eISSN: 1509-572x
ISSN: 1641-4640
Folia Neuropathologica
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3/2019
vol. 57
 
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abstract:
Review paper

Lipopolysaccharide-stimulated, NF-kB-, miRNA-146a- and miRNA-155-mediated molecular-genetic communication between the human gastrointestinal tract microbiome and the brain

Peter N. Alexandrov
1
,
Yuhai Zhao
2, 3
,
Wenhong Li
2, 4
,
Walter J. Lukiw
2, 5, 6

  1. Russian Academy of Medical Sciences, Moscow, Russian Federation
  2. LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
  3. Department of Anatomy and Cell Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
  4. Department of Pharmacology, School of Pharmacy, Jiangxi University of TCM, Nanchang, Jiangxi, China
  5. Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
  6. Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
Folia Neuropathol 2019; 57 (3): 211-219
Online publish date: 2019/09/30
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Through the use of RNA sequencing, microRNA (miRNA) and messenger RNA (mRNA) microfluidic array analysis, LED Northern, Western and ELISA analysis and multiple bioinformatics algorithms we have discovered a novel route for pathogenic communication between the human gastrointestinal (GI)-tract microbiome and the brain. The evidence suggests that this pathogenic gut-brain circuit involves: (i) lipopolysaccharide (LPS) from the GI-tract resident enterotoxigenic Gram-negative bacteria Bacteroides fragilis (BF-LPS); (ii) LPS transit across the GI-tract barrier into the systemic circulation; (iii) transport of a highly pro-inflammatory systemic BF-LPS across the blood-brain barrier (BBB) into the brain-parenchyma and neuronal-cytoplasm; (iv) activation and signaling via the pro-inflammatory NF-kB (p50/p65) transcription-factor complex; (v) NF-kB-coupling and significant up-regulation of the inducible pro-inflammatory microRNA-146a (miRNA-146a) and microRNA-155 (miRNA-155); each containing multiple NF-kB DNA-binding and activation sites in their immediate promoters; and (vi) subsequent down-regulation of miRNA-146a-miRNA-155 regulated mRNA targets such as that encoding complement factor H (CFH), a soluble complement control glycoprotein and key repressor of the innate-immune response. Down-regulated CFH expression activates the complement-system, the major non-cellular component of the innate-immune system while propagating neuro-inflammation. Other GI-tract microbes and their highly complex pro-inflammatory exudates may contribute to this pathogenic GI-tract-brain pathway. We speculate that it may be significant that the first Gram-negative anaerobic bacterial species intensively studied as a potential contributor to the onset of Alzheimer’s disease (AD), that being the bacillus Bacteroides fragilis appears to utilize damaged or leaky physiological barriers and an activated NF-kB (p50-p65) – pro-inflammatory miRNA-146a-miRNA-155 signaling circuit to convey microbiome-derived pathogenic signals into the brain.
keywords:

Alzheimer’s disease, Bacteroides fragilis (B fragilis), complement factor H (CFH), dysbiosis, microRNA-146a, microRNA-155, NF-kB (p50/p65)

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