Role of the microbiome in neurodegenerative disease

The gut microbiota (GM) has an essential role in human health directly and/or indirectly affecting several essential human functions including immunity development, host metabolism, and inflammation. Long-lasting changes in the composition and functionality of GM can promote the onset or progression of brain disorders and neurodegenerative diseases. The GM can be involved in neuropathogenesis due to its effect on the kynurenine pathway (KP) of tryptophan metabolism. Several studies have reported that altered levels of kynurenine pathway metabolites contribute to several neurodegenerative diseases. GM has multiple impacts on the KP, affecting the availability of tryptophan and KP metabolites and modulating the expression of several enzymes. Moreover, it modulates maturation and function of kynurenine-metabolising microglia by affecting serotoninergic and glutamatergic transmission in the central nervous system.
The project proposed here will address the hypothesis that KP metabolites produced by the gut microbiota directly influence the phenotypes of neurodegenerative disease, specifically Huntington's disease (HD). The fruit fly Drosophila melanogaster will be used as an animal model since it has a well-characterised nervous system which shares well-known similarities to the human nervous system. A Drosophila model of HD which exhibit altered KP metabolism and control flies will be used in order to address the three following overarching aims: investigation of the gut microbiota contribution in modulating HD through KP metabolites; investigation of how the altered production of KP metabolites by intestinal bacteria modulates the phenotype of HD model flies; determine if the feeding of elements of the KP alters the microbiota and/or phenotype of Drosophila lines.