory signals may contribute to systemic immune activation in some patients.

Other gut-linked candidates include cyanobacterial neurotoxins such as beta-N-methylamino-L-alanine, BMAA, which has been discussed in relation to ALS clusters such as Guam, as well as formaldehyde and sulphur amino acid metabolites such as homocysteine-related compounds (Lee et al., 2024). These remain areas of investigation rather than settled clinical tools.

The immune system’s unwelcome guests

ALS is not only a disease of dying motor neurones. It is also a disease involving neuroinflammation.

In the brain and spinal cord, microglia and astrocytes become activated. Microglia are the resident immune cells of the central nervous system. In health, they behave a bit like gardeners: pruning, clearing debris, and maintaining the local environment. But in chronic neurodegeneration, they can become more like overzealous security guards, releasing inflammatory chemicals that may damage the very tissue they are meant to protect.

In ALS, microglia appear to change over time. Earlier in disease, some immune responses may be protective or reparative. Later, they may become more inflammatory, with increased production of cytokines such as tumour necrosis factor alpha and interleukin-1 beta (Mudda et al., 2026; Oriquat et al., 2026).

The gut may influence this process.

Gut microbes help shape the balance between inflammatory T helper 17 cells and regulatory T cells. Regulatory T cells, or Tregs, are the immune system’s brakes. They do not shut immunity down completely. They stop it from skidding out of control.

People with ALS have been reported to show reduced Treg number or function, and lower Treg activity has been associated with faster disease progression (Mudda et al., 2026; Oriquat et al., 2026). Early-phase clinical research using expanded autologous Tregs with low-dose interleukin-2 has suggested that this approach can be biologically active and tolerable, although the evidence remains preliminary and larger trials are needed (Thonhoff et al., 2022).

This immune pathway matters because it links the gut to the nervous system in a plausible way. Dysbiosis may reduce immune restraint. Barrier dysfunction may allow microbial products into circulation. Microglia and astrocytes may become more inflammatory. Motor neurons, already under metabolic and oxidative stress, may then face a more hostile environment.

Again, this is not a simple cause-and-effect chain. It is more like several dimmer switches being turned in the wrong direction at the same time.

Cousins in the same family

ALS is not alone in this gut–brain story.

In Parkinson’s disease, constipation can appear years before motor symptoms. Gut inflammation, intestinal permeability, and abnormal alpha-synuclein accumulation in the gut wall have all been investigated as part of Parkinson’s biology (Kalyan et al., 2022).

In Alzheimer’s disease, studies have reported altered gut microbial patterns and inflammatory microbial products, including LPS, in brain-related contexts (Kalyan et al., 2022).

In multiple sclerosis, a different disease but one strongly shaped by immune regulation, dysbiosis and intestinal permeability have also been studied as potential contributors to central nervous system inflammation (Kalyan et al., 2022).

None of these diseases is the same as ALS. But the repeated pattern is hard to ignore: gut ecology, barrier integrity, microbial metabolites, and immune tone keep appearing in the biology of neurodegeneration.

The gut is not the whole story. But it may be one of the places where the story begins to widen.

What this means, carefully, for people living with ALS today

The most important word here is carefully.

The current evidence supports the idea that the gut microbiome, intestinal barrier, microbial metabolites, and immune signalling may be involved in ALS biology in at least some people (Lee et al., 2024; Oriquat et al., 2026).

It does not prove that ALS starts in the gut.

It does not prove that a specific diet, probiotic, postbiotic, or microbiome test can alter the course of disease.

It does not justify aggressive supplement protocols, restrictive diets, or gut interventions that risk weight loss, reduced intake, or added stress. In ALS, maintaining nutritional status and body weight is often clinically important, so any gut-focused strategy must be considered in that wider context.

What the evidence does justify is a change in how we think.

Gut symptoms in ALS should not be dismissed as minor inconveniences. Constipation, bloating, reflux, altered motility, and feeding changes may all affect comfort, nutrition, microbial ecology, immune tone, and quality of life.

The gut should be seen as part of the terrain in which ALS unfolds.

For researchers, this opens up new questions. Which patients have meaningful dysbiosis? Which microbial metabolites matter most? Can barrier dysfunction be measured reliably? Are there subgroups, such as people with C9ORF72-related ALS, who are more sensitive to gut-derived immune triggers? Could microbial glycogen, butyrate, nicotinamide, or LPS-related pathways become useful biomarkers or intervention targets?

For clinicians and nutritional therapists, the message is more grounded. Support digestion. Protect nutritional status. Avoid unnecessary restriction. Consider constipation, motility, fibre tolerance, hydration, medication effects, swallowing safety, and microbiome-supportive dietary patterns within the person’s wider care plan.

And for people living with ALS, the message is not that the gut holds a miracle answer. It is that the body is connected in more ways than older models allowed. The bowel, immune system, metabolism, and nervous system are not separate departments. They are more like musicians in the same orchestra. If one section is out of tune, the whole performance can change.

Where part two goes next

Part two of this series will move from mechanism to action.

We will examine what the science currently says about diet, prebiotics, probiotics, postbiotics, faecal microbiota transplantation, butyrate, nicotinamide, methylcobalamin, and other emerging gut-relevant strategies in ALS.

We will also look at what not to overclaim.

The honest hope is that gut–brain research may eventually help identify safer, more targeted, more personalised ways to support people living with ALS.

The honest reality is that we are still early in that journey.

But knowing where we stand on the map is the first step in walking it well.

Continued in part two: from mechanism to hope: diet, the microbiome, and the search for ALS therapies that work.

References

Blacher, E., Bashiardes, S., Shapiro, H., Rothschild, D., Mor, U., Dori-Bachash, M., Kleimeyer, C., Moresi, C., Harnik, Y., Zur, M., Zabari, M., Brik, R. B.-Z., Kviatcovsky, D., Zmora, N., Cohen, Y., Bar, N., Levi, I., Amar, N., Mehlman, T., … Elinav, E. (2019). Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature, 572(7770), 474–480. https://doi.org/10.1038/s41586-019-1443-5

Cusumano, G., Flores, G. A., Venanzoni, R., & Angelini, P. (2025). The impact of antibiotic therapy on intestinal microbiota: Dysbiosis, antibiotic resistance, and restoration strategies. Antibiotics, 14(4), 371. https://doi.org/10.3390/antibiotics14040371

Di Gioia, D., Bozzi Cionci, N., Baffoni, L., Amoruso, A., Pane, M., Mogna, L., Gaggìa, F., Lucenti, M. A., Bersano, E., Cantello, R., & Mazzini, L. (2020). A prospective longitudinal study on the microbiota composition in amyotrophic lateral sclerosis. BMC Medicine, 18, 153. https://doi.org/10.1186/s12916-020-01607-9

Kalyan, M., Tousif, A. H., Sonali, S., Vichitra, C., Sunanda, T., Praveenraj, S. S., Ray, B., Gorantla, V. R., Rungratanawanich, W., Mahalakshmi, A. M., Qoronfleh, M. W., Monaghan, T. M., Song, B.-J., Essa, M. M., & Chidambaram, S. B. (2022). Role of endogenous lipopolysaccharides in neurological disorders. Cells, 11(24), 4038. https://doi.org/10.3390/cells11244038

Lee, A., Henderson, R., Aylward, J., & McCombe, P. (2024). Gut symptoms, gut dysbiosis and gut-derived toxins in ALS. International Journal of Molecular Sciences, 25(3), 1871. https://doi.org/10.3390/ijms25031871

McCourt, B., Lemr, K., Maltby, D. A., Beedle, A. M., Stanley, S. A., & Burberry, A. (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

Mudda, N. S., Zhang, L., & Sampelli, P. (2026). Targeting gut-brain-immune axis in amyotrophic lateral sclerosis. Frontiers in Immunology, 16, 1637976. https://doi.org/10.3389/fimmu.2025.1637976

Nicholson, K., Bjornevik, K., Abu-Ali, G., Chan, J., Cortese, M., Dedi, B., Jeon, M., Xavier, R., Huttenhower, C., Ascherio, A., & Berry, J. D. (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

Oriquat, G., Malathi, H., Maharana, L., Dhyani, A., Al-Hasnaawei, S., Singh-Chauhan, A., Arora, V., Sharma, J., & Sadeghi-Samarjan, R. (2026). The gut microbiome in amyotrophic lateral sclerosis: Emerging mechanisms and therapeutic potential. Molecular Neurobiology, 63(1), 549. https://doi.org/10.1007/s12035-026-05826-8

Thonhoff, J. R., Berry, J. D., Macklin, E. A., Beers, D. R., Mendoza, P. A., Zhao, W., Thome, A. D., Triolo, F., Moon, J. J., Paganoni, S., Cudkowicz, M., & Appel, S. H. (2022). Combined regulatory T-lymphocyte and IL-2 treatment is safe, tolerable, and biologically active for 1 year in persons with amyotrophic lateral sclerosis. Neurology: Neuroimmunology & Neuroinflammation, 9(6), e200019. https://doi.org/10.1212/NXI.0000000000200019

Xie, S., Zhang, C., Ma, X., Niu, L., & Wang, Y. (2026). Neuroprotective mechanisms of Lactiplantibacillus plantarum in neurodegenerative diseases. Academia Neuroscience and Brain Research, 2. https://doi.org/10.20935/AcadNeurosci8210

Zeng, Q., Shen, J., Chen, K., Zhou, J., Liao, Q., Lu, K., Deng, Z., Zhong, L., Wang, X., & Wu, A. (2020). The alteration of gut microbiome and metabolism in amyotrophic lateral sclerosis patients. Scientific Reports, 10, 12998. https://doi.org/10.1038/s41598-020-69845-8

Zhang, Y.-G., Wu, S., Yi, J., Xia, Y., Jin, D., Zhou, J., Sun, J., & others. (2017). Target intestinal microbiota to alleviate disease progression in amyotrophic lateral sclerosis. Clinical Therapeutics, 39(2), 322–336. https://doi.org/10.1016/j.clinthera.2016.12.014