A growing weight of evidence indicates that changes in the gut microbiome taking place over the course of aging contribute to the onset and progression of neurodegenerative conditions. Species producing beneficial metabolites, such as butyrate to upregulate expression of BDNF to encourage neurogenesis, decline in number. Species that are harmful because they contribute to the constant, unresolved inflammation that is characteristic of old age increase in number. It is thought that the decline of immune function plays a role in this shift, as the immune system becomes ever less capable of gardening the gut microbiome to remove problematic microbes. Other factors are likely in play, such as barrier dysfunction, both in the intestine and brain, allowing microbes and unwanted, pro-inflammatory metabolites to pass into tissue in increasing numbers.
The aging of the gut microbiome is longer-term process of change, taking place over decades and leading to a distinctly dysfunctional gut microbiome in patients with neurodegenerative conditions. But in the short term, the presence of infectious agents in the aged gut microbiome can accelerate neurodegenerative processes via the same inflammatory mechanisms. In today's open access paper, researchers illustrate this point using a mouse model of Alzheimer's disease infected with a common species of bacteria that causes pneumonia. Infection clearly worsens the neurodegenerative pathology in these mice, as one might expect for any significant cause of inflammation.
Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied. Thus a preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis.
K. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic "pathobiome" signature implicated in gut-brain perturbations.
The findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.
View the full article at FightAging
