Abstract
The first indication of a potential mechanistic link between the pathobiology of the human gastrointestinal (GI)-tract microbiome and its contribution to the pathogenetic mechanisms of sporadic Alzheimer’s disease (AD) came a scant 4 years ago (1). Ongoing research continues to strengthen the hypothesis that neurotoxic microbial-derived components of the GI tract microbiome can cross aging GI tract and blood–brain barriers and contribute to progressive proinflammatory neurodegeneration, as exemplified by the AD-process. Of central interest in these recent investigations are the pathological roles played by human GI tract resident Gram-negative anaerobic bacteria and neurotropic viruses—two prominent divisions of GI tract microbiome-derived microbiota—which harbor considerable pathogenic potential. It is noteworthy that the first two well-studied microbiota—the GI tract abundant Gram-negative bacteria Bacteroides fragilis and the neurotropic herpes simplex virus-1 both share a final common pathway of NF-κB (p50/p65) activation and microRNA-146a induction with ensuing pathogenic stimulation of innate-immune and neuroinflammatory pathways. These appear to strongly contribute to the inflammation-mediated amyloidogenic neuropathology of AD. This communication: (i) will review recent research contributions that have expanded our understanding of the nature of the translocation of microbiome-derived neurotoxins-across biophysiological barriers; (ii) will assess multiple-recent investigations of the induction of the proinflammatory pathogenic microRNA-146a by these two prominent classes of human microbiota; and (iii) will discuss the role of molecular neurobiology and mechanistic contribution of polymicrobial infections to AD-type neuropathological change.
Highlights
Reviewed by: Karen Ann Scott, University College Cork, Ireland Richard O’Connor, Icahn School of Medicine at Mount Sinai, United States
It is noteworthy that the first two well-studied microbiota—the GI tract abundant Gram-negative bacteria Bacteroides fragilis and the neurotropic herpes simplex virus-1 both share a final common pathway of NF-κB (p50/p65) activation and microRNA-146a induction with ensuing pathogenic stimulation of innate-immune and neuroinflammatory pathways. These appear to strongly contribute to the inflammation-mediated amyloidogenic neuropathology of Alzheimer’s disease (AD). This communication: (i) will review recent research contributions that have expanded our understanding of the nature of the translocation of microbiome-derived neurotoxins-across biophysiological barriers; (ii) will assess multiple-recent investigations of the induction of the proinflammatory pathogenic microRNA-146a by these two prominent classes of human microbiota; and (iii) will discuss the role of molecular neurobiology and mechanistic contribution of polymicrobial infections to AD-type neuropathological change
One recently described benefit of GI tract microbiota is that they may help protect against inflammatory neurodegeneration, such as those encountered in Alzheimer’s disease (AD) brain, in part by supporting the generation of select short chain fatty acids which interfere with the formation and aggregation of toxic soluble amyloid beta (Aβ) peptides [12]
Summary
Many unanswered questions remain concerning the role of microbiome-derived neurotoxins and their contribution to the progressive inflammatory neurodegeneration of sporadic AD—and these include, prominently: Does life-long exposure to specific infectious agents predispose one to develop AD at a later age? What combinations of bacterial- and viral-based neurotoxins and perhaps other microbiome-derived toxins are the most efficient in inducing a progressive proinflammatory neurodegeneration? Carbohydrates and specialized plant-based dietary fibers that nourish beneficial microbes already in the GI tract, or probiotics, consisting of beneficial “health-promoting” microbes have any role in AD onset or progression? Would it possible to tailor a life-long dietary intake that minimizes the risk of CNS-based age-related neuroinflammatory diseases such as AD? Is it possible to devise prebiotic, probiotic, anti-neurotoxin, anti-NF-κB, anti-microRNA, or combinations of these approaches for therapeutic benefit in the clinical management of AD?
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