ABSTRACT
Sub-chronic inflammation, caused by age-related dysbiosis, primes the brain to neuroinflammation and neurodegenerative diseases. Evidence revealed that Parkinson's disease (PD) might originate in the gut, demonstrating gastro-intestinal disturbances, as reported by PD patients long before developing motor symptoms. In this study, we conducted comparative analyses in relatively young and old mice maintained in conventional or gnotobiotic conditions. We aimed to confirm that the effects induced by age-related dysbiosis, rather than aging itself, sensitize to PD onset. This hypothesis was confirmed in germ-free (GF) mice, which proved resistant to the pharmacological induction of PD, regardless of their age. Contrary to conventional animals, old GF mice did not develop an inflammatory phenotype or an accumulation of iron in the brain, two catalysts sensitizing to disease onset. The resistance of GF mice to PD is reverted when colonized with stool collected from conventional old animals, but not if receiving bacterial content from young mice. Hence, changes in gut microbiota composition are a risk factor for PD development and can be targeted preventively by iron chelators, shown to protect the brain from pro-inflammatory intestinal priming that sensitizes to neuroinflammation and the development of severe PD.
ABSTRACT
Iron (Fe) is essential to almost all organisms, as required by cells to satisfy metabolic needs and accomplish specialized functions. Its ability to exchange electrons between different substrates, however, renders it potentially toxic. Fine tune-mechanisms are necessary to maintain Fe homeostasis and, as such, to prevent its participation into the Fenton reaction and generation of oxidative stress. These are particularly important in the context of inflammation/infection, where restricting Fe availability to invading pathogens is one, if not, the main host defense strategy against microbial growth. The ability of Fe to modulate several aspects of the immune response is associated with a number of "costs" and "benefits", some of which have been described in this review. © 2017 IUBMB Life, 69(6):442-450, 2017.
