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ISSN: 1641-4640
Folia Neuropathologica
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vol. 57
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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
Yuhai Zhao
Wenhong Li
Walter J. Lukiw

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.

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

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