Gut Microbiota in Amyotrophic Lateral Sclerosis: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Ana Cristina Calvo.

The gut microbiota is able to modulate the development and homeostasis of the central nervous system (CNS) through the immune, circulatory, and neuronal systems. In turn, the CNS influences the gut microbiota through stress responses and at the level of the endocrine system. This bidirectional communication forms the “gut microbiota–brain axis” and has been postulated to play a role in the etiopathology of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).

  • amyotrophic lateral sclerosis
  • gut dysbiosis
  • gut microbiota

1. Introduction

Sequencing of the human genome has greatly improved our understanding of our genetic variability and improved our knowledge on the etiopathogenic origin of diseases. Despite this, causes of many diseases of a multifactorial nature such as amyotrophic lateral sclerosis (ALS) remain largely unknown, which has contributed to the fact that there is still no effective treatment that slows down the degenerative process in ALS patients.
ALS, one of the most-known rare diseases, is an adult-onset, devastating, neurodegenerative disease characterized by the loss of cortical, brain stem and spinal motor neurons and by progressive muscle atrophy. The majority of ALS patients, close to 90%, are classified as sporadic cases (sALS) of unknown cause, while the rest of the patients are identified as familial cases (fALS), since they carry a mutation in one of the genes related to the disease. These genes include TAR DNA binding protein (TARDBP/TDP-43), superoxide dismutase 1 (SOD1), FUS RNA binding protein (FUS/TLS), or the most recently discovered gene C9orf72-SMCR8 complex subunit (C9orf72) with ALS-causing hexanucleotide repeat expansions [1,2,3][1][2][3]. Most fALS cases have an autosomal dominant inheritance pattern, except for some autosomal recessive patterns that have been reported in the case of specific mutations in the ALS gene, especially detected in families from Germany, Asia, and North Africa [4].
The onset age of fALS follows a normal Gaussian distribution and takes place a decade earlier than the onset of sALS, which is approximately 60 years of age. In rare cases, disease onset may occur before the age of 25 years, and this juvenile form of the disease is almost always genetically determined. The crude annual incidence rate of ALS in the general European population has risen during the last five years and it is estimated to be two to three cases per 100,000 person-years [5,6][5][6]. The incidence is higher among men than among women in a ratio as high as 2.6:1, although some recent studies have reported a more balanced gender ratio [6]. Spinal-onset ALS is more common among men when compared to women, particularly by the age of 70–80 years. Albeit, though the disease occurrence decreases rapidly after 80 years of age, the median survival ranges between 3 and 5 years from symptom onset [5,6,7][5][6][7]. The multisystemic nature of ALS has prevented the exact identification of its first steps of neurodegenerative progress. ALS results from a complex array of factors, including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, dysregulated transcription and RNA processing, dysregulated endosomal trafficking, impaired axonal transport, protein aggregation, excitotoxicity, apoptosis, inflammation, and genetic susceptibility. To date, increased phosphorylated neurofilament heavy chain in cerebrospinal fluid and neurofilament light chain in plasma, serum, or cerebrospinal fluid can support the diagnosis and prognosis evaluation in ALS patients. However, increased levels of these neurofilaments are also observed in other neurodegenerative diseases. Consequently, the combination of neurofilaments with other methods rather than their use alone in the diagnosis and prognosis of ALS could be valuable. Actually, the diagnosis of ALS follows the revised El Escorial, the Airlie-House criteria, and the Awaji-shima criteria, to discriminate any pathologic evidence of other disease processes that might explain upper or lower motor neuron degeneration [8,9][8][9]. More recently, an emerging Gold Coast criteria has proven to be more sensitive and specific for characterizing progressive muscular atrophy and for excluding primary lateral sclerosis as a form of ALS. This criteria also investigates findings that exclude alternative diseases and, therefore, it can enable a more accurate diagnosis, ruling out confusions from the early stages of the disease [10]. Another useful instrument for the evaluation of the functional status of ALS patients is the revised ALS Functional Rating Scale (ALSFRS-r). This parameter can be used to monitor the functional state of the patient over time, and it is strongly related to survival and ALS prognosis. In addition, recent neuroimaging tools and novel algorithms have paved the way to the conversion of ALSFRS-r into clinical stages to predict disease progression [11,12][11][12]. A great proportion of the molecular mechanisms that are potentially involved in ALS pathogenesis have been discovered through mouse models, especially the ones expressing human SOD1 with ALS-associated mutations, such as SOD1G93A [13]. In particular, the transgenic SOD1G93A mice show a phenotype that resembles the disease progression in patients and therefore, they are one of the most used in preclinical trials.
Despite the above-mentioned clinical findings, an early diagnosis and prognosis of the disease is urgently needed. In the field of neurodegenerative diseases, the composition of the bacterial microbiota is a novel and growing area of research interest, as communication between the brain and gut microbiota is essential to maintain homeostasis. In this “gut microbiota–brain axis”, the central nervous system (CNS), the neuroendocrine and neuroimmune systems, autonomic nervous system, enteric nervous system, and intestinal microbiota signal bidirectionally to each other [14]. Signals from the brain can influence the motor, sensory, and secretory activities of the gastrointestinal tract and, conversely, visceral messages from the gastrointestinal tract can influence brain function [15]. One group of the main molecular messengers that support the communication between the nervous system and the gastrointestinal are the short-chain fatty acids (SCFA), which are metabolic products of anaerobic bacteria by fermentation of dietary fiber [16]. SCFA are water soluble and can be easily absorbed or transported into cells. In particular, SCFA can modify the recruitment of circulating leukocytes to the inflammatory site, preventing inflammation and immune responses through the modulation of regulatory T lymphocytes (Treg). This bidirectional communication has been postulated to have a role in the etiopathology of various neurodegenerative diseases including ALS [16]. Albeit, although earlier immune responses need further investigation, numerous studies indicate that inflammation contributes to neurodegenerative progress in ALS. In fact, alterations in peripheral monocytes, neutrophils, and various T-cell populations correlate with the rate of ALS progression. Such modifications have been identified even in presymptomatic ALS mutation carriers [17] suggesting an active contribution of immune alterations to the pathology and degenerative progress of the disease.

2. Implication of Gut Dysbiosis in Animal Model of ALS

ALS models such as SOD1G93A are important tools to investigate presymptomatic alterations as well as the onset and progression of the disease in genetically homogenous populations and controlled environment. SOD1G93A mice show increased intestinal epithelial permeability due to elevated levels of proinflammatory cytokines, which directly affect the junctions of the intestinal epithelium [36][18]. This “leaky gut” phenomenon facilitates the translocation of bacterial toxins through the intestinal lumen to the bloodstream from where they may further translocate to different tissues and organs, including the CNS. This may be especially relevant in ALS, because the blood–brain barrier in patients and in animal models for the disease is negatively affected [37][19]. The dysfunction of the intestinal barrier can promote the passage of toxins from the intestinal lumen to the blood and increase the immune response in addition to the increase of circulating lipopolysaccharides (LPS). This could have a pivotal role in the pathogenesis of ALS, since LPS favor inflammatory processes that affect the function of the afferent neurons of the vagus nerve [32,38][20][21]. All of these factors that are linked to ALS can be favorably modulated by some microbial populations and their metabolites in the intestine. In line with this, an abnormal density of Paneth cells in the intestinal crypt and increasing levels of IL-17 inflammatory cytokines have been also reported in transgenic SOD1G93A mice, suggesting that altered gut microbiota could affect disease progression in this murine model [39][22]. Another potential factor that could influence the pathogenesis of ALS is the dysregulation of bacterial populations in the gut. The observed imbalance between two main phylae of bacteria, Firmicutes and Bacteriodetes, could contribute to the alteration of pro-inflammatory factors by changes in the levels of endotoxins and exotoxins secreted by these bacteria, and hence, affect the progress of the disease [40][23]. Interestingly, one published work in a SOD1G93A animal model [41][24] proposes that the population of Firmicutes bacteria is diminished before the onset of symptoms and possibly reflects a disease-stage-dependent (presymptomatic vs. symptomatic) modulation of microbiota in this model. In line with this, early changes in the composition of the gut microbiota in at least ten phylae of bacteria in SOD1G93A mice have also been described and been correlated with a more aggressive progression of the disease in mice, which can be exacerbated under germ-free conditions or after antibiotics administration [40,42][23][25]. Nevertheless, Akkermansia muciniphila and nicotinamide supplementation improve motor function and survival in the mice [40,42][23][25]. Furthermore, dietary butyrate increases the abundance of at least some members of Firmicutes population in the SOD1G93A model [32][20]. Collectively, this suggests that the Firmicutes/Bacteriodetes ratio may be dynamically and environmentally altered during the disease’s progression, and that the SOD1G93A related abnormalities in the gut microbiota may be corrected using relatively simple dietary interventions. In this sense, it could be possible to consider that targeting the gut microbiota could counteract the inflammatory response and metabolic alterations inherent in ALS. The imbalance of the bacterial populations in the gut of SOD1G93A mice is also reinforced in a detailed longitudinal study performed in this model that highlighted an early alteration before the disease onset [43][26]. Actinobacteria, Bacteriodetes, Firmicutes, and Verrucomicrobia communities were found to be dysregulated during early stages of disease progression, not only in fecal pellets but also in colon and ileum sections, exacerbating the metabolic disturbances. In parallel, leukocyte infiltration into the CNS, myeloid activation, and increased global 5-Hydroxymethylcytosine levels in the brain of the SOD1G93A mice were observed along disease progression, suggesting that epigenetic changes may possibly be considered as a new factor affected by the gut-brain axis [43][26]. Although most studies have been carried out in SOD1G93A mice, new models, such as those based on mutations in C9orf72 gene have been under much attention recently. Related to the microbiota, a reduction of the immune-stimulating bacteria in C9orf72-mutant mice as well as the transplantation of gut microflora in this murine model protected it from systemic inflammation and autoimmunity mediated by the gut microbiota, reinforcing the connection between this microbiota and ALS at preclinical level [44][27].

3. Role of the Gut Microbiota in ALS Patients

Studies carried out to characterize potential alterations the gut microbiota in ALS patients are often contrasting due to the heterogeneity observed among the different cohorts of patients studied, to the different experimental methodologies, and, last but not least, due to the protocol of conservation of fecal samples. The first two studies conducted on gut microbiota in ALS patients showed a different expression and a lower diversity in the genus and class level with respect to healthy controls [45,46][28][29]. The ratio between Firmicutes and Bacteriodetes, the two major phylae contributing to the gut microbiota, has been proposed to alter in different pathological states [47][30]. In the first study conducted by Fang and coworkers [45][28], a decreased Firmicutes-to-Bacteriodetes ratio and a decrease in beneficial bacteria, such as Anaerostipes, Lachnospiraceae and Oscillobacter, were observed in ALS patients and not in healthy individuals, suggesting that this altered gut microbiota could influence disease progression. In the other study, an alteration of the Firmicutes-to-Bacteriodetes ratio was observed in ALS patients, accompanied with increased fecal inflammatory markers [46][29], suggesting that the imbalance of the gut microbiota could be associated with the pathogenesis of the disease. These findings were also in accordance with a more recent study performed in patients with probable or definite ALS and their caregivers, in which Firmicutes at the phylum level and Megamonas at the genus level, as well as gene profile related to different metabolic pathways, were decreased with respect to healthy individuals [47][30]. However, another study using 16S rRNA analysis reported a higher abundance of Firmicutes and a lower abundance of Negativicutes and Bacilli in patients with respect to control individuals, albeit no significant differences were found in the levels of metabolites, such as human endotoxin, SCFA and NO2-N/NO3-N, and c-aminobutyric acid [48][31]. However, the above studies were based on very few subjects in each group. More recently, a study performed in an Italian cohort of patients using the selective quantification of bacterial species and yeast by quantitative PCR also indicated an imbalance of the gut microbiota in ALS patients, which showed increasing Escherichia coli and Enterobacteria populations [49][32]. In contrast, a study conducted in a German cohort of patients found no significant alterations in the gut microbiota of ALS patients with respect to healthy controls, except for a differential abundance of Ruminococcaceae at the genus level [50][33]. In this studPy, pyrosequencing of the 16S rRNA gene and modeling of predicted metagenomes were used but the findings obtained in this study were consistent with those obtained in another study, performed in an American cohort of patients, in which metagenomic sequencing was used. In this latter study, nNo association between individual taxa and clinical variables was found, albeit a reduced abundance of butyrate-producing bacteria, such as  Eubacterium rectale and Roseburia intestinalis was observed in ALS patients [51][34], which was also in accordance with a study focusing on three CNS disorders, including ALS [52][35]. Studies on gut microbiota in other neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, stroke, and Alzheimer’s disease [53,54,55,56][36][37][38][39] have also provided variable results in patients, probably due to the high inter-individual variability, the difficult management of these diseases, as previously mentioned, and the need of standardizing the methodology and including homogeneous patient groups to avoid bias. It is also important to understand that most of the above-mentioned studies were based on quantitative PCR and pyrosequencing, two methodologies that have been now largely replaced by direct sequencing and platforms with lower error rates [57][40]. A very recent two-sample Mendelian randomization study based on 98 bacterial genera of the human gut supported the close relationship between the gut microbiota and ALS. In particular, OTU10032, unclassified Enterobacteriaceae species-level OTU, and unclassified Acidaminococcaceae correlated with a higher risk of ALS. In addition, an increasing relative abundance of OTU4607_Sutterella and Lactobacillales_ORDER was also found to be related to a higher ALS susceptibility, which could enhance a higher degree of permeability in the gut. These genera were found to be related to γ-glutamyl-related metabolite levels, suggesting that a trans-synaptic, glutaminergic, excitotoxic mechanism could be involved in the pathogenic basis for ALS [58][41]. Furthermore, a recent translational study that aimed to analyze the human gut profile considering previous findings in transgenic SOD1G93A mice suggested a functional decrease in bacterial genes related to nicotinamide (NAM) metabolism the in stool samples of ALS patients with respect to healthy individuals, which was in clear connection with the results obtained in the murine model [42][25]. Interestingly, significantly reduced NAM levels were also found in the CSF samples of patients, highlighting that the metabolites produced under gut dysbiosis could finally reach the CNS [42][25]. Finally, environmental neurotoxins, such as β-Methylamino-l-alanine (BMAA) that has been related to people from Guam Isle, have been proposed as key factors that might be involved in the pathogenesis of ALS disease. Increasing levels of BMAA were observed in the brain tissues of ALS patients of Guam, suspecting that they may have ingested this compound through their diet. Due to the permeability of the gut in ALS patients, BMAA was thought to exert its detrimental effect in the patients. In fact, Cyanobacteria and the Archaea can produce BMAA, which could promote a higher degree of gut dysbiosis [39][22]. Altogether these findings in animal models of ALS and ALS patients underline the close crosstalk between gut microbiota and ALS. At the same time, the possibility of modulating the gut microbiota can yield novel therapeutic strategies, particularly interesting in ALS.

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