Altered Gut Microbial Load and Immune Activation in a Drosophila Model of Human Tauopathy

Abstract

Tau is a microtubule-associated protein that stabilizes the neuronal cytoskeleton. In the family of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE), abnormal tau aggregation destabilizes microtubule structure, contributing to a cascade of cellular processes leading to neuronal cell death. The gut microbiome has increasingly become a target of neurodegenerative disease research since gut microbiome imbalances have been linked to protein aggregation and inflammation through a bidirectional axis linking the gut and brain. Accordingly, the present study examined tau-mediated changes to gut microbiome composition and immune activation in a Drosophila melanogaster model of human mutant tauopathy. Fecal deposit quantification and gastric emptying time courses suggested an abnormal food distribution and reduced gut motility in tau transgenic flies compared to controls. Tau transgenic flies also showed an increase in gut bacteria colony forming units (CFUs) from diluted fly homogenate, indicating an increased bacterial load. Finally, we showed that tau transgenic flies have a trend towards elevated systemic levels of antimicrobial peptides targeting gram-negative bacteria using qPCR, suggesting an enhanced innate immune response to bacterial insult. These data demonstrate qualifiable and quantifiable gut microbial and innate immune responses to tauopathy. Furthermore, these results provide a framework for future studies targeting the gut microbiome as a modifier of neurodegenerative disease.

Towards early detection of neurodegenerative diseases: A gut feeling

“…Interestingly, these bacterial species display similar health-promoting proprieties in Drosophila and mammals (Erkosar et al, 2013). For instance study of microbiota in transgenic fly models for NDs have revealed correlation between shift in microbial population and aging (Kitani-Morii et al, 2021;Neophytou and Pitsouli, 2022;Schretter, 2020;von Frieling et al, 2020) or the onset of NDs similar to that observed in humans (Mertsalmi et al, 2020;Rydbom et al, 2021).…”

“…Neurological diseases, such as NDs are co-morbid with gastrointestinal alterations (Vandvik et al, 2004;Sampson and Sarkis, 2015). It has indeed been reported that in both mouse and Drosophila models of human PD, the neurodegenerative pathologies in the brain have been observed in concurrence with commensal dysbiosis in the gut (Erny et al, 2015;Challis et al, 2020;Peterson, 2020;Kitani-Morii et al, 2021;Rydbom et al, 2021).…”

“…Moreover, both β-amyloid and also tau tangles/plaques promote local intestinal inflammation and weakening of the gut epithelial barrier ( Kowalski and Mulak, 2019 ). The weakening of the gut epithelial barrier can cause metaflammation (low-grade chronic systemic inflammation) that has been linked to NDs ( Komleva et al, 2021 ; Rydbom et al, 2021 ). For a review on metaflammation we refer the readers to ( Itoh et al, 2022 ).…”

The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases

“…Finally, microbiome studies on Drosophila flies carrying the transgenic mutant human FTDP-17-associated tau showed reduced gut motility and subsequently increased gut bacterial load in aged tau transgenic compared to control flies [ 121 ].…”