Molecular Neurobiology https://doi.org/10.1007/s12035-018-1015-y Bacteroidetes Neurotoxins and Inflammatory Neurodegeneration Yuhai Zhao1,2 & Walter J. Lukiw1,3,4 Received: 15 January 2018 /Accepted: 16 March 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract The gram-negative facultative anaerobe Bacteroides fragilis (B. fragilis) constitutes an appreciable proportion of the human gastrointestinal (GI)-tract microbiome. As is typical of most gram-negative bacilli, B. fragilis secretes an unusually complex mixture of neurotoxins including the extremely pro-inflammatory lipopolysaccharide BF-LPS. LPS (i) has recently been shown to associate with the periphery of neuronal nuclei in sporadic Alzheimer’s disease (AD) brain and (ii) promotes the generation of the inflammatory transcription factor NF-kB (p50/p65 complex) in human neuronal-glial cells in primary-culture. In turn, the NF-kB (p50/p65 complex) strongly induces the transcription of a small family of pro-inflammatory microRNAs (miRNAs) including miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155. These ultimately bind with the 3′-untranslated region (3′-UTR) of several target messenger RNAs (mRNAs) and thereby reduce their expression. Down-regulated mRNAs include those encoding complement factor-H (CFH), an SH3-proline-rich multi-domain-scaffolding protein of the postsynaptic density (SHANK3), and the triggering receptor expressed in myeloid/microglial cells (TREM2), as is observed in sporadic AD brain. Hence, a LPS normally confined to the GI tract is capable of driving a NF-kB-miRNA-mediated deficiency in gene expression that contributes to alterations in synaptic-architecture and synaptic-deficits, amyloidogenesis, innate-immune defects, and progressive inflammatory signaling, all of which are characteristics of AD-type neurodegeneration. This article will review the most recent research which supports the idea that bacterial components of the GI tract microbiome such as BF-LPS can transverse biophysical barriers and contribute to AD-type change. For the first-time, these results indicate that specific GI tract microbiome-derived neurotoxins have a strong pathogenic role in eliciting alterations in NF-kB-miRNA-directed gene expres- sion that drives the AD process. Keywords Alzheimer’sdisease. Amyloidogenesis . Bacteroides fragilis . Lipopolysaccharide . Messenger RNA . microRNA . Microbiome . Neuroinflammation . Phagocytosis . Synaptogenesis Abbreviations LPS Lipopolysaccharide AD Alzheimer’sdisease BF-LPS Bacteroides fragilis lipopolysaccharide B. fragilis Bacteroides fragilis mRNA Messenger RNA miRNA microRNA * Walter J. Lukiw [email protected] Overview The human gastrointestinal (GI) tract, containing about 98% of our entire microbiome, harbors a genetically 1 LSU Neuroscience Center, Louisiana State University Health diverse microbial population that plays major roles in diges- Sciences Center, 2020 Gravier Street, Suite 904, New tion, nutrition, inflammation, growth, and immunity against Orleans, LA 70112, USA foreign pathogens; in addition to these bacteria are microbial 2 Department of Cell Biology and Anatomy, Louisiana State eukaryotes, archaea, fungi, protozoa, viruses, and other com- University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA 70112, USA mensal microorganisms which make up 2% or less of the remaining microbiota. Several excellent and comprehensive 3 Department of Neurology, Louisiana State University Health reviews have recently appeared [1–9]. The largest proportion Sciences Center, 2020 Gravier Street, Suite 904, New 14 Orleans, LA 70112, USA of the human GI tract microbiome (i) consists of ~ 10 bac- 3 4 Departments of Ophthalmology, Louisiana State University Health teria from at least ~ 10 distinct bacterial species that form a Sciences Center, 2020 Gravier Street, Suite 904, New complex, dynamic, and highly interactive microbial commu- Orleans, LA 70112, USA nity [7–11]; (ii) exhibits significant variations in abundance, Mol Neurobiol stoichiometry, and aerobic requirements along the ~ 10-m human GI tract microbiome. Of these, the Bacteroidetes mem- length of the GI tract [11–17]; (iii) has symbiotic associations ber B. fragilis (phyla Bacteroidetes) and the facultative anaer- and interactions with the host indispensable for human health obe Escherichia coli (E. coli; phyla Proteobacteria): (i) togeth- and homeostatic physiological functions [17–21]; and (iv) ex- er constitute about ~ 30–40% of all bacteria within the GI tract hibits alterations in abundance, speciation, and complexity in microbiome [32, 49]; (ii) constitute about ~ 30–50% of the dry response to developmental stage, dietary factors, GI tract dis- weight of human fecal matter [49, 50]; (iii) are normally the turbances, aging, and disease [6, 21–26]. most abundant gram-negative bacilli, respectively, of the mid- Our acknowledgment that the human microbiome is a sig- dle and lower colon of the human GI tract [32, 50, 51]; (iv) nificant contributor to human health, disease is a relatively under optimal bacterial growth conditions B. fragilis or E. coli recent one, and direct experimental evidence linking microbial abundance doubles every 20 min [32]; and (v) unless special activities and secretory products to the development of human biophysical processes of growth dynamics that are in opera- neurological diseases of the central nervous system (CNS) are tion, such as dormancy or hibernation, have a life span of up to surprisingly few. Only very recently has investigational evi- several hundred minutes [51–53]. Hence, large amounts of B. dence been provided that microbial nucleic acids and/or the fragilis-orE. coli-generated neurotoxins can be generated highly toxic exudates of human GI tract resident anaerobic quite rapidly. Obligate anaerobes such as B. fragilis display gram-negative bacteria such as LPS (i) are abundant in CNS remarkably diverse antibiotic resistance mechanisms and dis- compartments in age-related neurodegenerative diseases such play one of the highest resistance-to-antibiotics of any anaer- as sporadic AD [7–10]; (ii) are capable of inducing an inflam- obic pathogen [54–56]. When compartmentalized within the matory signaling program in human neuronal-glial (HNG) GI tract microbiome B. fragilis is known to be generally ben- cells in primary co-culture [8, 9, 24]; and (iii) contribute to eficial to human health through their ability to break down the activation of the pro-inflammatory transcription factor dietary fiber containing substances such as cellulose, lignin, NF-kB (p50/p65) complex [9, 27, 28]. LPSs appear to be and pectin that are normally resistant to the action of directly involved in the up-regulation of a small family of host-encoded degradative enzymes. These dietary fibers are NF-kB sensitive microRNAs (miRNAs) that down regulate further broken down into digestible short-chain fatty acids their messenger RNA (mRNA) targets to contribute to inflam- (SCFAs) such as acetate, propionate and butyrate, polysaccha- matory signaling and neuropathological change within the rides, and volatile fatty acids in part through the biosynthetic CNS. This paper is a current overview of what we currently and enzymatic capabilities of this GI tract-abundant microbe know concerning the contribution of the human GI tract [57–60]. However, under stressful or sub-optimal growth con- microbiome-resident gram-negative facultative anaerobe ditions B. fragilis can release an unusually complex, neuro- Bacteroides fragilis (B. fragilis) to human neurological dis- toxic array of components of four major classes: (i) endotoxins ease, with specific emphasis on AD wherever possible. and exotoxins, (ii) microbial amyloids, (iii) small Based on these emerging data and evolving perspectives our microRNA-like non-coding RNAs (sncRNAs), and (iv) overall hypothesis is that neurotoxic exudates such as lipooligosaccharides (LOSs) and lipopolysaccharides (LPSs; BF-LPS, a remarkably abundant and pro-inflammatory glyco- see below and Fig. 1). Together, these neurotoxins may be lipid, and perhaps the most pro-inflammatory LPS known, is released acutely and rapidly, or chronically, such as over the capable of triggering systemic inflammation and the release of course of aging. When B. fragilis or their highly toxic secre- pro-inflammatory cytokines after translocation across the GI tions escape the microorganism-dense environment of the GI tract into systemic circulation [28–32]. This specific LPS rep- tract (~ 1011 microbes/g of fecal matter), they can induce sub- resents an important pathogenic initiator component of a stantial systemic inflammatory pathology with significant BF-LPS initiated NF-kB-miRNA-mRNA signaling program morbidity and mortality [59–64]. Interestingly, enterotoxigen- that has potential to down regulate specific gene expression ic strains of B. fragilis have been associated with bacteremia, known to be required for normal CNS homeostasis, and hence colitis, diarrhea, sepsis, systemic infection, systemic inflam- contribute progressively to AD-type neurodegenerative mation, the development of GI tract cancers and neurological change (Fig. 1). disorders including AD, and those neurological conditions that have significantly increased incidence with aberrant de- velopmental programming and aging [57–59]. Indeed several Bacteroidetes species have also been recently shown to prop- Neurotoxic Pro-Inflammatory Exudates agate in dietary fiber-deprived animal models fed high from B. fragilis fat-cholesterol