Microbiome and Metabolome Insights into the Role of the Gastrointestinal-Brain Axis in Parkinson's and Alzheimer's Disease: Unveiling Potential Therapeutic Targets

Abstract

Neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's disease (AD), the prevalence of which is rapidly rising due to an aging world population and westernization of lifestyles, are expected to put a strong socioeconomic burden on health systems worldwide. Clinical trials of therapies against PD and AD have only shown limited success so far. Therefore, research has extended its scope to a systems medicine point of view, with a particular focus on the gastrointestinal-brain axis as a potential main actor in disease development and progression. Microbiome and metabolome studies have already revealed important insights into disease mechanisms. Both the microbiome and metabolome can be easily manipulated by dietary and lifestyle interventions, and might thus offer novel, readily available therapeutic options to prevent the onset as well as the progression of PD and AD. This review summarizes our current knowledge on the interplay between microbiota, metabolites, and neurodegeneration along the gastrointestinal-brain axis. We further illustrate state-of-the art methods of microbiome and metabolome research as well as metabolic modeling that facilitate the identification of disease pathomechanisms. We conclude with therapeutic options to modulate microbiome composition to prevent or delay neurodegeneration and illustrate potential future research directions to fight PD and AD.

Keywords: Alzheimer’s disease; Parkinson’s disease; gastrointestinal–brain axis; metabolomics; microbiome; microbiome modelling; neurodegenerative diseases; therapeutic interventions.

Figure 1

Schematic illustration of the gastrointestinal (GI)–brain axis (red) that could be modulated via potential therapeutic targets involving indirect (lifestyle/diet) and direct modulation of the microbiome (orange circle) and metabolome (green circle). Such therapeutic modulation of the GI-brain axis may represent a promising strategy for the early prevention of neurodegenerative processes in Parkinson’s and Alzheimer’s disease. Further research and analyses of biosamples regarding the microbiome and metabolome are needed and facilitated by methodological advances: sequencing allows the taxonomic and functional characterization of the microbiome (orange arrows) of stool samples of the gut and biospecimens from various other body sites. Metabolomics (green arrows) is facilitated by mass spectrometry (left) or nuclear magnetic resonance spectroscopy (right).

Figure 2

Microbial community modeling approaches. Circles correspond to metabolites, arrows to reactions. Shapes indicate exchanged metabolites. (A) General modeling approach. Genomes of bacterial species are translated into their corresponding metabolic network models. Additionally, information on the nutritional environment of the community is added (e.g., reported dietary uptake of a study participant). Subsequently, metabolic activities in individual bacterial species and metabolic exchanges between them can be predicted. (B) Community flux balance analysis. Bacterial metabolic networks are combined into a community level metabolic network and it is assumed that bacteria optimize their respective metabolic networks for most efficient community growth. (C) Individual-based modeling of microbial communities. Individual bacterial metabolic networks are simulated in a grid-like environment over time. Metabolic interactions occur as part of the secretion/consumption of metabolites by individual bacteria and diffusion of metabolites between grid cells. (D) Whole-body modeling. Metabolic networks of individual bacteria are joined with metabolic networks representing individual host tissues. Metabolic exchanges between bacteria and colon occur via a luminal compartment, metabolic exchanges between host tissues are mediated by the blood stream.