Can microbes combat neurodegeneration? | Science

Nervous System–Microbiome Cross Communication

Recent evidence suggests that the human brain constantly communicates with the gut microbiome—an ecosystem of thousands of bacterial species that inhabit the gastrointestinal tract along a “microbiome-gut-brain axis” (4, 5). Cross-talk on this axis can be mediated by small-molecular metabolites secreted by gut bacteria and absorbed into the blood stream. These metabolites can then access the central nervous system through the choroid plexus, where it is believed they reprogram transcriptional responses of brain cells (6). The gut microbiome responds quickly to environmental factors and represents a central component in their impact on the host’s physiology. Therefore, we hypothesized that gut bacteria influence ALS pathogenesis.

We began our investigation by depleting the microbiome of Sod1-transgenic (Sod1-Tg) mice through wide-spectrum antibiotic treatment. Microbiome depletion resulted in a substantial exacerbation of ALS symptoms (3). We then compared the gut microbiome of antibiotic-treated Sod1-Tg mice to that of wild-type littermate controls raised in several specific-pathogen–free facilities. We discovered vivarium-dependent dysbiosis and microbiome-driven alteration in systemic metabolite’s configuration that preceded clinical motor symptoms. We then demonstrated that several key bacterial genes that encode for biosynthetic enzymes of nicotinamide and its precursor, tryptophan, were reduced in the microbiome of Sod1-Tg mice.

Shown is a colored scanning electron micrograph (SEM) of Escherichia coli, one of hundreds of bacterial species residing in the human gut. Research is now revealing cross-talks between those microbes and distant organs, such as the brain, in health and disease.

PHOTO: STEPHANIE SCHULLER/SCIENCE SOURCE

Distinct Microbial Transplantation Ameliorates Mouse ALS

Using a comprehensive metagenomic assessment throughout disease progression, we identified 11 distinct microbial strains that were correlated to disease severity. To test their clinical effects on ALS severity, we adopted a “probiotic” approach in which we anaerobically cultured individual strains and administered them to Sod1-Tg mice pretreated with antibiotics. Supplementation of these strains demonstrated that Akkermansia muciniphila ameliorated whereas Ruminococcus torques and Parabacteroides distasonis exacerbated ALS symptoms in the mice. We then used metabolomic approaches to characterize bacterial-associated metabolites in the A. muciniphila–treated Sod1-Tg mice and found that supplementation with the bacterium significantly increased nicotinamide concentrations in the nervous system. Direct administration of nicotinamide, through subcutaneously implanted osmotic pumps, also substantially improved motor abilities and spinal cord gene expression patterns in Sod1-Tg mice. These findings highlight nicotinamide as a potential therapeutic agent for ALS. Treating Sod1-Tg mice with either the bacterium A. muciniphila or with its associated metabolite nicotinamide enriched the expression of neuroprotective genes involved in mitochondrial structure and function, nicotinamide adenine dinucleotide⁺ (NAD⁺) homeostasis, and removal of superoxide radicals in the spinal cord—functions that are known to be disrupted in ALS (see the figure).

Microbiome and Nicotinamide Change in ALS Patients

To determine whether our findings could be translated into a potential cure for human ALS, we sequenced the gut microbiome metagenomes of ALS patients and healthy family members that shared the same household environment. This observational study showed that the composition and function of the microbiome of ALS patients substantially differed from that of healthy family members. Moreover, we found a significant reduction in nicotinamide concentrations in both sera and cerebrospinal fluids of ALS patients. We posit that these findings are linked to our previous observations in mice and may lay the foundation for a larger clinical study in the future.

The Future: Microbiome-Metabolome–Based Therapies?

Harnessing rapidly developing microbiome sequencing, culturing, and computational technologies enabled us to identify a skewed metabolic pathway involved in ALS pathogenesis in mice that is highly affected by the composition and function of the gut microbiome. Similarly, studies performed during my graduate work in the laboratory of Reuven Stein showed that inhibition of CD38, the most efficient NAD+-consuming enzyme, is a promising strategy to treat brain pathologies (7–10). Disrupted microbial metabolites profiles may also contribute to neurodegeneration, as we demonstrated in Sod1-Tg ALS mice (3). These results exemplify how microbiome profiling can be used to identify disease-modifying metabolites.

Further research implementing mass-spectrometry informatics with molecular networking has the potential to reveal the mechanisms behind microbiome-associated phenotypes (11, 12). This approach may pave the way to rationally genetically engineer a transplantable metabolome that would hopefully assist in delaying or even preventing detrimental age-related illnesses.