Temporal evolution of the microbiome, immune system, and epigenome with disease progression in ALS mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease. Genetic predisposition, epigenetic changes, aging and accumulated lifelong environmental exposures are known ALS risk factors. The complex and dynamic interplay between these pathological influences plays a role in disease onset and progression. Recently, the gut microbiome has also been implicated in ALS development. In addition, immune cell populations are differentially expanded and activated in ALS compared to healthy individuals. However, the temporal evolution of both the intestinal flora and the immune system relative to symptom onset in ALS is presently not fully understood. To better elucidate the timeline of the various potential pathological factors, we performed a longitudinal study to simultaneously assess the gut microbiome, immunophenotype and changes in ileum and brain epigenetic marks relative to motor behavior and muscle atrophy in the mutant superoxide dismutase 1 (SOD1 G93A) familial ALS mouse model. We identified alterations in the gut microbial environment early in the life of SOD1 G93A animals followed by motor dysfunction and muscle atrophy, and immune cell expansion and activation, particularly in the spinal cord. Global brain cytosine hydroxymethylation was also altered in SOD1 G93A animals at disease end-stage compared to control mice. Correlation analysis confirmed interrelationships with the microbiome and immune system. This study serves as a starting point to more deeply comprehend the influence of gut microorganisms and the immune system on ALS onset and progression. Greater insight may help pinpoint novel biomarkers and therapeutic interventions to improve diagnosis and treatment for ALS patients.

Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

“…However, an increase in DNA methylation was found in the blood of ALS subjects, regardless of the time of onset of the disorder (Tremolizzo et al, 2014). Moreover, total cytosine hydroxymethylation has been found in the brains of end-stage SOD1 transgenic animals (Figueroa-Romero et al, 2019), while altered levels of DNA methylation have been reported in postmortem brains from sALS individuals when compared to age-matched controls (Morahan et al, 2009). Curiously, 60% of the genes affected by such changes are involved in neurotransmission, oxidative stress, and calcium handling, mechanisms that are thought to be disrupted in ALS (Morahan et al, 2009).…”

Rofecoxib Attenuates the Pathogenesis of Amyotrophic Lateral Sclerosis by Alleviating Cyclooxygenase-2-Mediated Mechanisms

“…Although there is no direct evidence suggesting the efficacy of rofecoxib on treating ALS via inhibiting peripheral inflammation, activated macrophages, mast cells, and T cells have been confirmed to be responsible for inducing the inflammation in the spinal cords of ALS (Graves et al, 2004). Consistently, dysregulation of immune system has been reported in the spinal cord of SOD1 G93A mice (Figueroa-Romero et al, 2019). By the involvement of immune system in the pathogenesis of ALS, stimulating the protective effects of the immune system in humans, including intravenous immunoglobulins, and other experimental interventions such as antibodies, vaccination, minocycline, and neural stem cells have shown the promise efficacy on treating animal models of ALS (Chio et al, 2010).…”

Peripheral Routes to Neurodegeneration: Passing Through the Blood–Brain Barrier

“…the vascular, and the nervous systems (Figure 2; Schroeder and Bäckhed, 2016;Cox and Weiner, 2018;Butler et al, 2019;Cryan et al, 2019). Modifications in the composition of the GM was reported in brain disorders, such as autism (Adams et al, 2011;Kang et al, 2019), depression (Kelly et al, 2016;Zheng et al, 2016), Parkinson's disease (Scheperjans et al, 2015;Sampson et al, 2016), and AD (Cattaneo et al, 2017;Vogt et al, 2017;Zhuang et al, 2018). Intriguingly, the extent of the amyloid pathology in AD mice appears to be dependent of the microbial status, which is specific to the animal housing facility.…”