The Microbiome as a Modifier of Neurodegenerative Disease Risk

Abstract

The gut microbiome is increasingly implicated in modifying susceptibility to and progression of neurodegenerative diseases (NDs). In this review, we discuss roles for the microbiome in aging and in NDs. In particular, we summarize findings from human studies on microbiome alterations in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We assess animal studies of genetic and environmental models for NDs that investigate how manipulations of the microbiome causally impact the development of behavioral and neuropathological endophenotypes of disease. We additionally evaluate the likely immunological, neuronal, and metabolic mechanisms for how the gut microbiota may modulate risk for NDs. Finally, we speculate on cross-cutting features for microbial influences across multiple NDs and consider the potential for microbiome-targeted interventions for NDs.

Keywords: ALS; Alzheimer's; Parkinson's; aging; microbiome; neurodegenerative disease.

Figure 1.. Proposed pathways for microbial modulation of neurodegenerative diseases.

The gut microbiome is increasingly implicated in modifying risk for NDs. While precise mechanisms are unknown, a few pathways have been proposed. The gut microbiome is critical for conditioning peripheral immune homeostasis and autoimmune responses, which could influence the manifestation of NDs (far left). In addition, the gut microbiome is important for promoting intestinal colonization resistance and protecting against pathogens, which could influence the likelihood of host exposure to infection and inflammation, as risk factors for subsets of NDs (center left). The gut microbiome regulates a vast repertoire of biochemicals, some of which may interact directly with amyloids to promote aggregation in neurons and propagation from the periphery to the brain (center right). The gut microbiome modulates biochemicals that modulate neuroimmune development and function, including the activity of brain microglia, which could impact the manifestation of subsets of NDs (far right).