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Bacteroides fragilis Lipopolysaccharide and Inflammatory Signaling in Alzheimer's Disease

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Bacteroides fragilis Lipopolysaccharide and Inflammatory Signaling in Alzheimer's Disease

Walter J Lukiw. Front Microbiol.

Abstract

The human microbiome consists of ~3.8 × 1013 symbiotic microorganisms that form a highly complex and dynamic ecosystem: the gastrointestinal (GI) tract constitutes the largest repository of the human microbiome by far, and its impact on human neurological health and disease is becoming increasingly appreciated. Bacteroidetes, the largest phylum of Gram-negative bacteria in the GI tract microbiome, while generally beneficial to the host when confined to the GI tract, have potential to secrete a remarkably complex array of pro-inflammatory neurotoxins that include surface lipopolysaccharides (LPSs) and toxic proteolytic peptides. The deleterious effects of these bacterial exudates appear to become more important as GI tract and blood-brain barriers alter or increase their permeability with aging and disease. For example, presence of the unique LPSs of the abundant Bacteroidetes species Bacteroides fragilis (BF-LPS) in the serum represents a major contributing factor to systemic inflammation. BF-LPS is further recognized by TLR2, TLR4, and/or CD14 microglial cell receptors as are the pro-inflammatory 42 amino acid amyloid-beta (Aβ42) peptides that characterize Alzheimer's disease (AD) brain. Here we provide the first evidence that BF-LPS exposure to human primary brain cells is an exceptionally potent inducer of the pro-inflammatory transcription factor NF-kB (p50/p65) complex, a known trigger in the expression of pathogenic pathways involved in inflammatory neurodegeneration. This 'Perspectives communication' will in addition highlight work from recent studies that advance novel and emerging concepts on the potential contribution of microbiome-generated factors, such as BF-LPS, in driving pro-inflammatory degenerative neuropathology in the AD brain.

Keywords: 42 amino acid amyloid-beta (Aβ42) peptides; Alzheimer’s disease; DAMPs and PAMPs; NF-kB; bacteroidetes; lipopolysaccharides; microbiome; systemic inflammation.

Figures

FIGURE 1
FIGURE 1
Relative induction of NF-kB (p50/p65)-DNA binding in pro-inflammatory factor and lipopolysaccharides (LPS)-treated primary human neuronal-glial (HNG) co-cultures. (A) HNG cells in primary co-culture for 1.5 weeks; HNG cells were stained with a neuron-specific β-tubulin III (red fluorescence λ max~650 nm; anti-βTUBIII antibody, Sigma-Aldrich, St Louis, MO, USA); an antibody against glial fibrillary acidic protein (GFAP; green fluorescence; λ max ~510 nm; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and DAPI nuclear stain (blue fluorescence; λ max~470 nm; Thermo Fisher Scientific, Waltham, MA, USA); 20×; (B) induction of the pro-inflammatory transcription factor NF-kB (p50/p65 activation complex) by various physiologically relevant, pro-inflammatory factors all at equal dosage (25 nM); NF-kB abundance was measured by NF-kB-DNA binding assay (a measure of NF-kB activation and binding to NF-kB-DNA recognition sequences) onto a 36 nucleotide end-labeled double stranded DNA fragment containing the canonical human NF-kB (p50/p65) recognition sequence 5′-GGGGACTTTCCC-3′ as previously described (Lukiw and Bazan, 1998; Lukiw et al., 2008; Devier et al., 2015; Clement et al., 2016); a scrambled control nucleotide containing no such NF-kB recognition sequence showed NF-kB-DNA binding activity (data not shown); (C) data from gel bands in panel (B) quantified in bar graph format; note robust induction of the NF-kB (p50/p65 complex) by Escherichia coli lipopolysaccharide (EC-LPS; LPS from Escherichia coli 0111:B4; Sigma L3012, St Louis, MO, USA) or B. fragilis lipopolysaccharide (BF-LPS; prepared by methods previously published; Eidhin and Mouton, 1993) that was ~45- to ~55-fold higher than that of the control human serum albumen (HSA) protein, and was fivefold to sevenfold higher than the combination of the pro-inflammatory Aβ42 peptide and IL-1β together (at 25 nM each); complex mixtures of microbiome bacterial LPS on NF-kB induction might be expected to be additive or synergistic; HSA = (control) human serum albumen; CFH = complement factor H; TNFα = tumor necrosis factor alpha (cachectin); IL-1β = interleukin 1-beta; Aβ40, Aβ42 = amyloid beta peptide, 40 and 42 amino acids in length; EC-LPS, BF-LPS = E. coli, Bacteroides fragilis lipopolysaccharide; error bars represent one standard error of the mean; N = 4; *p < 0.05; **p < 0.01; ***p < 0.001, ANOVA.

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