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Bacteroidetes Neurotoxins and Inflammatory Neurodegeneration

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Abstract

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.

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Abbreviations

AD:

Alzheimer’s disease

B. fragilis :

Bacteroides fragilis

LPS:

Lipopolysaccharide

BF-LPS:

Bacteroides fragilis lipopolysaccharide

mRNA:

Messenger RNA

miRNA:

microRNA

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Acknowledgements

This work was presented in part at the Vavilov Institute of General Genetics (VIGG) Autumn Seminar Series (Институт общей генетики имени Вавилова Осень 2017 Семинар серии) in Moscow, Russia, October 2017, at the Society for Neuroscience (SFN) 47th Annual Meeting November 2017 in Washington DC, USA. Sincere thanks are extended to Drs. F Culicchia, C Eicken, C Hebel, and W Poon for short post-mortem interval (PMI) human brain tissues or extracts, DNA and miRNA array work, and initial data interpretation, and to AI Pogue, D Guillot, Lin Cong, and J Lockwood for expert technical assistance. Additional thanks are extended to the many physicians and neuropathologists of Canada, the USA, and Russia who have provided high-quality and short post-mortem interval human brain and retinal tissues and GI tract extracts for scientific study. Additional human control and AD brain tissues were provided by the Memory Impairments and Neurological Disorders (MIND) Institute and the University of California, Irvine Alzheimer’s Disease Research Center (UCI-ADRC; NIA P50 AG16573). Research on miRNA in the Lukiw laboratory involving the microbiome and innate-immune responses in AD, amyloidogenesis, and neuroinflammation was supported through a COBRE III Pilot Project NIH/NIGMS grant P30-GM103340, an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research Network (LBRN) and NIH grants NEI EY006311, NIA AG18031, and NIA AG038834.

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Authors and Affiliations

  1. LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112, USA

    Yuhai Zhao & Walter J. Lukiw

  2. Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112, USA

    Yuhai Zhao

  3. Department of Neurology, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112, USA

    Walter J. Lukiw

  4. Departments of Ophthalmology, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112, USA

    Walter J. Lukiw

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Zhao, Y., Lukiw, W.J. Bacteroidetes Neurotoxins and Inflammatory Neurodegeneration. Mol Neurobiol 55, 9100–9107 (2018). https://doi.org/10.1007/s12035-018-1015-y

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  • DOI: https://doi.org/10.1007/s12035-018-1015-y

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