Modulation of Alzheimer's Disease Brain Pathology in Mice by Gut Bacterial Deletion: The Role of Il-17a and Microglial MyD88

Gut bacteria regulate brain pathology of Alzheimer disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene, or haploinsufficiency of MyD88 in microglia were treated with antibiotics-supplemented or normal drinking water for two months. Antibiotic treatment eradicated gut bacteria, particularly in the phyla Bacteroidetes and Firmicutes, and reduced Il-17a-expressing CD4-positive T lymphocytes. Deletion of gut bacteria inhibited inflammatory activation in the brain and microglia of APP-transgenic mice, which was abolished by deficiency of Il-17a or haploinsufficiency of MyD88 in microglia. Deletion of gut bacteria also reduced Aβ levels in the brain of APP-transgenic mice, but not in AD mice with knockout of Il-17a gene or haploinsufficiency of microglial MyD88. As possible mechanisms regulating Aβ pathology, deletion of gut bacteria inhibited β-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also abrogated by the absence of Il-17a. Thus, deletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a and microglial MyD88-involved pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology. ### Competing Interest Statement The authors have declared no competing interest.