C9orf72 suppresses systemic and neural inflammation induced by gut bacteria
Open accessAbstract
A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3–9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6–9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics—as well as transplanting gut microflora from a protective environment—attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system. Reduced abundance of immune-stimulating gut bacteria ameliorated the inflammatory and autoimmune phenotypes of mice with mutations in C9orf72, which in the human orthologue are linked to amyotrophic lateral sclerosis and frontotemporal dementia.
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Studies on animal models have provided compelling evidence that the altered gut microbiome drives neurodegenerative disease pathogenesis, primarily through the modulation of microglial functions and activation.
“Moreover, studies on animal models have provided compelling evidence that the altered gut microbiome drives neurodegenerative disease pathogenesis, primarily through the modulation of microglial functions and activation.54–57”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [57]
Lifelong antibiotic administration prevents accumulation of infiltrating myeloid cells within the spinal cord and microglial activation in C9orf72−/− mice.
“Moreover, lifelong antibiotics administration prevented the accumulation of infiltrating myeloid cells within the spinal cord and microglial activation.57”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [57]
Administration of antibiotics before onset or after establishment of inflammation suppresses inflammatory and autoimmune phenotypes in C9orf72−/− mice.
“The administration of antibiotics, either prior to the onset or after the establishment of inflammation, effectively suppressed the emergence of inflammatory and autoimmune phenotypes in C9orf72−/− mice.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [57]
FMT from C9orf72(Broad)−/− mice significantly ameliorated the autoimmune and inflammatory phenotypes in C9orf72(Harvard)−/− mice.
“Importantly, FMT from C9orf72(Broad)−/− mice significantly ameliorated the autoimmune and inflammatory phenotypes in C9orf72(Harvard)−/− mice.57”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [57]
FMT from C9orf72-mutant mice housed at pro-survival environment (Broad Institute) effectively ameliorated autoimmune inflammatory phenotypes in recipient C9orf72-mutant mice, whereas FMT from those housed at pro-inflammatory environment (Harvard Institute) did not improve these phenotypes.
“A recent study showed that FMT from C9orf72-mutant mice housed at pro-survival environment (Broad Institute) effectively ameliorated the autoimmune inflammatory phenotypes in recipient C9orf72-mutant mice, whereas FMT from those housed at pro-inflammatory environment (Harvard Institute) did not improve these phenotypes.57”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [57]
The rearing environment of FMT donors may influence the outcomes of FMT.
“Interestingly, the rearing environment of FMT donors may influence the outcomes of FMT.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [57]
The most common genes identified in clinical practice include SOD1, C9ORF72, TARDBP, FUS, and OPTN/TDP-43.
“The most common genes identified in clinical practice include SOD1, C9ORF72, TARDBP, FUS, and OPTNTD-P43 (55–57, 73, 74).”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [74]
Akkermansia muciniphila alleviates symptoms of ALS, whereas Ruminococcus torques and Parabacteroides distasonis exacerbate them.
“Akkermansia muciniphila (AM) was found to alleviate symptoms of ALS, whereas Ruminococcus torques and Parabacteroides distasonis were found to exacerbate them.”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [74]
In mice, broad-spectrum antibiotics reduce the burden of intestinal microbes, improve the phenotype, and prolong lifespan.
“When broad-spectrum antibiotics are used to reduce the burden of intestinal microbes, this phenotype is improved, and the lifespan of such mice is prolonged (74).”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [74]
A relevant contribution of gut microbiota is not restricted to neuroinflammatory and psychiatric disorders but also extends to brain development.
“Moreover, a relevant contribution of gut microbiota is not only restricted to neuroinflammatory and psychiatric disorders (23–32) but also to brain development (13).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [31]
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- Authors
- Burberry, A., Wells, M. F., Limone, F., Couto, A., Smith, K. S., Keaney, J., Gillet, G., van Gastel, N., Wang, J.-Y., Pietilainen, O., Qian, M., Eggan, P., Cantrell, C., Mok, J., Kadiu, I., Scadden, D. T., & Eggan, K.
- Affiliations
- Broad Institute (US)
- UCB Pharma (Belgium) (BE)
- Harvard University (US)
- Corresponding author
- Eggan, Kevin
- ORCID
- Venue
- Nature
- Published
- 2020-05-13
- Volume
- 582
- Issue
- 7810
- Pages
- 89-94
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7416879
- OpenAlex
- W3026019136
- Cited by
- 314
- References
- 40
- Citations by year
- 2026: 31 · 2025: 29 · 2024: 51 · 2023: 63 · 2022: 70 · 2021: 46 · 2020: 24
- FWCI
- 23.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R00AG057808, K99AG057808)
- National Heart, Lung, and Blood Institute (P01HL131477)
- National Institute of Mental Health (R00MH119327, K99MH119327)
- National Institute of Neurological Disorders and Stroke (R01NS089742)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- C9orf72, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, gut microbiota, systemic inflammation, neuroinflammation, autoimmunity, broad-spectrum antibiotics, microbiota transplantation, disease modifiers
- MeSH terms
- Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Loss of Function Mutation, C9orf72 Protein, Brain-Gut Axis, Amyotrophic Lateral Sclerosis, Animals, Anti-Bacterial Agents, Cell Movement, Disease Models, Animal, Female, Gliosis, Inflammation, Male, Spinal Cord, Autoimmunity, Survival Rate, Cytokines, Microglia, Mice, Frontotemporal Dementia
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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