Abstract
Since the inception of the human microbiome project (HMP) by the US National Institutes of Health (NIH) in 2007 there has been a keen resurgence in our recognition of the human microbiome and its contribution to development, immunity, neurophysiology, metabolic and nutritive support to central nervous system (CNS) health and disease. What is not generally appreciated is that (i) the ~1014 microbial cells that comprise the human microbiome outnumber human host cells by approximately one hundred-to-one; (ii) together the microbial genes of the microbiome outnumber human host genes by about one hundred-and-fifty to one; (iii) collectively these microbes constitute the largest ‘diffuse organ system’ in the human body, more metabolically active than the liver; strongly influencing host nutritive-, innate-immune, neuroinflammatory-, neuromodulatory- and neurotransmission-functions; and (iv) that these microbes actively secrete highly complex, immunogenic mixtures of lipopolysaccharide (LPS) and amyloid from their outer membranes into their immediate environment. While secreted LPS and amyloids are generally quite soluble as monomers over time they form into highly insoluble fibrous protein aggregates that are implicated in the progressive degenerative neuropathology of several common, age-related disorders of the human CNS including Alzheimer’s disease (AD). This general commentary-perspective paper will highlight some recent findings on microbial-derived secreted LPS and amyloids and the potential contribution of these neurotoxic and proinflammatory microbial exudates to age-related inflammatory amyloidogenesis and neurodegeneration, with specific reference to AD wherever possible.
Highlights
Humans contain a complex and dynamic community of microbes called ‘the microbiome’ that forms a ‘metaorganism’ with commensal or symbiotic benefit to the host [1,2,3,4,5,6,7]
(i) microbial cells outnumber human host cells by about one hundred-to-one and microbial genes collectively outnumber human genes by about one hundred-and-fifty-to-one [2,3,4,11,12]; (ii) the vast majority of GI tract microbiota are anaerobic or facultative anaerobic bacteria, with fungi, protozoa, archaebacteria and other microorganisms making up the remainder [2,3,4,5]; (iii) of all mammalian species human GI tract microbiota with bacterial densities of up to 1012 per ml are the highest recorded density of any known microbial ecosystem [3,4,5]; and (iv) only two bacterial divisions are prominent in GI tract microbiota, and these include the Gram-positive Firmicutes (~51%) and anaerobic Gram-negative Bacteroidetes (~48%)
Recent literature has provided evidence that LPS is involved in the inflammatory and pathological processes associated with Aβ peptide-mediated amyloidosis characteristic of Alzheimer’s disease (AD). For example it has been demonstrated just this year: (i) that the chronic infusion of LPS into the fourth ventricle of rats reproduces many of the inflammatory and pathological features seen in the AD suggesting that bacterial LPS potentiates the fibrillogenesis of Aβ peptides [24]; (ii) that LPS-induced neuroinflammation is associated with AD-type amyloidogenic axonal pathology and dendritic degeneration in rodent models of AD [59]; and (iii) that the glycosylphosphatidyl-inositol-anchored LPS and ‘microbedetecting receptor cluster of differentiation innate-immune protein 14 (CD14), crucial in the neutralization of invading microbes, is stimulated by Aβ fibrils further linking innate-immune signaling with AD amyloidogenesis [60,64]
Summary
Humans contain a complex and dynamic community of microbes called ‘the microbiome’ that forms a ‘metaorganism’ with commensal or symbiotic benefit to the host [1,2,3,4,5,6,7]. (i) Aβ42 peptides as monomers, dimers and fibrils induce patterns of inflammatory gene expression typical of the classical innate-immune and inflammatory response induced by infectious agents such as bacterial LPS, a common endotoxin of the outer membrane of gram-negative bacteria [49,52; see below]; (ii) the presence of bacterial LPS or endotoxinmediated inflammation strongly contributes to amyloid neurotoxicity [19,24,25,26,27,32,42,50,51,52,53,54,55]; and (iii) AD amyloids, like prion amyloids, once formed, may induce a selfperpetuating process leading to amplification, aggregation and spreading of pathological protein assemblies, and serial propagation of distinct strains of Aβ prion-like amyloids from AD patients have been recently observed [56,57]. The contribution of LPS to the serial transmissibility of certain amyloidogenic Aβ peptides and their aggregates is currently not well understood, it has recently been shown that Aβ peptide fibrillogenesis is strongly potentiated by soluble bacterial endotoxins, suggesting the contribution of infectious events and/or microbial-released factors to the pathogenesis of AD [24,54,57]
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