The microbiota-gut-brain axis in Alzheimers disease

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ABSTRACT Host-microbe interactions are paramount for maintaining normal physiology of the human host, including the brain and behavior. Bacterial colonization of the gastrointestinal (GI) tract, formation of GI mucosal barrier function, neurogenesis, and myelination of neurons all occur during a critical developmental window in early life. Thus, exposure to trauma such as stress, infection or inflammation during neonatal life could detrimentally impact the developing microbiota, gut and brain (MGB) axis. Disrupted MGB axis signaling, including dysbiosis, mucosal barrier defects and/or changes in behavior, occur in multiple diseases, including Alzheimer’s disease. Antibiotics (Abx) are administered to children more frequently than adults, due to increased susceptibility to bacterial pathogens. Since the MGB axis is developing during this critical time, Abx administration may have long-lasting effects. Beneficial bacterial metabolites, including short chain fatty acids (SCFAs) can ameliorate numerous pathologies, including dysbiosis, mucosal barrier dysfunction, inflammation and behavioral defects. We have demonstrated that modifying the gut microbiota, for example using Lactobacillus-containing probiotics, can prevent stress-induced MGB axis deficits following infection with a bacterial pathogen. We hypothesize that administration of specific SCFAs can prevent neonatal Abx-induced deficits in the adult MGB axis. Therefore, our primary objective is to address the effects of neonatal dysbiosis on the development of the MGB axis using a model of neonatal Abx administration. Our overall goal is to determine whether intestinal dysbiosis disrupts the gut-brain axis, and whether administration of SCFAs beneficially modulates the MGB axis. This goal will be accomplished by the following Specific Aims: (1) Neonatal dysbiosis disrupts myelination leading to neurodegeneration and (2) SCFAs regulate the MBG axis via myelination Taken together, these proposed studies will demonstrate whether neonatal dysbiosis disrupts the developing MGB axis, impacting the microbiota composition, altering myelination in the brain, and causing behavioral deficits in late adulthood. Furthermore, we will determine whether administering select SCFAs ameliorates these effects, in part restoration of impaired myelination in the brain. Finally, our results may promote use of SCFAs to prevent development MGB axis deficits, particularly in older adults.