Gastrointestinal (GI) Tract Microbiome-Derived Neurotoxins—Potent Neuro-Inflammatory Signals From the GI Tract via the Systemic Circulation Into the Brain

The microbiome of the human gastrointestinal (GI)-tract is a rich and dynamic source of microorganisms that together possess a staggering complexity and diversity. Collectively these microbes are capable of secreting what are amongst the most neurotoxic and pro-inflammatory biopolymers known. These include lipopolysaccharide (LPS), enterotoxins, microbial-derived amyloids and small non-coding RNA (sncRNA). One of the major microbial species in the human GI-tract microbiome, about ~100-fold more abundant than Escherichia coli, is Bacteroides fragilis, an anaerobic, rod-shaped Gram-negative bacterium that secretes: (i) a particularly potent, pro-inflammatory LPS glycolipid subtype (BF-LPS); and (ii) a hydrolytic, extracellular zinc metalloproteinase known as B. fragilis toxin (BFT) or fragilysin. Ongoing studies support multiple observations that BF-LPS and BFT (fragilysin) disrupt paracellular barriers by cleavage of intercellular proteins, such as E-cadherin, between epithelial cells, resulting in ‘leaky’ barriers. These defective barriers, which also become more penetrable with age, in turn permit entry of microbiome-derived neurotoxic biopolymers into the systemic circulation from which they can next transit the blood-brain barrier (BBB) and gain access into the brain. This short communication will 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 human central nervous system (CNS) with reference to Alzheimer's disease (AD) wherever possible.