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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Administration of butyrate increases abundance of butyrate-producing Butyrivibrio fibrisolvens, restores Paneth cell homeostasis, and enhances intestinal barrier integrity in SOD1G93A mice.
“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]
Butyrate supplementation has neuroprotective effects in SOD1G93A mice.
“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]
Butyrate treatment reduces SOD1G93A aggregation in the intestine, thereby slowing disease progression and prolonging lifespan of SOD1G93A mice.
“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]
Butyrate-producing bacteria 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.
“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]
Treatment of ALS mice with oxalate extended their life span by an average of 38 days.
“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]
Treatment of ALS mice with butyrate resulted in a significant decrease in the percentage of abnormal Paneth cells in the intestine, restored the levels of lysozyme 1 and antimicrobial peptide defensin 5α in the intestine, and improved and slowed pathological progression of the intestine.
“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]
Butyrate plays an important role in maintaining the physiological integrity of the intestine.
“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]
Oxalate, a natural bacterial product, is effective in restoring microbial and intestinal homeostasis.
“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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“69,70 Besides, butyrate could reverse downregulation of the mitochondrial melatonergic pathway in ALS through upregulating mitochondrial sirtuin-3 and pyruvate dehydrogenase complex (PDC) disinhibition 71 (Fig.”
The human gut microbiota in people with amyotrophic lateral sclerosis
Nicholson, K., Bjornevik, K., Abu-Ali, G., Chan, J., Cortese, M., Dedi, B., Jeon, M., Xavier, R., Huttenhower, C., Ascherio, A., et al. (2021) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2020.1828475 · Cited by 123 · see citing works
Maguire, M., & Maguire, G. (2018) · Reviews in the Neurosciences · doi:10.1515/revneuro-2018-0024 · Cited by 111 · see citing works
Microbiota-brain interactions: Moving toward mechanisms in model organisms
Nagpal, J. K., & Cryan, J. F. (2021) · Neuron · doi:10.1016/j.neuron.2021.09.036 · Cited by 107 · see citing works
Gut microbiota-derived metabolites and their importance in neurological disorders
Swer, N. M., Venkidesh, B. S., Murali, T. S., & Mumbrekar, K. D. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-08038-0 · Cited by 111 · see citing works
“1 3 to have improved gut homeostasis and a longer life span [45].”
BackgroundThe Role of Microbiome in Brain Development and Neurodegenerative Diseases
Nandwana, V., Nandwana, N. K., Das, Y., Saito, M., Panda, T., Das, S., Almaguel, F. A., Hosmane, N. S., & Das, B. C. (2022) · Molecules · doi:10.3390/molecules27113402 · Cited by 113 · see citing works
Gut Microbiota Interaction with the Central Nervous System throughout Life
Ojeda, J., Ávila, A., & Vidal, P. M. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10061299 · Cited by 107 · see citing works
Potential Role of Gut Microbiota in ALS Pathogenesis and Possible Novel Therapeutic Strategies
Mazzini, L., Mogna, L., Marchi, F. D., Amoruso, A., Pane, M., Aloisio, I., Cionci, N. B., Gaggìa, F., Lucenti, A., Bersano, E., et al. (2018) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0000000000001042 · Cited by 100 · see citing works
The amyotrophic lateral sclerosis exposome: recent advances and future directions
Goutman, S. A., Savelieff, M. G., Jang, D., Hur, J., & Feldman, E. L. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00867-2 · Cited by 102 · see citing works
The microbiota–microglia axis in central nervous system disorders
Mossad, O., & Erny, D. (2020) · Brain Pathology · doi:10.1111/bpa.12908 · Cited by 98 · see citing works
“Replenishment of probiotics and the relevant metabolites in SOD1G93A transgenic mice ameliorates the motor deficits (110).”
BackgroundFigueroa-Romero, C., Guo, K., Murdock, B. J., Paez-Colasante, X., Bassis, C. M., Mikhail, K. A., Raue, K. D., Evans, M. C., Taubman, G. F., McDermott, A. J., et al. (2019) · Disease Models & Mechanisms · doi:10.1242/dmm.041947 · Cited by 94 · see citing works
“Interestingly, although a lower F/B and higher B is generally associated with ALS (Rowin et al., 2017; Fang et al., 2016; Wu et al., 2015; Zhang et al., 2017), two species belonging to B, Bacteroides caccae and Bacteroides vulgatus , were lower in our cohort of SOD1 G93A mice.”
Role of Akkermansia in Human Diseases: From Causation to Therapeutic Properties
Pellegrino, A., Coppola, G., Santopaolo, F., Gasbarrini, A., & Ponziani, F. R. (2023) · Nutrients · doi:10.3390/nu15081815 · Cited by 105 · see citing works
Butyric Acid and Leucine Induce α-Defensin Secretion from Small Intestinal Paneth Cells
Takakuwa, A., Nakamura, K., Kikuchi, M., Sugimoto, R., Ohira, S., Yokoi, Y., & Ayabe, T. (2019) · Nutrients · doi:10.3390/nu11112817 · Cited by 89 · see citing works
“cell number, HD5 mRNA and lysozyme mRNA expression, were decreased in an amyotrophic lateral sclerosis mouse model, and were recovered by administration of 2% butyric acid in the drinking water to the same levels as those in wild-type mice following [31].”
MethodBrain modulation by the gut microbiota: From disease to therapy
Mitra, S., Dash, R., Nishan, A. A., Habiba, S. U., & Moon, I. S. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2022.12.001 · Cited by 87 · see citing works
“Studies using the SOD1 G93A mouse model reported that low levels of Butyrivibrio fib-risolvens , which produces butyrate, are associated with ALS, and supplementation with butyrate improved intestinal barrier function and delayed death in comparison to untreated controls [160–161].”
MethodMoțățăianu, A., Şerban, G. M., & Andone, S. R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015094 · Cited by 90 · see citing works
“Consequently, there is an increase in intestinal inflammation and permeability [110–112].”
BackgroundTherapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside
Ma, Y., Li, X., Yu, J., & Wang, Y. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00404-1 · Cited by 87 · see citing works
Tilocca, B., Pieroni, L., Soggiù, A., Britti, D., Bonizzi, L., Roncada, P., & Greco, V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21114045 · Cited by 86 · see citing works
Mandrioli, J., Amedei, A., Cammarota, G., Niccolai, E., Zucchi, E., D’Amico, R., Ricci, F., Quaranta, G., Spanu, T., & Masucci, L. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01021 · Cited by 78 · see citing works
“(58) reported a correlation between gut dysbiosis and morphofunctional alterations of intestinal permeability in the same model, since the earliest stages of the disease.”
BackgroundAppel, S. H., Beers, D. R., & Zhao, W. (2021) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000983 · Cited by 77 · see citing works
“In mSOD1 transgenic mice, intestinal tight junctions are impaired, gut permeability increased and butyrateproducing bacteria reduced [24].”
BackgroundMicrobiota and neurodegenerative diseases
Marizzoni, M., Provasi, S., Cattaneo, A., & Frisoni, G. B. (2017) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000496 · Cited by 78 · see citing works
Gut microbiome differences between amyotrophic lateral sclerosis patients and spouse controls
Hertzberg, V., Singh, H., Fournier, C. N., Moustafa, A., Polak, M. A., Kuelbs, C., Torralba, M., Tansey, M. G., Nelson, K. E., & Glass, J. D. (2021) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2021.1904994 · Cited by 76 · see citing works
“Inclusion criteria included: (1) patients with live-in spouses who were willing and eligible to participate, and (2) participants between the age of 18–79 years.”
BackgroundZhai, C.-D., Zheng, J.-J., An, B.-C., Huang, H.-F., & Tan, Z.-C. (2019) · Chinese Medical Journal · doi:10.1097/cm9.0000000000000351 · Cited by 72 · see citing works
“In addition, the host-bacterial interactions were apparently reduced in ALS mice treated with butyrate.([4]) The SCFA could be used as the metabolic substrates by Methanobrevibacter genus to produce methane (CH4), which resulted in the weight loss of patients with intestinal diseases.”
InfluentialAntibiotics use and risk of amyotrophic lateral sclerosis in Sweden
Sun, J., Zhan, Y., Mariosa, D., Larsson, H., Almqvist, C., Ingre, C., Zagai, U., Yudi Pawitan, Y., & Fang, F. (2019) · European Journal of Neurology · doi:10.1111/ene.13986 · Cited by 69 · see citing works
“Recent animal studies have shown a clear gut dysbiosis and altered intestinal permeability in the SOD1 mouse model [1] and suggested butyrate as a potential treatment to improve gut integrity, restore homeostasis and prolong survival in these mice [2].”
BackgroundSelf-citationLiu, T., Sun, Z., Yang, Z., & Qiao, X. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114586 · Cited by 67 · see citing works
Potential Role of the Gut Microbiome in ALS: A Systematic Review
Wright, M. L., Fournier, C. N., Houser, M. C., Tansey, M. G., Glass, J. D., & Hertzberg, V. (2018) · Biological Research For Nursing · doi:10.1177/1099800418784202 · Cited by 67 · see citing works
Gut Microbiota Alteration and Its Time Course in a Tauopathy Mouse Model
Sun, B., Li, W., Wang, J., Xu, Y., Sun, H., Tian, D., Wang, Y., & Yao, X. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181220 · Cited by 66 · see citing works
“All rights reserved Alterations in gut microbiota composition can be related to the development of several neurological disorders,includingAD[9],Parkinson’sdisease[10], andamyotrophiclateralsclerosis[8].”
Peripheral and Central Nervous System Immune Response Crosstalk in Amyotrophic Lateral Sclerosis
Liu, Z., Cheng, X., Zhong, S., Zhang, X., Liu, C., Liu, F., & Zhao, C. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00575 · Cited by 66 · see citing works
“Amyotrophic lateral sclerosis is considered as a heterogeneous disease because of the variable progression rates and survival time (Appel et al., 2010; Beers et al., 2017; Zhao et al., 2013).”
BackgroundInfluentialThe Gut Microbiota-Immunity Axis in ALS: A Role in Deciphering Disease Heterogeneity?
Niccolai, E., Pilato, V. D., Nannini, G., Baldi, S., Russo, E., Zucchi, E., Martinelli, I., Menicatti, M., Bartolucci, G., Mandrioli, J., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9070753 · Cited by 66 · see citing works
“The reduction of butyrate-producing bacteria has been previously documented in ALS [53,54] as in other immune-mediated deregulatory conditions, and butyrate supplementation appeared to ameliorate the clinical features of ALS and the immunological abnormalities found in the ALS mice model [55].”
BackgroundGut Microbiota Regulation and Their Implication in the Development of Neurodegenerative Disease
Sun, P., Su, L., Zhu, H., Li, X., Guo, Y., Du, X., Zhang, L., & Qin, C. (2021) · Microorganisms · doi:10.3390/microorganisms9112281 · Cited by 66 · see citing works
“peripheral symptoms of the disease, G93A mice demonstrated a prolonged survival time and reduced body weight [147].”
BackgroundZeng, S.-Y., Liu, Y., Liu, J., Zeng, Z., Xie, H., & Liu, J. (2023) · Aging and Disease · doi:10.14336/ad.2023.0325 · Cited by 63 · see citing works
“In ALS mice, the number of butyrate-producing bacteria was reduced, whereas supplementation with 2% butyrate resulted in a delayed onset of ALS-related symptoms and increased lifespan [112].”
BackgroundYadav, S., Dwivedi, A., Tripathi, A., & Tripathi, A. K. (2022) · Nutrition Research · doi:10.1016/j.nutres.2022.07.007 · Cited by 63 · see citing works
Aberrant enteric neuromuscular system and dysbiosis in amyotrophic lateral sclerosis
Zhang, Y., Ogbu, D., Garrett, S., Xia, Y., & Sun, J. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1996848 · Cited by 61 · see citing works
“Targeting the intestinal microbiome was able to improve neuromuscular function in ALS.”
BackgroundMethodInfluentialSelf-citationWhat Are the Key Gut Microbiota Involved in Neurological Diseases? A Systematic Review
Bonnechère, B., Amin, N., & van Duijn, C. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213665 · Cited by 64 · see citing works
“AD [32], PD [33], MS [34], and ALS [35].”
BackgroundImmune mechanisms and shared immune targets in neurodegenerative diseases
Weiner, H. L. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-01046-7 · Cited by 63 · see citing works
Immunoregulatory effect of mast cells influenced by microbes in neurodegenerative diseases
Girolamo, F., Coppola, C., & Ribatti, D. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.06.017 · Cited by 60 · see citing works
tRNA Queuosine Modification Enzyme Modulates the Growth and Microbiome Recruitment to Breast Tumors
Zhang, J., Lu, R., Zhang, Y., Matuszek, Ż., Zhang, W., Xia, Y., Pan, T., & Sun, J. (2020) · Cancers · doi:10.3390/cancers12030628 · Cited by 60 · see citing works
“These microbial alteration was confirmed by real-time PCR with primers target for 16S rRNA gene of Lactobacillus, Lachnospiraceae and Butyrivibrio fibrisolvens, as described before [26-28] (Figure S6) in the intestinal feces from the MCF7 injected mice.”
MethodSelf-citationGut Microbiota and Neuroplasticity
Murciano-Brea, J., García-Montes, M. E., Geuna, S., & Herrera‐Rincon, C. (2021) · Cells · doi:10.3390/cells10082084 · Cited by 59 · see citing works
“[83] showed, in an ALS mouse model, that butyrate administration restored intestinal microbial homeostasis, improved gut integrity, and prolonged life span.”
BackgroundRawat, K., Singh, N., Kumari, P., & Saha, L. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2020-0078 · Cited by 58 · see citing works
Walker, A. C., Bhargava, R., Vaziriyan-Sani, A. S., Pourciau, C., Donahue, E. T., Dove, A. S., Gebhardt, M. J., Ellward, G. L., Romeo, T., & Czyż, D. M. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009510 · Cited by 54 · see citing works
“In agreement with our results, the protective effects of butyrate have been previously demonstrated in a mouse model and in humans [21,32].”
BackgroundResultGentile, F., Doneddu, P. E., Riva, N., Nobile‐Orazio, E., & Quattrini, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207471 · Cited by 57 · see citing works
“, who showed that supplementation of butyrate restored gut integrity, microbial composition and prolonged survival in SOD1G93A mice, suggesting that targeting SCFAs may be an additional strategy for therapeutic intervention [372].”
BackgroundLabarre, A., Guitard, E., Tossing, G., Forest, A., Bareke, E., Labrecque, M., Tétreault, M., Ruiz, M., & Parker, J. A. (2022) · Communications Biology · doi:10.1038/s42003-022-04295-8 · Cited by 53 · see citing works
Amyotrophic lateral sclerosis and intestinal microbiota—toward establishing cause and effect
Gotkine, M., Kviatcovsky, D., & Elinav, E. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1767464 · Cited by 55 · see citing works
A Gut Feeling in Amyotrophic Lateral Sclerosis: Microbiome of Mice and Men
Martin, S., Battistini, C., & Sun, J. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.839526 · Cited by 54 · see citing works
Self-citationInterplay between immunity and amyotrophic lateral sclerosis: Clinical impact
Marchi, F. D., Munitić, I., Amedei, A., Berry, J. D., Feldman, E. L., Aronica, E., Nardo, G., Weehaeghe, D. V., Niccolai, E., Prtenjača, N., et al. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.06.027 · Cited by 52 · see citing works
Progression and survival of patients with motor neuron disease relative to their fecal microbiota
Ngo, S. T., Restuadi, R., McRae, A. F., van Eijk, R. P. A., Garton, F. C., Henderson, R. D., Wray, N. R., McCombe, P., & Steyn, F. J. (2020) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2020.1772825 · Cited by 53 · see citing works
Lian, L., Liu, M., Cui, L., Guan, Y., Liu, T., Cui, B., Zhang, K., Tai, H., & Shen, D. (2019) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2019.05.036 · Cited by 52 · see citing works
The microbiota restrains neurodegenerative microglia in a model of amyotrophic lateral sclerosis
Cox, L. M., Calcagno, N., Gauthier, C., Madore, C., Butovsky, O., & Weiner, H. L. (2022) · Microbiome · doi:10.1186/s40168-022-01232-z · Cited by 53 · see citing works
“Furthermore, administering butyrate to SOD1 mice increased lifespan, increased gut barrier function, and modulated microbiota composition [61], suggesting that of the multiple bacteria targeted by our antibiotic treatment, the disease worsening may be linked to the depletion of butyrate producers.”
BackgroundKim, H. S., Son, J. L., Lee, D., Tsai, J., Wang, D., Chocrón, E. S., Jeong, S., Kittrell, P., Murchison, C., Kennedy, R., et al. (2022) · BMC Neurology · doi:10.1186/s12883-022-02586-5 · Cited by 52 · see citing works
“Correcting gut-dysbiosis slowed down ALS progression, whereas exacerbating gut-dysbiosis accelerated disease progression in animal models [33, 35].”
BackgroundEffects of gut microbiota on neurodegenerative diseases
Khatoon, S., Kalam, N., Rashid, S., & Bano, G. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1145241 · Cited by 51 · see citing works
“fibrosolvens, improving the function of the intestinal barrier (Zhang et al., 2017).”
BackgroundInfluentialFeng, R., Zhu, Q., Wang, A., Wang, H., Wang, J., Chen, P., Zhang, R., Liang, D., Teng, J., Ma, M., et al. (2024) · BMC Medicine · doi:10.1186/s12916-024-03781-6 · Cited by 49 · see citing works
Lee, B., Lee, S. M., Song, J. W., & Choi, J. W. (2024) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2024.009 · Cited by 48 · see citing works
“Zhang et al .”
BackgroundInfluentialThe increasing importance of environmental conditions in amyotrophic lateral sclerosis
Riancho, J., Bosque‐Varela, P., Pérez‐Pereda, S., Povedano, M., de Munaín, A. L., & Santurtún, A. (2018) · International Journal of Biometeorology · doi:10.1007/s00484-018-1550-2 · Cited by 47 · see citing works
“Regarding ALS, microbiota changes have been reported inALSmurinemodels (Fang 2016; Zhang et al. 2017) thus postulating it as both a new pathogenic issue to elucidate and at the same time as a new potential therapeutic approach.”
BackgroundDobrowolny, G., Barbiera, A., Sica, G., & Scicchitano, B. M. (2021) · Cells · doi:10.3390/cells10061307 · Cited by 49 · see citing works
Gut microbiota in ALS: possible role in pathogenesis?
McCombe, P. A., Henderson, R. D., Lee, A., Lee, J. D., Woodruff, T. M., Restuadi, R., McRae, A., Wray, N. R., Ngo, S., & Steyn, F. J. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1623026 · Cited by 46 · see citing works
“Butyrate treatment was beneficial in SOD1 mice [249], and it would be reasonable to trial the addition of butyrate to the diet of ALS”
BackgroundAmyotrophic lateral sclerosis: The complement and inflammatory hypothesis
Kjældgaard, A.-L., Pilely, K., Olsen, K. S., Pedersen, S. W., Lauritsen, A. Ø., Møller, K., & Garred, P. (2018) · Molecular Immunology · doi:10.1016/j.molimm.2018.06.007 · Cited by 45 · see citing works
Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications
Calma, A. D., Pavey, N., Menon, P., & Vucic, S. (2024) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001279 · Cited by 47 · see citing works
Modification of the gut microbiome to combat neurodegeneration
Sasmita, A. O. (2019) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0005 · Cited by 46 · see citing works
Zhang, Y., Xia, Y., & Sun, J. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2363880 · Cited by 42 · see citing works
“11 In the past several years, the novel concepts and the role of gut microbiome and microbial metabolites in ALS pathogenesis have been slowly recognized by the neurology research field.”
BackgroundInfluentialSelf-citationCastanedo-Vazquez, D., Bosque-Varela, P., Sainz-Pelayo, A., & Riancho, J. (2019) · Journal of Neurology · doi:10.1007/s00415-018-8919-3 · Cited by 41 · see citing works
Gut microbiome and amyotrophic lateral sclerosis: a systematic review of current evidence
Sun, J., Huang, T., Debelius, J. W., & Fang, F. (2021) · Journal of Internal Medicine · doi:10.1111/joim.13336 · Cited by 43 · see citing works
Self-citationThe Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration
Borbolis, F., Mytilinaiou, E., & Palikaras, K. (2023) · Cells · doi:10.3390/cells12030429 · Cited by 39 · see citing works
Butyrate as a potential therapeutic agent for neurodegenerative disorders
Chakraborty, P., Gamage, H. K. A. H., & Laird, A. S. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105745 · Cited by 41 · see citing works
Convergent pathways of the gut microbiota–brain axis and neurodegenerative disorders
Gubert, C., Gasparotto, J., & Morais, L. H. (2022) · Gastroenterology report · doi:10.1093/gastro/goac017 · Cited by 40 · see citing works
“In the G93A mouse model of ALS, treatment with butyrate restored alterations in the gut microbiota composition and intestinal barrier deficits, decreased SOD1 protein aggregation in the intestine, and prolonged mice lifespan [85].”
Chiu, L. S., & Anderton, R. S. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15892 · Cited by 35 · see citing works
“GI dysfunction and dysbiosis is often reported decades prior to diagnosis of PD and AD and may be implicated in other neurodegenerative diseases such as MND and multiple sclerosis (MS) (Kong et al., 2018; Ochoa-Rep araz et al., 2017; Zhang et al., 2017).”
BackgroundKumar, N., Sahoo, N. K., Mehan, S., & verma, B. (2023) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2023.104547 · Cited by 40 · see citing works
Hong, D., Zhang, C., Wu, W., Lu, X., & Zhang, L. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1133546 · Cited by 38 · see citing works
Huang, Z., Liu, Q., Peng, Y., Dai, J., Xie, Y., Chen, W., Long, S., Pei, Z., Su, H., & Yao, X. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00218 · Cited by 38 · see citing works
“The oral administration of butyrate restored intestinal microbiota homeostasis, and thus delayed disease onset and progression in the SOD1G93A mice (47).”
BackgroundChen, S., Cai, X., Lao, L., Wang, Y., Su, H., & Sun, H. (2024) · Aging and Disease · doi:10.14336/ad.2023.0524 · Cited by 38 · see citing works
“In addition to increased proinflammatory cytokines, decreased secretion of anti-inflammatory cytokines such as IL-10 and inflammatory regulatory products such as butyric acid may also promote the progression of ALS [53, 99].”
BackgroundChen, S., Zhang, P., Duan, H., Wang, J., Qiu, Y., Cui, Z., Yin, Y., Wan, D., & Xie, L. (2023) · The Innovation · doi:10.1016/j.xinn.2023.100479 · Cited by 39 · see citing works
“The intestinal microbial homeostasis, gut integrity, and lifespan of the ALS mice are improved by feeding them butyrate, which is accompanied by a dramatically reduced number of aberrant Paneth cells.(43) Blue arrows represent promotive effects.”
Winiarska‐Mieczan, A., Tomaszewska, E., Donaldson, J., & Jachimowicz-Rogowska, K. (2022) · Nutrients · doi:10.3390/nu14122498 · Cited by 39 · see citing works
Hasan, A., Scuderi, S. A., Capra, A. P., Giosa, D., Bonomo, A., Ardizzone, A., & Esposito, E. (2025) · Brain Sciences · doi:10.3390/brainsci15060654 · Cited by 36 · see citing works
“Further supporting this, Zhang et al. found that 2% butyrate in drinking water improved gut microbial balance, strengthened the gut barrier, delayed disease progression, and extended lifespan in SOD1-G93A mice, while reducing Paneth cell accumulation and mutant protein aggregation [121].”
The gut microbiota modulate locomotion via vagus-dependent glucagon-like peptide-1 signaling
Lai, T.-T., Tsai, Y.-H., Liou, C.-W., Fan, C., Hou, Y.-T., Yao, T.-H., Chuang, H.-L., & Wu, W. (2024) · npj Biofilms and Microbiomes · doi:10.1038/s41522-024-00477-w · Cited by 36 · see citing works
Chatterjee, A., Kumar, S., Sarkar, S. R., Halder, R., Kumari, R., Banerjee, S., & Sarkar, B. (2024) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2024.109622 · Cited by 36 · see citing works
Andrés‐Benito, P., Moreno, J., Domínguez, R., Aso, E., Povedano, M., & Ferrer, I. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00546 · Cited by 35 · see citing works
“Recent studies have also shown modifications in the intestinal microbiota in ALS (19, 20), thus categorizing ALS as a disease with multisystem involvement.”
ResultGut microbiota immune cross-talk in amyotrophic lateral sclerosis
Kaul, M., Mukherjee, D., Weiner, H. L., & Cox, L. M. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00469 · Cited by 35 · see citing works
Dovrolis, N., Kolios, G. C., Spyrou, G. M., & Maroulakou, I. G. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbx154 · Cited by 34 · see citing works
Zhang, J., Zhang, Y., Xia, Y., & Sun, J. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1957408 · Cited by 34 · see citing works
“Dysbiosis of the microbiome not only leads to intestinal inflammatory and infectious diseases but also to diseases beyond the gastrointestinal tract.(5,35) Moreover, dysbiosis of intestinal microbiota could influence internally through interaction and metabolites, such as bacteriophages and bacteria.”
BackgroundSelf-citation
- 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 › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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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