Readers of Evmedreview are becoming used to the idea that the bugs you have in your gut can influence the way your brain develops, and can change your behaviour. But several recent papers are implicating the gut microbiome in the development and exacerbation of symptoms of neurodegenerative diseases like Alzheimer’s and Parkinson’s. In a paper in Cell at the beginning of the month, a number of scientists from Sarkis Mazmanian’s laboratory at Caltech have revealed some sensational work in a mouse model that will force us to take the role of the gut microbiome very seriously indeed as a major component of Parkinson’s disease.
The motor dysfunction typical of Parkinson’s is caused by build up and aggregation of alpha-synuclein protein in the brain cortex. This causes neuro-inflammation (aided by primed microglia which contribute to an inflammatory state by producing pro-inflammatory cytokines) which in turn produces more alpha-synuclein in a vicious spiral.
Mazmanian’s team used ASO (alpha-synuclein over-expressing) mice which typically show loss of motor control from about 12 weeks onwards. But when these mice were raised germ-free, or were treated with antibiotics early in life, the symptoms were much ameliorated. Furthermore, when ASO mice were given microbiota transplants from human Parkinson’s patients, their symptoms got much worse, while transplants from normal healthy human donors dialled back the tremors. Microbiota transplants from Parkinson’s patients had no deleterious effects on normal wild-type mice suggesting that the bugs act in concert with a predisposing genotype.
Mazmanian believes the microbiota have these effects by producing a certain range of short-chain fatty acids (SCFAs) and it is these that activate the microglia and produce neuroinflammation. Giving SCFAs directly to ASO mice made their symptoms worse. He further believes that it is not just any old microbiome that is capable of kicking off Parkinson’s in susceptible individuals. There is evidence that the microbiome of affected individuals differs in important respects with regard to which microbial species are present and and how abundant they are. In the ASO mice these included depletions in members of the bacterial families Lachnospiraceae and Ruminococceae while Filip Scheperjans et al in Helsinki have shown that a Parkinson’s gut contains a much reduced abundance of Prevotella species and an enhanced abundance of Enterobacter species – and that this shift was associated with marked deficits in posture and gait.
No-one has yet sorted out cause and effect here. Does Parkinson’s disease alter the structure of the microbiome because of the reduced gastric motility and other intestinal problems often reported by Parkinson’s patients, or even because excessive amounts of alpha-synuclein, like beta-amyloid, act as anti-microbials, thereby shaping a typical Parkinson’s microbiome? The Caltech team says that whether microbial community alterations are caused by extrinsic or intrinsic factors, the Parkinson’s disease microbiota may be missing or reduced in protective microbes, harbor increased pathogenic resident microbes, or both. In turn, they say, dysbiosis will result in differential production of microbial molecules in the gut. Metabolites produced by a deranged microbiota may enter the circulation (or even the brain) and impact neurological function. These scientists are in no doubt as to the range and relevance of this work to other brain disorders: “Coupled with emerging research that has linked gut bacteria to disorders such as anxiety, depression, and autism, we propose the provocative hypothesis that certain neurologic conditions that have classically been studied as disorders of the brain may also have etiologies in the gut.”