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Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis
Open accessAbstract
Purpose Emerging evidence has demonstrated that gut microbiome plays essential roles in the pathogenesis of human diseases in distal organs. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Treatment with the only drug approved by the US Food and Drug Administration for use in ALS, riluzole, extends a patient׳s life span by only a few months. Thus, there is an urgent need to develop novel interventions that for alleviate disease progression and improve quality of life in patients with ALS. Here we present evidence that intestinal dysfunction and dysbiosis may actively contribute to ALS pathophysiology.Methods We used G93A transgenic mice as a model of human ALS. The G93A mice show abnormal intestinal microbiome and damaged tight junctions before ALS disease onset. The mice were given 2% butyrate, a natural bacterial product, in the drinking water.Results In mice fed with butyrate, intestinal microbial homeostasis was restored, gut integrity was improved, and life span was prolonged compared with those in control mice. At the cellular level, abnormal Paneth cells-specialized intestinal epithelial cells that regulate the host-bacterial interactions-were significantly decreased in the ALS mice treated with butyrate. In both ALS mice and intestinal epithelial cells cultured from humans, butyrate treatment was associated with decreased aggregation of the G93A superoxide dismutase 1 mutated protein.Implications The findings from this study highlight the complex role of the gut microbiome and intestinal epithelium in the progression of ALS and present butyrate as a potential therapeutic reagent for restoring ALS-related dysbiosis.
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In the citing paper
“The administration of butyrate has been shown to increase the abundance of butyrate-producing Butyrivibrio fibrisolvens, restore Paneth cell homeostasis and enhance the intestinal barrier integrity of SOD1G93A mice.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [347]
In the citing paper
“Butyrate supplementation has demonstrated neuroprotective effects in SOD1G93A mice.222,347”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [347]
In the citing paper
“This is accompanied by reduced SOD1G93A aggregation in the intestine, thereby slowing disease progression and prolonging the lifespan of SOD1G93A mice.347”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [347]
In the citing paper
“Zhang et al. (72) found, using the 16sRDNA technique, that butyrate-producing bacteria (Butyrivibrio Fibrisolvens) were reduced in SOD1G93A mice, but after butyrate treatment, the mice exhibited restoration of homeostasis of the intestinal flora, restoration of intestinal epithelial barrier integrity, and improvement in clinical signs.”
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 [72]
In the citing paper
“Zhang et al. (72) found that treatment of ALS mice with oxalate extended their life span by an average of 38 days.”
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 [72]
In the citing paper
“Additionally, treatment of ALS mice with butyrate resulted in a significant decrease in the percentage of abnormal Paneth cells in the intestine. This treatment also restored the levels of lysozyme 1 and antimicrobial peptide defensin 5α in the intestine, as well as improving and slowing pathological progression of the intestine.”
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 [72]
In the citing paper
“This indicates the important role of butyrate in maintaining the physiological integrity of the intestine.”
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 [72]
In the citing paper
“This demonstrates the effectiveness of oxalate, a natural bacterial product, in restoring microbial and intestinal homeostasis.”
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 [72]
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ALS and the Microbiome: Understanding the Gut’s Impact on Motor Neuron Degeneration
Deepika, N. P., & Muhasina, K. M. (2026) · Springer eBooks · doi:10.1007/978-981-95-7494-0_5
Therapeutic Interventions: Modulating the Microbiome to Combat Neurodegeneration
Anandan, A., Unais, A. M., Prabhu, A. V., Saju, M. K., Sonaimuthu, K., Murugesan, H., Danielraj, F., Marimuthu, D., Shibu, M. A., & Viswanadha, V. P. (2026) · Springer eBooks · doi:10.1007/978-981-95-7494-0_8
Khodve, G., Raval, S., & Banerjee, S. (2026) · International review of neurobiology · doi:10.1016/bs.irn.2026.05.015
Kumari, J., Das, S., Ranjan, S., & Singh, S. (2026) · 3 Biotech · doi:10.1007/s13205-026-04885-x
“Supporting this, additional studies have reported bacterial amyloid proteins driving early α-synuclein deposition in intestinal neurons, alongside clinical symptoms such as constipation and anosmia years before PD diagnosis (Braak et al. 2003 ; Fernández-Calvet et al. 2024; Sampson et al. 2020).”
Sanchis, E. S., Ortí, J. E. D. L. R., Sancho-Cantus, D., Cunha-Pérez, C., & Mohedo, J. C. (2026) · Pathophysiology · doi:10.3390/pathophysiology33030059
“…mechanisms have been explicitly validated in SOD1G93A ALS transgenic mouse models, where targeted butyrate supplementation significantly restored intestinal epithelial integrity, normalized dysbiotic microflora, reduced systemic inflammation, and delayed neuromuscular disease progression [77,78].”
InfluentialDresel, F. C., Michaelis, M., & Gourlay, C. W. (2026) · International Journal of Cell Biology · doi:10.1155/ijcb/3022967
“It has been reported that ALS patients lack butyrate producing bacteria [36] and that NaB supplementation could improve motor function in a mouse model of ALS [58].”
The microbiota–proteostasis axis: implications in neurodegenerative diseases
Czyż, D. M., & Brown, B. M. (2026) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2025.0265
“Butyrate supplementation has been shown to improve memory in AD mice, ameliorate pathology in the ALS murine model and directly suppress protein misfolding in tissue culture [184 ,185 ].”
The Microbiota-Gut-Brain Axis in Neurological and Neuropsychiatric Disorders: A Literature Review
Brar, H., Do, N., Kelser, C., Pattipati, S. N., & Nalamolu, K. R. (2026) · Cureus · doi:10.7759/cureus.118684
Metadata
- Authors
- Zhang, Y.-G., Wu, S., Yi, J., Xia, Y., Jin, D., Zhou, J., & Sun, J.
- Affiliations
- Rush University Medical Center (US)
- Kansas City University (US)
- University of Illinois Chicago (US)
- Corresponding author
- Sun, Jun
- Venue
- Clinical Therapeutics
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 39
- Issue
- 2
- Pages
- 322-336
- ISSN
- 0149-2918 (ISSN-L)
- PMC
- PMC5344195
- OpenAlex
- W2580573536
- Cited by
- 287
- References
- 49
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 50 · 2023: 35 · 2022: 37 · 2021: 43 · 2020: 26 · 2019: 20 · 2018: 25 · 2017: 8
- FWCI
- 8.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK105118)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR057404)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- amyotrophic lateral sclerosis, gut microbiota, dysbiosis, butyrate, intestinal epithelium, Paneth cells, tight junctions, neurodegeneration
- MeSH terms
- Gastrointestinal Microbiome, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Humans, Mice, Transgenic, Motor Neurons, Quality of Life, Superoxide Dismutase, Disease Progression, Mice
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