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Cited by 151Gut microbiota and healthAmyotrophic Lateral Sclerosis ResearchProbiotics and Fermented Foods

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A prospective longitudinal study on the microbiota composition in amyotrophic lateral sclerosis

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Di Gioia, Diana, Bozzi Cionci, Nicole, Baffoni, Loredana, Amoruso, Angela, Pane, Marco, Mogna, Luca, Gaggìa, Francesca, Lucenti, Maria Ausiliatrice, Bersano, Enrica, Cantello, Roberto, De Marchi, Fabiola, Mazzini, Letizia·2020·BMC Medicine
DOI 10.1186/s12916-020-01607-9PMC PMC7298784
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Abstract

Background: A connection between amyotrophic lateral sclerosis (ALS) and altered gut microbiota composition has previously been reported in animal models. This work is the first prospective longitudinal study addressing the microbiota composition in ALS patients and the impact of a probiotic supplementation on the gut microbiota and disease progression. Methods: Fifty patients and 50 matched controls were enrolled. The microbial profile of stool samples from patients and controls was analyzed via PCR-Denaturing Gradient Gel Electrophoresis, and the main microbial groups quantified via qPCR. The whole microbiota was then analyzed via next generation sequencing after amplification of the V3–V4 region of 16S rDNA. Patients were then randomized to receive probiotic treatment or placebo and followed up for 6 months with ALSFRS-R, BMI, and FVC%. Results: The results demonstrate that the gut microbiota of ALS patients is characterized by some differences with respect to controls, regardless of the disability degree. Moreover, the gut microbiota composition changes during the course of the disease as demonstrated by the significant decrease in the number of observed operational taxonomic unit during the follow-up. Interestingly, an unbalance between potentially protective microbial groups, such as Bacteroidetes, and other with potential neurotoxic or pro-inflammatory activity, such as Cyanobacteria, has been shown. The 6-month probiotic treatment influenced the gut microbial composition; however, it did not bring the biodiversity of intestinal microbiota of patients closer to that of control subjects and no influence on the progression of the disease measured by ALSFRS-R was demonstrated. Conclusions: Our study poses the bases for larger clinical studies to characterize the microbiota changes as a novel ALS biomarker and to test new microbial strategy to ameliorate the health status of the gut. Trial registration: CE 107/14, approved by the Ethics Committee of the “Maggiore della Carità” University Hospital, Italy.

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Fig. 1 Study flowchart for baseline analysis and phase 1 trial. ALS, amyotrophic lateral sclerosis; T0, baseline; T1, 3 months from baseline; T2, 6 months from baseline; ALSFRS-R, ALS Functional Rating Scale–Revised; BMI, body mass index; FVC%, force vital capacity %; DGGE, denaturing gradient gel electrophoresis; qPCR, quantitative polymerase chain reaction; NGS, next-generation sequencing
Fig. 1 Study flowchart for baseline analysis and phase 1 trial. ALS, amyotrophic lateral sclerosis; T0, baseline; T1, 3 months from baseline; T2, 6 months from baseline; ALSFRS-R, ALS Functional Rating Scale–Revised; BMI, body mass index; FVC%, force vital capacity %; DGGE, denaturing gradient gel electrophoresis; qPCR, quantitative polymerase chain reaction; NGS, next-generation sequencingCC BY · PubMed Central
Fig. 2 Gut bacteria and yeast profiles at baseline obtained by DGGE. a UPGMA dendrogram and DGGE profiles of Eubacteria. Three main cluster groups are indicated as G1, G2, and G3: G1 and G2 represent controls (C) and G3 represents diseased subjects (D). b UPGMA dendrogram and DGGE profiles of total yeasts in controls (C) and diseased (D) subjects
Fig. 2 Gut bacteria and yeast profiles at baseline obtained by DGGE. a UPGMA dendrogram and DGGE profiles of Eubacteria. Three main cluster groups are indicated as G1, G2, and G3: G1 and G2 represent controls (C) and G3 represents diseased subjects (D). b UPGMA dendrogram and DGGE profiles of total yeasts in controls (C) and diseased (D) subjectsCC BY · PubMed Central
Fig. 3 Gut bacterial characteristics at the baseline and main differences between controls and diseased subjects. a Relative abundance of the main bacterial phyla in the control group. b Relative abundance of the main bacterial phyla in diseased group. c Differences (P < 0.05) in Cyanobacteria between controls (C) and diseased (D) subjects; data are expressed as absolute abundance (number of OTUs). d Bacterial groups classified at family level showing significant differences (P < 0.05) between controls (C) and diseased (D) subjects. e Differences (P < 0.05) in α-diversity Chao1 index between diseased (D) and controls (C). f Differences (P < 0.05) in α-diversity Chao1 index in ALS patients subgrouped for their ALSFRS-R scale values (HFRS ≥ 35, LFRS < 35). g PCoA representing β-diversity among individuals at baseline (controls = red, ALS subjects = blue)
Fig. 3 Gut bacterial characteristics at the baseline and main differences between controls and diseased subjects. a Relative abundance of the main bacterial phyla in the control group. b Relative abundance of the main bacterial phyla in diseased group. c Differences (P < 0.05) in Cyanobacteria between controls (C) and diseased (D) subjects; data are expressed as absolute abundance (number of OTUs). d Bacterial groups classified at family level showing significant differences (P < 0.05) between controls (C) and diseased (D) subjects. e Differences (P < 0.05) in α-diversity Chao1 index between diseased (D) and controls (C). f Differences (P < 0.05) in α-diversity Chao1 index in ALS patients subgrouped for their ALSFRS-R scale values (HFRS ≥ 35, LFRS < 35). g PCoA representing β-diversity among individuals at baseline (controls = red, ALS subjects = blue)CC BY · PubMed Central
Fig. 4 Relative abundance of gut microbial phyla in ALS patients during the intervention. Group A consists of subjects receiving the probiotic treatment for 6 months (T0 = baseline, T1 = 3 months from baseline, T2 = 6 months from baseline). Group B consists of subjects receiving the placebo treatment for 3 months (T1) and the probiotic treatment for the following 3 months (T2). Phyla with a percentage of relative abundance less than 0.002% are grouped in “other”
Fig. 4 Relative abundance of gut microbial phyla in ALS patients during the intervention. Group A consists of subjects receiving the probiotic treatment for 6 months (T0 = baseline, T1 = 3 months from baseline, T2 = 6 months from baseline). Group B consists of subjects receiving the placebo treatment for 3 months (T1) and the probiotic treatment for the following 3 months (T2). Phyla with a percentage of relative abundance less than 0.002% are grouped in “other”CC BY · PubMed Central
Fig. 5 Gut bacterial characteristics and main differences within the study groups during the intervention. a Differences (P < 0.05) in Tenericutes relative abundance after 3 months (T1), not considering the type of treatment. b Differences (P < 0.05) in Bacteroidetes relative abundance after 3 months (T1), not considering the type of treatment. c F/B ratio in the different time-treatment groups. d Differences (P < 0.05) in relative abundance of other families belonging to Bacteroidales within time, not considering the type of treatment. e Differences (P < 0.05) in Bacteroidaceae relative abundance within time, not considering the type of treatment. f Relative abundance of Bacteroidaceae in ALS patients considering the time and the type of treatment. g Differences (P = 0.05) in Rikenellaceae relative abundance in patients considering the time and the type of treatment. h Differences in α-diversity index observed OTU (P < 0.05) within time, not considering the type of treatment. i Differences in α-diversity index observed OTU (P < 0.05) considering the controls (C) and patients at T2 subgrouped in spinal (S) and bulbar (B) onset
Fig. 5 Gut bacterial characteristics and main differences within the study groups during the intervention. a Differences (P < 0.05) in Tenericutes relative abundance after 3 months (T1), not considering the type of treatment. b Differences (P < 0.05) in Bacteroidetes relative abundance after 3 months (T1), not considering the type of treatment. c F/B ratio in the different time-treatment groups. d Differences (P < 0.05) in relative abundance of other families belonging to Bacteroidales within time, not considering the type of treatment. e Differences (P < 0.05) in Bacteroidaceae relative abundance within time, not considering the type of treatment. f Relative abundance of Bacteroidaceae in ALS patients considering the time and the type of treatment. g Differences (P = 0.05) in Rikenellaceae relative abundance in patients considering the time and the type of treatment. h Differences in α-diversity index observed OTU (P < 0.05) within time, not considering the type of treatment. i Differences in α-diversity index observed OTU (P < 0.05) considering the controls (C) and patients at T2 subgrouped in spinal (S) and bulbar (B) onsetCC BY · PubMed Central
Fig. 6 CCA on multivariate association between gut microbial families and ALSFRS-R, BMI, and FVC parameters. a Plot of all patients during the study. b Plot representing the bacterial families that influenced the most the parameters considered (ALSFRS-R, BMI, and FVC). c Plot representing the trend of study groups
Fig. 6 CCA on multivariate association between gut microbial families and ALSFRS-R, BMI, and FVC parameters. a Plot of all patients during the study. b Plot representing the bacterial families that influenced the most the parameters considered (ALSFRS-R, BMI, and FVC). c Plot representing the trend of study groupsCC BY · PubMed Central

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Metadata

Authors
Di Gioia, D., Bozzi Cionci, N., Baffoni, L., Amoruso, A., Pane, M., Mogna, L., Gaggìa, F., Lucenti, M. A., Bersano, E., Cantello, R., De Marchi, F., & Mazzini, L.
Affiliations
  • University of Bologna (IT)
  • Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
Corresponding author
Mazzini, Letizia
ORCID
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2020-06-17
Volume
18
Issue
1
Pages
153-153
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-020-01607-9
PMC
PMC7298784
OpenAlex
W3035761210
Cited by
151
References
88
Citations by year
2026: 16 · 2025: 24 · 2024: 34 · 2023: 27 · 2022: 24 · 2021: 21 · 2020: 5
FWCI
6.24
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Probiotical S.p.A. (--)
  • Università degli Studi del Piemonte Orientale (AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Università del Piemonte Orientale, Novara, Italy)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
Keywords
amyotrophic lateral sclerosis, gut microbiota, probiotic supplementation, disease progression, Bacteroidetes, cyanobacteria, microbial diversity, ALS biomarkers, 16S rRNA gene sequencing, stool microbiome
MeSH terms
Gastrointestinal Microbiome, Adolescent, Adult, Aged, Amyotrophic Lateral Sclerosis, Animals, Female, Humans, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Young Adult

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