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Molecular Neurobiology https://doi.org/10.1007/s12035-018-1015-y

Bacteroidetes 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 , B. fragilis secretes an unusually complex mixture of neurotoxins including the extremely pro-inflammatory 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 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 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 . . 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, , growth, and immunity against Orleans, LA 70112, USA foreign pathogens; in addition to these 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 (E. coli; phyla ): (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 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 , (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 (LPSs; BF-LPS, a remarkably abundant and pro-inflammatory glyco- see below and Fig. 1). Together, these neurotoxins may be , 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 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, , 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 (HFC) diets [7–9, 50, 60]. Overall, this sug- gests that sufficient dietary fiber may have a significant role Of the 54 general divisions of known bacteria, evolution has in regulating the abundance, complexity, and stoichiometry of selected just a few major groups—Bacteroidetes and certain microbial species resident in the GI tract microbiome, Proteobacteria for example—as major components of the including B. fragilis. Therefore, dietary fiber may have an Mol Neurobiol

Fig. 1 Association of LPS with the periphery of neuronal nuclei in the peptides and neuroinflammation have been shown to result in the activa- superior temporal lobe of AD neocortex. A LPS (red stain; λmax = tion of PARP enzymes and cell death [33–35]. The abundance of 690 nm) and DAPI (blue stain; λmax = 470 nm) show the relationship Bacteroidetes (and hence BF-LPS) in the human GI tract is regulated between LPS and nuclei in AD brain. B The addition of a neuron-specific by diet and dietary fiber intake. Highly pro-inflammatory GI tract- NeuN stain (green stain; λmax = 520 nm) shows the relationship between derived neurotoxins such as LPS must first cross two biophysical barriers LPS and neuronal nuclei. The sizes of all microscope fields in these two from the GI tract into the CNS; these include the GI tract barrier and the photos (A and B) are equal; for all panels magnification × 60, note that blood-brain barrier (BBB). The pathogenic effects of other B. fragilis LPS deposits Bbundled^ or in some cases Bcaged^ around the neuronal exudate such as endotoxins (such as fragilysin), amyloids, and nuclear periphery in a Bclathrin-like^ lattice or Bnet^ (yellow arrows in a). sncRNAs have not been studied in detail. They may be expected to exert LPS did not associate with astroglial nuclei to anywhere near the same additional, and possibly synergistic, detrimental effects to normal brain extent as neuronal nuclei (data not shown; 7–9). C Highly schematized cell homeostasis within the CNS including the support of pro- depiction of a microbiome-mediated and BF-LPS-driven pathogenic inflammatory neurodegeneration. Much of the support for these pathways pathway in inflammatory neurodegeneration. This pathogenic pathway comes from in vitro studies using human neuronal-glial (HNG) cell co- involves neurotoxic exudates of the microbiome (LPS, endotoxins, amy- cultures, Western immunoassay, and ELISA, DNA, microRNA loids, and/or sncRNA), stress-induced reactive oxygen and reactive nitro- (miRNA), and messenger RNA (mRNA) arrays, specific reactive oxygen gen species (ROS, RNS; see text), and modulated increases in NF-kB and nitrogen species (ROS, RNS), PARP and NF-kB inhibitors, anti- (p50/p65) driving Bpro-inflammatory^ microRNA signaling. Poly-ADP- miRNA blocking strategies, and bioinformatics analyses including ribose polymerases (PARPs) and other factors may also be involved in the miRNA-mRNA-linking algorithms [7–9, 22, 33–48]. regulation and intracellular trafficking of NF-kB. Interestingly, Aβ indirect effect on the abundance and profusion of the noxious an increasing bacterial pressure is essential to exclude an in- secretions of B. fragilis and hence its neurotoxic potential creasing bacterial load, in keeping GI tract-derived neuro- [7–9, 58–61, unpublished observations]. like LPS out of the portal and/or systemic circulation, and in minimizing LPS access to brain compartments. In fact, early GI tract or BBB dysfunction has been evidenced in AD Neurotoxins and Biophysical Barriers long before inflammatory neurodegeneration and cognitive impairment occur [7, 9, 63, 64]. Aging may further support As humans age, senescence of the GI tract and immune sys- the persistence and proliferation of anaerobic bacteria in the tem results in an increased bacterial burden as host-cell medi- oral cavity that elicits a robust systemic pathogenic response ated biophysical barriers become Bleaky^ and innate-immune mediated by pro-inflammatory cytokines such as responses progressively decline. Maintaining the fidelity and epithelium-derived (TNFα). TNFα rep- integrity of biophysical barriers—including, prominently, the resents a major pro-inflammatory involved in sys- GI tract barrier, and the blood-brain barrier (BBB)—against temic inflammation, and prolonged exposure to high levels Mol Neurobiol of circulating TNFα together with LPS further compromises exceptionally potent inducer of NF-kB [69–73]. The recent the integrity of the these important biophysical barriers of the discovery of inducible, chronically up-regulated, and NF-kB- GI tract and the brain [63–67]. controlled miRNAs in the human CNS and altered miRNA- In addition to their prodigious biosynthesis of the highly mRNA-coupled networks in sporadic AD brain has revealed an neurotoxic BF-LPS, B. fragilis exotoxins are a leading cause entirely new level of post-transcriptional gene control [73]. For of anaerobic bacteremia, sepsis, and systemic inflammatory instance, LPS induced up-regulation of miRNA-34a and distress through their export of the highly pro-inflammatory miRNA-146a and their down-regulated mRNA and gene ex- zinc metalloproteinase fragilysin, also known as B. fragilis pression targets that include SHANK3, TREM2, CFH, and or BFT [7–9, 14, 49, 52, 54, 62]. Interestingly, BFT TSPAN12 may be part of a much larger and dynamic has been shown to effectively disrupt epithelial cells of GI miRNA-mRNA-coupled signaling system operating in the spo- tract barriers via cleavage of E-cadherin, a radic AD brain [23, 26, 27, 72, 73, 77, 79](Fig.1). For exam- calcium-dependent transmembrane zonula adhesion protein ple, SHANK3 is a major multi-domain proline-rich scaffold and important structural component of the BBB [49, 66–68]. and synaptonuclear protein of the postsynaptic density that in- Currently, it is not well understood if GI tract- or terconnects and organizes neurotransmitter receptors, ion chan- BBB-disrupting proteolytic endotoxins such as BFT are able nels, and other membrane proteins to the actin cytoskeleton and to propagate their pathogenic activities via the systemic circu- G-protein-coupled signaling pathways; each of which are lation to further disrupt the GI tract barrier or BBB at distant known to be affected in sporadic AD tissues [39, 40, 77, 79]. sites, to ultimately transfer endotoxins, exotoxins, LPSs, am- The triggering receptor expressed in myeloid/microglia cells yloids, and/or sncRNAs into the systemic and cerebrovascular (TREM2) is a microglial membrane integral protein that forms circulation, to ultimately target brain cells within the CNS a receptor signaling complex with the tyrosine kinase-binding [69–75]. It has also recently been reported that along with protein (TYROBP); TREM2 deficits are observed in AD that BFT, amyloid peptide-dependent changes in synaptic adhe- associate with ineffective amyloid plaque removal while trig- sion and barrier function affect the structure, integrity and gering deficits in the normal activation of innate-immune re- function of synapses, suggesting that the observed failure of sponses [23, 41–43]. Similar deficits in complement factor H synaptic adhesion and barrier integrity in the AD brain play (CFH) further support abnormal innate-immune signaling, as is key roles in the progressive disruption of inter-neuronal sig- observed in AD [44], and deficits in the tetraspanin 12 naling throughout brain communication networks, itself a (TSPAN12) transmembrane protein leads to altered proteolysis pathological feature characteristic of AD brain [7, 9, 66, 68, of the beta-amyloid precursor protein (βAPP; by physically 76, 77]. interacting with the βAPP secretases) to yield more neurotoxic βAPP-derivatives [45, 46]. Interestingly, even though the exact cause of sporadic AD Lipopolysaccharide (LPS), Activation of NF-kB, remains elusive, and there are currently no effective treatments and Pro-Inflammatory microRNAs to stop or reverse the progression of this unique human and age-related neurological disorder, anti-NF-kB and/or LPS, the major component of the outer membrane of anti-miRNA strategies pose a realistically and readily avail- gram-negative bacteria, is localized to the outer layer of the able therapeutic approach for intervention of progressive de- bacterial and in non-capsulated strains is secreted from generative processes in the CNS, and as such may be highly the bacterial cell surface [32, 76, 77]. With a molecular mass of efficacious in the clinical management of sporadic AD. ~10–20 kDa, LPS is a highly immunogenic made up of three structural components: (i) a hydrophobic lipid section, , which is responsible for the toxic properties of the LPS and Association with Neuronal Nuclei ; (ii) a hydrophilic core chain; and (iii) a repeating hydrophilic O-antigenic oligosaccharide side Very recently, in immunohistological studies, LPS has been chain that is specific to the bacterial serotype. LPS and its observed to closely associate with the periphery of the nucleus hydrophobic lipid A moiety stimulate cells of the of neuronal cells in AD brain, and in some cases, LPS deposi- innate- by the Toll-like receptor 4 (TLR4) that tion (i) appears to be in a structured Bclathrin-like^ lattice for- recognizes common pathogen-associated molecular-patterns mat adjacent to neuronal nuclei (yellow arrows in Fig. 1A); and (PAMPs) and stimulates the production of reactive oxygen (ii) in some cases, completely envelops or ‘encapsulates’ nor- and nitrogen species (ROS, RNS) in human cells [78–80]. mally transcriptionally active AD nuclei [8, 9, 81](Fig.1A, B). (https://www.sigmaaldrich.com/technical-documents/articles/ Moreover, run-on transcription studies using the incorporation biology/glycobiology/lipopolysaccharides.html). ROS and of [α-32’P]-uridine triphosphate into newly synthesized total RNS are strong oxidizers of neuronal , proteins, and RNA further indicates that LPS is capable of significantly genetic materials (such as DNA and RNA) and both are an quenching the normally high output of genetic information Mol Neurobiol

(in the form of mRNA) from neuronal nuclei [7–9]. Taken cell-based BBB and the epithelial cell-based GI tract bar- together, these studies strongly suggest that in AD, LPS may riers during many decades of life may be more important impair the efficient read-out of neuronal genetic information than once thought [7, 8, 78, 79]. Virtually, nothing in normally required for the homeostatic operation of brain cell known about -derived microbiomes or their exudates, function, impairing the exit of mRNAs (but not the significant- plant microRNAs and viroids, natural sncRNAs, and cir- ly smaller miRNAs), and this may contribute to a progressive cular RNAs (circRNAs) widely distributed throughout the disruption in the read-out of genetic information from the plant and/or animal kingdoms which are ingested daily in a AD-affected CNS. typical human diet, and how they may contribute to the human microbiome in health and disease [7, 8, 36, 80, 81]. Unanswered Questions Many important and significant un- answered questions remain. Currently, microbiome and Concluding Remarks Well over 110 years since its original microbial genetics researchers have studied the description, AD is now the leading cause of intellectual im- molecular-genetics and LPS association of precisely just pairment and progressive dementia in our aging population, two of the ~ 1000 species of bacteria which make up the and represents a rapidly expanding socioeconomic and GI tract microbiome. While different LPS species appear to healthcare concern in Westernized societies [82, 83, 87]. have different potential for inducing the pro-inflammatory Few common, insidious, and lethal neurological disorders of transcription factor NF-kB (p50/p65 complex), and hence the aging human CNS present the neurologist and neurosci- the potential to induce pro-inflammatory miRNAs, it is ence researcher with the complexity and heterogeneity of spo- currently not well understood what might be the conse- radic AD. Susceptibility genes that have been identified for quence of a neurotoxic cocktail of endotoxins and exo- AD are involved in an exceptionally wide and varied range of toxins, microbial amyloids, sncRNAs, and LPS, which is basic neurobiological functions; however, their generalized a physiologically and pathologically more realistic scenar- down-regulation in expression appears to contribute to a com- io in the aging human brain [27, 73–75, 80–84]. plex mixture of altered synaptogenesis, deficits in Altogether, the ~ 1000 or so species of bacteria in the hu- neurotrophism and phagocytosis, increases inflammation man GI tract might be expected to secrete exceedingly and/or amyloidogenesis that together characterize the major complex mixtures of neurotoxins of many different types, pathological pathways of sporadic AD (Fig. 1C). Elucidation compositions, and toxicities and whose actions might well of the genetic, epigenetic, environmental, and life-style factors exhibit synergism in their neurotoxic potential, and their that contribute to the initiation, progression, and spreading of abilities to transverse normally protective physiological this chronic and fatal neurodegenerative disease mechanism barriers. For example, the co-incubation of Aβ42 peptide will ultimately result in improved and effective diagnostics with LPS potentiates Aβ42-peptide translocation, and intervention strategies. Indeed, the preliminary identifica- amyloidogenesis, and fibrillogenesis [61, 76, 77, 84–86]. tion and characterization of GI tract and its con- There are recent reports of general role for bacterial cell tribution to neurobiology have together greatly expanded our wall products in multiple amyloidopathies associated with perception, knowledge, and understanding of the complexity chronic and inflammatory diseases such as AD; to cite just and dynamics of the GI tract microbiome, the one example that both LPS and lipoteichoic acids potently microbial-mediated regulation of the neuronal transcriptome induce anomalous fibrillar amyloid formation and complex and pathogenic miRNA-mediated gene expression patterns in electrostatic interactions appear to be required to efficient- the human CNS [22, 36–38, 73, 84–86]. ly sequester amyloid folds with LPS at the bacterial mem- brane surface [47, 48]. Other factors such as Acknowledgements This work was presented in part at the Vavilov poly-ADP-ribose polymerases (PARPs) may also be in- Institute of General Genetics (VIGG) Autumn Seminar Series (Институт общей генетики имени Вавилова Осень 2017 Семинар volved in the regulation and intracellular trafficking of серии) in Moscow, Russia, October 2017, at the Society for NF-kB and amyloidogensis; interestingly, Aβ peptides Neuroscience (SFN) 47th Annual Meeting November 2017 in and neuroinflammation have been recently shown to result Washington DC, USA. Sincere thanks are extended to Drs. F Culicchia, in the activation of PARP enzymes and cell death [33–35]. C Eicken, C Hebel, and W Poon for short post-mortem interval (PMI) human brain tissues or extracts, DNA and miRNA array work, and initial (Fig. 1). Convincing evidence for the first bacterial prod- data interpretation, and to AI Pogue, D Guillot, Lin Cong, and J ucts such as LPS within CNS compartment appeared less Lockwood for expert technical assistance. Additional thanks are extended than 1 year ago, and studies on LPS and its association to the many physicians and neuropathologists of Canada, the USA, and with the periphery of the neuronal nuclei of AD brain, Russia who have provided high-quality and short post-mortem interval human brain and retinal tissues and GI tract extracts for scientific study. and its effects on inflammatory signaling in cultured hu- Additional human control and AD brain tissues were provided by the man brain cells and AD tissues appeared in the literature Memory Impairments and Neurological Disorders (MIND) Institute and just 4 months ago [7–9, 61]. 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