Gastrointestinal (GI)-Tract Microbiome Derived Neurotoxins and their Potential Contribution to Inflammatory Neurodegeneration in Alzheimer's Disease (AD).

The human gastrointestinal (GI)-tract microbiome is a rich, complex and dynamic source of microorganisms that possess a staggering diversity and complexity. Importantly there is a significant variability in microbial complexity even amongst healthy individuals-this has made it difficult to link specific microbial abundance patterns with age-related neurological disease. GI-tract commensal microorganisms are generally beneficial to human metabolism and immunity, however enterotoxigenic forms of microbes possess significant potential to secrete what are amongst the most neurotoxic and pro-inflammatory biopolymers known. These include toxic glycolipids such as lipopolysaccharide (LPS), enterotoxins, microbial-derived amyloids and small non-coding RNA. One major microbial species of the GI-tract microbiome, about ~100-fold more abundant than Escherichia coli in deep GI-tract regions is Bacteroides fragilis, an anaerobic, rod-shaped Gram-negative bacterium. B. fragilis can secrete: (i) a particularly potent, pro-inflammatory and unique LPS subtype (BF-LPS); and (ii) a zinc-metalloproteinase known as B. fragilis-toxin (BFT) or fragilysin. Ongoing studies indicate that BF-LPS and/or BFT disrupt paracellular-and transcellular-barriers by cleavage of intercellular-proteins resulting in 'leaky' barriers. These barriers: (i) become defective and more penetrable with aging and disease; and (ii) permit entry of microbiome-derived neurotoxins into the systemic-circulation from which they next transit the blood-brain barrier and gain access to the CNS. Here LPS accumulates and significantly alters homeostatic patterns of gene expression. The affinity of LPS for neuronal nuclei is significantly enhanced in the presence of amyloid beta 42 (Aβ42) peptides. Recent research on the appearance of the brain thanatomicrobiome at the time of death and the increasing likelihood of a complex brain microbiome are reviewed and discussed. This paper will also highlight some recent advances in this extraordinary research area that links the pro-inflammatory exudates of the GI-tract microbiome with innate-immune disturbances and inflammatory-signaling within the CNS with reference to Alzheimer's disease (AD) wherever possible.