Impact of modulating gut bacteria using antibiotic, probiotic, and prebiotic interventions in the APP NL‐G‐F mouse model of Alzheimer disease

Abstract Background Alzheimer's disease (AD) is a multifactorial, neurodegenerative disorder and several factors are known to contribute to its etiology. Evidence suggests that AD may be associated with a dysbiosis of the intestinal microbiota but whether is it is a cause, or an effect is yet to be understood. Method In order to understand the effect of gut bacteria on the pathophysiology of AD, we used two approaches to manipulate gut bacteria in mice; probiotic and antibiotic therapies. Female wild type control C57BL/6 mice were compared to a mouse line that has the human Aβ sequence knocked into the mouse APP gene along with three disease causing mutations ( App NL‐G‐F ). The animals at 2.5 months of age were randomly divided into five groups and three groups were treated with a cocktail of non‐absorbable antibiotics (ABX) in drinking water and two groups were given water only for 10 days. Following ABX treatment, animals were either given normal diet, a probiotic (VSL#3) containing diet, or a diet containing both probiotic and prebiotic for 2 months. Upon completion, learning and memory was assessed along with brain Aβ and cytokines levels. GFAP and Iba‐1 immunohistochemistry was performed on brain sections. Result App NL‐G‐F mice showed a significant deficit in memory performance compared to controls. An increase in pro‐inflammatory cytokines and Aβ along with increased GFAP and Iba‐1 immunoreactivity was observed in App NL‐G‐F brains. No change was observed in intestinal permeability across all groups. Two months of probiotic supplementation improved memory and decreased plaque load in App NL‐G‐F mice. Consistent with this, probiotic feeding attenuated GFAP and Iba‐1 immunoreactivity in App NL‐G‐F brains. On other hand, antibiotic treatment alone or in combination with probiotic/prebiotics appeared to increase microgliosis and astrogliosis in App NL‐G‐F brains. Conclusion These results demonstrate that transiently depleting gut bacteria with antibiotic treatment has a long‐term effect on worsening AD‐associated parameters in App NL‐G‐F brains. On the other hand, modulating gut bacteria using probiotic feeding decreases plaque load and gliosis. This data suggests that gut microbiota modulate host brains and probiotics might be useful as supplementary therapy in AD.