Gastrointestinal Status and Microbiota Shaping in Amyotrophic Lateral Sclerosis: A New Frontier for Targeting?

Mazzini, Letizia; Marchi, Fabiola De; Niccolai, Elena; Mandrioli, Jessica; Amedei, Amedeo

doi:10.36255/exonpublications.amyotrophiclateralsclerosis.microbiota.2021

Cited by 6 publications

(6 citation statements)

References 92 publications

(104 reference statements)

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“…Citramalate, a metabolite once known as being exclusively present in yeast or anaerobic bacteria, is commonly used to diagnose gut dysbiosis in humans [ 55 ]. Alterations in gut microbiota can impact the gut-to-brain axis and have been associated with the occurrence of neurodegenerative diseases, including ALS [ 56 , 57 , 58 ]. Different microbiomes in ALS mouse models and patients were reported, with consequent differences in microbiome-related metabolites [ 59 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

et al. 2022

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Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients and correlated these findings with the clinical status and pathological alterations observed in the muscle. We obtained data from 20 controls and 17 ALS patients (disease duration: 9.4 ± 6.8 months). Multivariate metabolomics analysis identified a distinct serum metabolome for ALS compared to controls (p-CV-ANOVA < 0.035) and revealed an excellent discriminant profile for muscle metabolome (p-CV-ANOVA < 0.0012). Citramalate was discriminant for both muscle and serum. High lauroylcarnitine levels in muscle were associated with low Forced Vital Capacity. Transcriptomics analysis of key antioxidant enzymes showed an upregulation of SOD3 (p = 0.0017) and GLRX2(1) (p = 0.0022) in ALS muscle. Analysis of mitochondrial enzymatic activity in muscle revealed higher complex II/CS (p = 0.04) and lower LDH (p = 0.03) activity in ALS than in controls. Our study showed, for the first time, a global dysfunction in the muscle of early-stage ALS patients. Furthermore, we identified novel metabolites to be employed as biomarkers for diagnosis and prognosis of ALS patients.

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Section: Discussionmentioning

confidence: 99%

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

et al. 2022

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“…In our study, we analyzed a broad spectrum of blood-based biological markers to delve into the increasingly recognized role of microbiome, metabolism, and immunity in ALS pathogenesis [ 47 ]. Our comprehensive assessment included 14 inflammatory cytokines, 18 free fatty acids (end products of human and microbial metabolism), and TTV viremia, a virome-related potential marker linked to immune system function [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…These factors are not only involved in the multistep process of ALS development, but also influence the pace of disease progression [ 48 ]. Their accessibility presents them as potential targets for research into diagnostic and prognostic biomarkers [ 47 ]. The underlying causes behind metabolic dysfunction, immune regulation failure, and sustained neuroinflammation in ALS remain mostly unknown.…”

Section: Introductionmentioning

confidence: 99%

Amyotrophic lateral sclerosis stratification: unveiling patterns with virome, inflammation, and metabolism molecules

Niccolai,

Pedone,

Martinelli

et al. 2024

J Neurol

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Amyotrophic lateral sclerosis (ALS) is an untreatable and clinically heterogeneous condition primarily affecting motor neurons. The ongoing quest for reliable biomarkers that mirror the disease status and progression has led to investigations that extend beyond motor neurons’ pathology, encompassing broader systemic factors such as metabolism, immunity, and the microbiome. Our study contributes to this effort by examining the potential role of microbiome-related components, including viral elements, such as torque tenovirus (TTV), and various inflammatory factors, in ALS. In our analysis of serum samples from 100 ALS patients and 34 healthy controls (HC), we evaluated 14 cytokines, TTV DNA load, and 18 free fatty acids (FFA). We found that the evaluated variables are effective in differentiating ALS patients from healthy controls. In addition, our research identifies four unique patient clusters, each characterized by distinct biological profiles. Intriguingly, no correlations were found with site of onset, sex, progression rate, phenotype, or C9ORF72 expansion. A remarkable aspect of our findings is the discovery of a gender-specific relationship between levels of 2-ethylhexanoic acid and patient survival. In addition to contributing to the growing body of evidence suggesting altered peripheral immune responses in ALS, our exploratory research underscores metabolic diversity challenging conventional clinical classifications. If our exploratory findings are validated by further research, they could significantly impact disease understanding and patient care customization. Identifying groups based on biological profiles might aid in clustering patients with varying responses to treatments. Graphical abstract

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“…One of the most discussed issues recently has been dysbiosis. Dysbiosis is defined as an imbalance in microbiota properties or functions because of decreased microbial diversity, increased pathogenic strains, and loss of beneficial strains [ 13 – 15 ]. It is hypothesized that the increased intestinal permeability in ALS in the interaction between microbiota and central nervous system facilitates the passage of toxins from the intestinal lumen into the blood, leading to an increase in circulating lipopolysaccharides and an immune response [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Is gut microbiota of patients with ALS different from that of healthy individuals?

ÖZAYDIN AKSUN,

ERDOĞAN,

KALKANCI

et al. 2024

Turkish Journal of Medical Sciences

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Background/aim Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Several studies have shown that alterations of microbiota increase the risk of neurodegenerative disorders. We aimed to reveal whether there is a difference in the gut microbiota of patients with ALS. Materials and methods The participants are divided into three groups. Group 1 comprised patients with ALS. Healthy family members living in the same house of the patients formed Group 2. Lastly, sex- and age-matched healthy people were included in Group 3. Fecal samples were collected in 15-mL falcon tubes and stored at −80 °C. Genomic DNA isolation was performed on samples. Bacterial primers selected from the 16S rRNA region for the bacterial genome and ITS1 and ITS4 (internal transcribed spacer) were used for the identification of DNA. Next generation sequence analysis (NGS) and taxonomic analyses were performed at the level of bacterial phylum, class, order, family, genus, and species. Alpha and beta diversity indexes were used. The linear discriminant analysis (LDA) effect size method (LEfSe) was applied to identify a microbial taxon specific to ALS disease. Results The relative abundances of the Succinivibrionaceae and Lachnospiraceae families were significantly lower in patients. The dominant families among patients were Streptococcaceae and Ruminococcaceae, while the dominant families among healthy controls were Bacteroidaceae and Succinivibrionaceae. The LEfSe analysis revealed that four families (Atopobiaceae, Actinomycetaceae, Erysipelatoclostridiaceae, Peptococcacceae) differed significantly between the patients and healthy controls (LDA values> 2.5, p < 0.05). Conclusion Comparison with family members living in the same house is the strength of this study. We found that there were changes in the microbiota of the patients, consistent with the literature. Studies that analyze the composition of the gut microbiota in the predisease period may be needed to understand whether dysbiosis is caused by the mechanisms inherent in the disease or whether it is dysbiosis that initiates the disease.

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Gastrointestinal Status and Microbiota Shaping in Amyotrophic Lateral Sclerosis: A New Frontier for Targeting?

Cited by 6 publications

References 92 publications

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis stratification: unveiling patterns with virome, inflammation, and metabolism molecules

Is gut microbiota of patients with ALS different from that of healthy individuals?

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