Alzheimer's disease and the microbiome

The recognition of the human microbiome (HM) as a substantial contributor to nutrition, health and disease is a relatively recent one, and currently, peerreviewed studies linking alterations in microbiota to the etiopathology of human disease are few. Emerging studies indicate that the HM may contribute to the regulation of multiple neuro-chemical and neuro-metabolic pathways through a complex series of highly interactive and symbiotic host-microbiome signaling systems that mechanistically interconnect the gastrointestinal (GI) tract, skin, liver, and other organs with the central nervous system (CNS). For example, the human GI tract, containing 95% of the HM, harbors a genetically diverse microbial population that plays major roles in nutrition, digestion, neurotrophism, inflammation, growth, immunity and protection against foreign pathogens (Forsythe et al., 2012; Collins et al., 2013; Douglas-Escobar et al., 2013; see below). It has been estimated that about 100 trillion bacteria from up to 1000 distinct bacterial species co-inhabit the human GI tract, albeit in different stoichiometries amongst individuals, and the varying combinations and strains of bacterial species amongst human populations might contribute, in part, to “humanbiochemical” or “genetic-individuality” and resistance to disease (Aziz et al., 2013; Lukiw, 2013). Interestingly, HM participation in human physiology may also help explain the genome-complexity conundrum—for example why the 26,600 protein-encoding transcripts in Homo sapiens are far fewer in number, than for example, the rice genome (Oryza sativa; which has about 46,000 functional genes). One thousand different strains of bacteria might be expected to contribute up to 4 × 106 potential mRNAs to the human transcriptome, thus making the human host-plus-microbiome genetic complexity closer to 4,026,600 mRNA transcripts, and a clear “winner” of human genetic complexity over that of rice and other species (Venter et al., 2001; Foster and McVey Neufeld, 2013; Lukiw, 2013). The very recent observation of microbiomederived small non-coding RNA (sncRNA) and micro RNA (miRNA) translocation and signaling across endothelial barriers, between cells and tissues, and even perhaps between individual species indicates that human neurobiology may be significantly impacted by the actions of HMmediated sncRNA or miRNA trafficking, and the integration of a cell, tissue or an entire organism into its local environment (Zhao et al., 2006; Alexandrov et al., 2012; Sarkies and Miska, 2013; Reijerkerk et al., 2013; unpublished). This opinion paper encompasses what we know concerning the contribution of the HM to neurological disease, with specific emphasis on Alzheimer’s disease (AD) wherever possible. Firstly, the microbiome of the human GI tract is the largest reservoir of microbes in the body, containing about 1014 microorganisms; over 99% of microbiota in the gut are anaerobic bacteria, with fungi, protozoa, archaebacteria and other microorganismsmaking up the remainder. There is currently an expanding interest in the ability of intestinal bacteria to influence neuro-immune functions well beyond the GI tract. Since mitochondria are believed to originate from bacteria via endosymbiotic relationships that formed very early in the evolutionary history of eukaryotes, cross-reactivity of mitochondria and immunological responses to intestinal bacterial constituents could have deleterious effects on mitochondrial function through some form of molecular mimicry; this is partially evidenced by the inflammatory basal ganglia disorder Sydenham’s chorea, rheumatic fever and the link to the facultative anaerobe Streptococcus (Carrasco-Pozo et al., 2012; Douglas-Escobar et al., 2013; Hayashi, 2013; Hornig, 2013 see below). Established pathways of GI-CNS communication currently include the autonomic nervous system (ANS), the enteric nervous system (ENS), the neuroendocrine system, and the immune system (Camfield et al., 2011; Heijtz et al., 2011; Forsythe et al., 2012; Aziz et al., 2013; Collins et al., 2013; Foster and McVey Neufeld, 2013; Schwartz and Boles, 2013). Stress further influences the composition of the HM, and reciprocal communication between the CNS and the HM also influences stress reactivity (Forsythe et al., 2012; Foster and McVey Neufeld, 2013). Surprisingly, neuronal signaling pathways along the bidirectional GI-CNS axis remain poorly understood despite their important roles: (i) in coordinating metabolicand nutritivefunctions, and (ii) in their functional disruption in chronic diseases such as metabolic syndrome, diabetes, obesity, anxiety, autoimmune-disease and stressinduced neuropsychiatric disease (Lukiw and Bazan, 2006; Bravo et al., 2012; Foster and McVey Neufeld, 2013; Hornig, 2013; Udit and Gautron, 2013). Studies of the ENS in “germ-free” mice, i.e., those