The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS)

Abstract

Background Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS. Main body The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications. Conclusion Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.

The Gut Microbiota-Immunity Axis in ALS: A Role in Deciphering Disease Heterogeneity?

“…Increasing studies, even if sometimes contrasting, support the role of the microbiotaimmunity axis as new player in the pathogenesis of neurodegenerative diseases, including ALS. The microbiota may influence the CNS and neuronal health in different ways; directly, by producing neuroactive metabolites or toxins, and indirectly, by modulating the immune system, as recently reviewed in [34].…”

Gut–Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders

“…Although ALS etiology remains not well established, the gut microbiota may mediate the disease pathology, mainly due to pro-inflammatory gut microbiomes [45,46] (Figure 1). Of note, the gut pro-inflammatory state leads to neural disturbance, and with time, to neurodegeneration [46].…”

Pyrroloquinoline-Quinone Is More Than an Antioxidant: A Vitamin-like Accessory Factor Important in Health and Disease Prevention

“…Bacteria and their products are vital contributors to impairment and permeability of the gut barrier, resulting in an increased influx of bacteria, endotoxin, bacterial DNA, and metabolites into the host circulation. Recent reviews show that microbial dysbiosis and impaired barrier function are associated with gastrointestinal disease [113][114][115], neurodegenerative disease [116][117][118][119], autoimmune disease [120][121][122][123][124][125], and an impaired metabolic status in the host manifested by obesity, insulin resistance and cardiovascular complications [126][127][128][129][130][131][132][133][134][135]. In several animal models [63,64,107,136,137], exposure to PQQ increases mRNA expression levels of tight junction proteins and improves jejunal barrier function, suggesting PQQ may act through the gut to affect tissues in the periphery.…”