Amyotrophic lateral sclerosis and intestinal microbiota—toward establishing cause and effect

Abstract

The intestinal microbiota may be involved, through metabolic gut-brain interactions, in a variety of neurological conditions. In this addendum, we summarize the findings of our recent study investigating the potentially modulatory influence of the microbiome in a transgenic ALS mouse model, and the possible application to human disease. We found that transgenic mice show evidence of dysbiosis, even at the pre-symptomatic stage, and have a more severe disease course under germfree conditions or after receiving broad-spectrum antibiotics. We demonstrated that Akkermansia muciniphila ameliorated the disease in mice and that this may be due to the production of nicotinamide. We then conducted a preliminary study in human ALS and identified functionally similar alterations within the metagenome. Furthermore, we found that patients with ALS had lower systemic and CSF levels of nicotinamide, suggesting that the changes observed in the mouse model may be relevant to human disease.

Microbiota‐Host Immunity Communication in Neurodegenerative Disorders: Bioengineering Challenges for In Vitro Modeling

“…The common experimental approach to study the whole microbiota‐immunity‐CNS axis is currently based on animal models. [ 121–124 ] According to the 3Rs principle (replacement, reduction, and refinement) and taking into account some differences of preclinical models with human physiology (e.g., different microbiota composition), advanced in vitro modeling offers a promising and challenging strategy to reduce the experimental in vivo variability and study the complexity of the axis by analyzing each single microenvironment and biological mediator. [ 125 ] The advent of bioengineering and organ‐on‐a‐chip (OOC) technology in the field of cell culture is providing new technological inputs toward more reliable in vitro tools suitable to model also human immune system‐based mechanisms.…”

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

“…Recently, Blacher and colleagues confirmed a pre-symptomatic distinct microbiome composition in transgenic SOD1 mice and identified commensals such as, Parabacteroides distasonis and Ruminococcus torques adversely affected the disease whereas Akkermansia muciniphila ameliorated the disease (51). Using a combination of untargeted metabolomic profiling and metagenomics, they found that A. muciniphila increased nicotinamide (NAM) levels in the mice' s cerebrospinal fluid, and NAM supplementation was able to improve the mice survival (43). Furthermore, the authors confirmed a distinct microbiome and metabolite configuration in a small group of ALS patients compared to healthy controls (51).…”

“…ALS is a very complex disease in which many conditions such as infections or antibiotic exposure, dysphagia, food replacement, motor dysfunction, and lack of movements, could impact the microbiome structure (43). Distinct microbial profiles have been found in many neurological disorders in which the modulation of microbiota (with fecal microbiota transplantation or probiotics administration) has proven to affect brain activity and disease progression (44)(45)(46).…”

The Association between Early-Life Gut Microbiota and Long-Term Health and Diseases

“…More recently, Gotkine et al identified dysbiosis in an ALS Sod1 transgenic mouse model and in humans with ALS, and further, Sod1 transgenic mice motor function was improved by the introduction of Akkermansia muciniphila , possibly due to its production of nicotinamide [ 202 ]. Another study on the Sod1 transgenic mouse model also found dysbiosis, epigenetic, and immunological changes prior to the onset of motor deficits [ 203 ].…”