When Gut Bugs Start a Civil War in the Brain
Curator’s Note: The article discusses new research revealing that Amyotrophic Lateral Sclerosis (ALS), traditionally viewed as a purely neurological disorder, may also involve interactions with the gut microbiome, particularly in patients with the C9ORF72 mutation. This study indicates that certain gut bacteria can trigger immune responses that lead to inflammation in the brain, challenging the neuron-centric view of ALS. It emphasizes that genetic predisposition alone is insufficient for disease development, suggesting that modifications in biological interactions, such as those originating from the gut, could influence both the onset and progression of ALS. Understanding these connections may shape future treatment approaches. This insightful essay was written by Dr. Michael Broadly, a retired scientist and public healthcare consultant. Dr. Broadly is also the chief editor of the Health and Science publication on Medium.com, which is part of ILLUMINATION Integrated Publications.
Dear Reader,
At science school decades ago, we learned that ALS is a disease that begins and ends in the nervous system. It is still the same. At a high level, motor neurons degenerate, muscles weaken, and over time, the body loses its ability to respond to the brain’s instructions.
The framing is clean, and in many ways convincing. Yet it may also be incomplete. I highlight this as there is still no cure for this lethal disease.
Recently, a scientific paper hit my inbox and gave me shockwaves. It looks very complicated for the public so I decided to introduce it in simple words that anyone can understand and gain insights into this exceptional research.
This eye-opening research, published in Cell Reports, suggests that for a subset of patients, particularly those carrying the C9ORF72 mutation, the initiating events may occur well outside the brain.
What appears at first to be a purely neurological disorder may, in part, reflect a disturbance in how the immune system interprets chemical signals originating in the gut.
This piece of research does not replace existing models of ALS. Instead, it adds a layer that has been overlooked. Let me clarify:
The C9ORF72 mutation is one of the strongest known genetic risk factors for ALS and frontotemporal dementia. However, many carriers never develop the disease.
This long-standing observation implies that genetic vulnerability alone is insufficient. Something else must interact with that vulnerability to shape disease onset and progression.
The study in question points to the gut microbiome as one such factor.
The researchers identified ten bacterial strains that, in the presence of the C9ORF72 mutation, stimulated immune cells to release inflammatory cytokines.
These bacteria were not closely related to one another, which suggested that the effect was not due to their taxonomy but rather to a shared metabolic behaviour.
Using metatranscriptomic analysis, the authors traced this effect to a common pathway: bacterial glycogen biosynthesis. Glycogen is typically regarded as a neutral storage molecule, a reserve of energy.
In this context, however, its structure appeared to act as an immune signal. Rather than nourishing the host, it activated immune pathways that promoted systemic inflammation.
To explore the consequences of this interaction, the researchers colonised germ-free mice carrying the ALS-associated mutation with one of these bacteria, Parabacteroides merdae. The results were not limited to the gut.
Immune cells expanded in the circulation, the blood–brain barrier became more permeable, and inflammatory cells entered the central nervous system. Microglia, the brain’s resident immune cells, shifted toward a reactive state. Then, neuroinflammation followed.
Importantly, the neurons themselves were not the initiating cause of this response. They were responding to an immune environment that had been reshaped by signals originating in the gut.
The most striking finding in my view came when the researchers altered only one variable. By enzymatically digesting bacterial glycogen in the gut, they reduced brain inflammation, dampened microglial activation, and extended survival in mutant mice. The gene remained unchanged.
The microbiota were still present. Yet, what differed was the chemical signal being produced. This is critical to understand. Why?
Because this suggests that in at least some forms of ALS, disease progression may not be fixed by genetics alone. It may be influenced by modifiable biological interactions that occur far from the nervous system.
The relevance of this mechanism was supported by analysis of human stool samples. Inflammatory forms of glycogen were detected in the majority of patients with ALS examined, including those with C9ORF72-related frontotemporal dementia, while appearing far less frequently in healthy controls. Although the sample size was limited, the pattern mirrored the experimental findings.
Taken together, these results challenge a purely neuron-centric view of ALS. They suggest that the disease may involve a broader systems-level failure in which genes, microbes, immune responses, and neural tissue interact dynamically.
I want to highlight that this does not imply that ALS is caused by gut bacteria, nor that modifying the microbiome alone will halt neurodegeneration.
Rather, it highlights how biological meaning is constructed through networks of communication. Immune systems do not simply defend; they interpret. When that interpretation is distorted, the consequences may extend into the brain itself.
The deeper implication is that neurodegenerative diseases may not always begin where symptoms appear. They may begin in the spaces between systems, where chemical messages are exchanged and misread.
If that is so, then understanding and eventually reshaping those messages may become an important part of how such conditions are approached in the future.
Thanks for reading my story.
If you don’t know what ALS is, here is a well-written story about it, which I enjoyed reading very much.
About me
I am a retired healthcare scientist in my mid-70s, and I have several grandkids who keep me going and inspire me to write on this platform. I am also the chief editor of the Health and Science publication on Medium.com. As a giveback activity, I volunteered as an editor for Illumination publications, supporting many new writers. I will be happy to read, publish, and promote your stories. You may connect with me on LinkedIn, Twitter where I share stories I read. You may subscribe to my account to get my stories in your inbox when I post. You can also find my distilled content on Substack: Health Science Research By Dr Mike Broadly. I also do guest-blogging. Welcome to Substackmastery.com! I started blogging at Blogger!
For free content you can check My Substack profile and My Guest Blogging Site
Leave a Reply