The Role of Gut Microbiome Dysbiosis in Alzheimer Disease

Michael Woolley

 Introduction. Alzheimer disease (AD) is the leading cause of dementia in the United States1. As many as 5 million new cases are diagnosed each year, and that number is expected to increase as the Baby Boomer generation ages2. Despite years of research in search of effective treatments, nothing has yet been developed to prevent or slow progress of the disease3,4. Continued research efforts have led to the emergence of the hypothesis that inflammation may play an essential role in the etiology of AD and may offer novel therapeutic targets1,4. At the same time, researchers noticed a link between AD and gut dysbiosis5-11. Work is currently underway to understand this link and the mechanisms that might be at play. One such study examined the effects of inducing gut dysbiosis in a Drosophila model of AD11. Methods. Researchers used a transgenic Drosophila strain that ectopically expresses amyloid-β in their brain. They infected the flies with a non- pathogenic enterobacteria (Ecc15). They examined gross phenotypic changes in behavior and lifespan, in addition to immunohistochemical staining for markers of inflammation and apoptosis. Results. The researchers found that infected transgenic flies showed significantly more neurodegeneration compared to the non-transgenic controls11. Immunostaining revealed significant increases in apoptotic and inflammatory markers in the infected transgenic flies11. In addition to the increased neuronal loss, infected transgenic flies displayed decreased locomotor activity and lifespan compared to controls11. Further examination revealed that these alterations were being mediated by upregulation of TNF eiger signaling in the infected transgenic flies11. Blocking eiger signaling resulted in significant decreases in neuronal loss and increases in lifespan11. Ecc15 infection was also shown to lead to increased hemocyte recruitment to the CNS in the infected transgenic flies11. Infected transgenic flies genetic depleted of hemocytes show significantly decreased neurodegeneration and markedly improved survival, strongly indicating that hemocyte activity in the CNS is an important factor in neuronal loss11. Conclusions. This study, though conducted using a Drosophila model of human disease and only adding a single bacterial species to alter the gut microbiome, offers evidence that there is an important gut-brain interplay at work in AD. A better understanding of the mechanisms involved may open the doors to novel therapeutic targets and the hope of better treatments for AD.


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