The Gram-negative facultative anaerobe Bacteroides fragilis (B. fragilis) constitutes an appreciable proportion of the human gastrointestinal (GI)‑tract microbiome. As is typical of most Gram-negative bacilli, B. fragilis secretes an unusually complex mixture of neurotoxins including 2 extremely pro-inflammatory species: (i) a B. fragilis‑associated lipopolysaccharide BF‑LPS; and (ii) a B. fragilis-derived proteolytic enterotoxin known as fragilysin (EC 3.4.24.74). BF‑LPS has recently been shown to be associated with the periphery of neuronal nuclei in sporadic Alzheimer’s disease (AD) brain; and the extracellular zinc metalloprotease fragilysin (i) induces endogenous E-cadherin cleavage thereby disrupting cell-cell adhesion and the GI‑tract‑blood barrier (GTBB); and (ii) promotes the generation of the inflammatory transcription factor NF‑kB (p50/p65 complex) in human neuronal‑glial cells in primary culture. In turn, the NF‑kB (p50/p65 complex) strongly induces the transcription of a small family of pro-inflammatory microRNAs (miRNAs) including miRNA‑9, miRNA‑34a, miRNA‑125b, miRNA‑146a, and miRNA‑155. These ultimately bind with the 3’‑untranslated region (3’‑UTR) of several target messenger RNAs (mRNAs) and thereby reduce their expression. Down‑regulated mRNAs include those encoding complement factor-H (CFH), an SH3-proline-rich multi domain-scaffolding protein of the postsynaptic density (SHANK3), and the triggering receptor expressed in myeloid/microglial cells (TREM2), as is observed in sporadic AD brain. Hence, a LPS and an enterotoxic metalloprotease normally confined to the GI tract are capable of driving a disruption in the GI-tract-blood barrier and a NF-kB-miRNA-mediated deficiency in gene expression that contributes to alterations in synaptic-architecture and synaptic-deficits, amyloidogenesis, innate-immune defects, and progressive inflammatory signaling, all of which are characteristic of AD‑type neurodegeneration. This paper will review the most recent research which supports the concept that bacterial components of the GI-tract microbiome such as BF-LPS and fragilysin can transverse normally protective biophysical barriers and contribute to AD‑type changes. For the first‑time, these results indicate that specific GI-tract microbiome-derived neurotoxins have a strong pathogenic potential in disrupting the GI-tract blood barrier and eliciting alterations in NF-kB-miRNA-directed gene expression that drive the AD process.
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