Bacteroidetes Neurotoxins and Inflammatory Neurodegeneration

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 the extremely pro-inflammatory lipopolysaccharide BF-LPS. LPS (i) has recently been shown to associate with the periphery of neuronal nuclei in sporadic Alzheimer's disease (AD) brain 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 normally confined to the GI tract is capable of driving 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 characteristics of AD-type neurodegeneration. This article will review the most recent research which supports the idea that bacterial components of the GI tract microbiome such as BF-LPS can transverse biophysical barriers and contribute to AD-type change. For the first-time, these results indicate that specific GI tract microbiome-derived neurotoxins have a strong pathogenic role in eliciting alterations in NF-kB-miRNA-directed gene expression that drives the AD process.