Abstract:

Gram-negative obligate anaerobic bacteria of the human GI-tract-microbiome and their immunogenic secretory products have significant potential to serve as a dynamic, life-long source of extremely potent pro-inflammatory enterotoxigenic compounds highly toxic to the central nervous system (CNS). These microbes and their secreted products: (i) are capable of generating a broad-spectrum of highly neurotoxic, pro-inflammatory and potentially pathogenic molecules; and (ii) these include a highly immunogenic class of amphipathic surface glycolipids known as lipopolysaccharide (LPS). Bacteroides fragilis (B. fragilis), a commensal, Gram negative, non-motile, non-spore forming obligatory anaerobic bacillus, and one of the most abundant bacteria found in the human GI tract, produces a particularly pro-inflammatory and neurotoxic LPS (Bf-LPS). Bf-LPS: (i) is secreted from the B. fragilis outer membrane into the external-medium; (ii) can damage biophysiological barriers via cleavage of zonula adherens cell-cell adhesion proteins, thereby disrupting both the GI-tract barrier and the blood-brain barrier (BBB); (iii) is able to transit GI-tract barriers into the systemic circulation and cross the BBB into the human CNS; and (iv) accumulates within CNS neurons in neurodegenerative disorders such as Alzheimer’s disease (AD). Some of these inflammatory signaling events appear to be mediated by the brain-enriched pro-inflammatory microRNA-146a. This presentation will provide evidence that the incubation of B. fragilis with aluminum sulfate [Al2(SO4)3] is a potent inducer of Bf-LPS. The results suggest for the first time that the pro-inflammatory properties of aluminum may not only be propagated by aluminum itself, but by a stimulation in the production of microbiome-derived Bf-LPS and other pro-inflammatory pathogenic microbial products normally secreted from human GI-tract-resident microorganisms.

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