Editors' ChoiceHost-Microbe Interactions

Triggering neurodegeneration from the gut

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Science Signaling  13 Dec 2016:
Vol. 9, Issue 458, pp. ec291
DOI: 10.1126/scisignal.aam5613

In Parkinson’s disease, aggregation of α-synuclein triggers the death of dopaminergic neurons, resulting in the development of motor deficits. Aggregates of α-synuclein are also found in enteric nerves, and the onset of gastrointestinal symptoms, such as constipation, often precedes that of motor deficits in Parkinson’s disease patients. Noting that Parkinson’s disease patients have dysbiosis, or altered microbiome composition, and that gut microbiota can alter signaling and function in both the gastrointestinal system and the brain, Sampson et al. investigated the link between gut microbiota and Parkinson’s disease, using mice that overexpress α-synuclein (ASO mice) and are a model for Parkinson’s disease. Compared with ASO mice with a complex microbiota, germ-free ASO mice had reduced motor deficits and normal fecal output (implying normal gastrointestinal function). Furthermore, germ-free ASO mice had reduced α-synuclein aggregation and microglia with morphology suggestive of reduced activation in the brain regions affected in Parkinson’s disease and decreased inflammatory cytokine concentrations in some brain regions. Postnatal colonization of germ-free ASO mice with a complex microbiota resulted in increased motor deficits, reduced fecal output, and increased microglial activation. In contrast, postnatal depletion of microbiota with antibiotic treatment partially or fully reversed motor deficits, gastrointestinal dysfunction, and microglial activation in ASO mice with a complex microbiota. Short-chain fatty acids released by gut bacteria during viral infection can activate microglia, and concentrations of short-chain fatty acids were lower in germ-free ASO mice than in ASO mice with a complex microbiota. Administration of short-chain fatty acids to germ-free ASO mice led to increased microglial activation and α-synuclein aggregation and to impairment of motor function. Mice that received fecal microbiota from Parkinson’s disease patients developed greater motor dysfunction than those that received microbiota from healthy controls. These results suggest that metabolites produced by the gut microbiota contribute to the microglial activation, α-synuclein aggregation, and motor deficits characteristic of Parkinson’s disease.

T. R. Sampson, J. W. Debelius, T. Thron, S. Janssen, G. G. Shastri, Z. E. Ilhan, C. Challis, C. E. Schretter, S. Rocha, V. Gradinaru, M.-F. Chesselet, A. Keshavarzian, K. M. Shannon, R. Krajmalnik-Brown, P. Wittung-Stafshede, R. Knight, S. K. Mazmanian, Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016). [PubMed]

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