Current State of Gut Microbiota: Where We Have Been, Where We Are Going
Giulio Maria Pasinetti, MD, PhD
Research in the gut microbiota field has been rapidly evolving over the past decade. Despite being confined to the gastrointestinal tract, the impact of the gut microbiota biology on human physiology is extremely broad. The gut microbiota itself forms a powerful endocrine organ with a unique metabolome that supplements the host’s biochemistry beyond what it is designed to provide for itself: a perfect symbiotic relationship! These metabolites, and the breadth of gut microbiota cells themselves, interact with, and/or transverse the protective gut epithelial barrier influencing several physiological systems including the immune system, metabolism, neurological signaling and perhaps the most unexpectedly, the brain, giving rise to the gut-brain-axis [1,2].
While microbiota is referred as all the microorganisms found in an environment, including bacteria or viruses, microbiome is here referred as the collection of genomes of the microorganisms found in a particular environment (i.e., gut or oral microbiota). In addition to the intrinsic heterogeneity in microbiota composition among each person, microbiome diversity also plays a major factor in microbiota heterogeneity. Indeed, microbiota and the microbiome in the gut can be radically different than oral, skin, eye, etc. Based on this, we believe this Handbook collection fully addresses the complex role of the microbiota and its microbiome heterogeneity and will bring to discussion novel approaches in Alzheimer’s disease (AD) leveraging, for example, the intervention of prebiotic, probiotic, and synbiotic supplementations. In this regard, we have chosen to discuss the influence of the gut and oral microbiota on the immune inflammatory signals including cytokines, neuroendocrine hormones, bacterial components, neuroactive molecules, or microbial metabolites among others. Given that the microbiome is a critical and often overlooked aspect of innate immunity, and which plays a role in cognition, the overarching goal of this Handbook is to review and summarize recent and current research of microbiota and microbiome and the far-reaching impacts on cognitive functioning and neurodegeneration, possibly through mechanisms involving immune inflammatory mechanisms. Interventions including probiotic supplementation, fecal microbiota transfer, and supplementation with microbial metabolites are also discussed. We want to point out that certain probiotics have been used not only to study the effects that the gut microbiota has on behavior and cognitive function, but also as potential therapeutics for AD.
Traditionally, the gut microbiota and its impact on biology were studied using surveillant and correlative techniques. The composition of the gut microbiota would be determined in the context of a disease state and related to a selection of biological markers such as cytokines, gene expression, or a behavioral output. Causality would be established by using germ-free mice or strong antibiotic treatment where the absence of a gut microbiota would create behavioral or biochemical changes [3,4]. While these seminal studies were absolutely essential to drive our current understanding of the breadth of the gut microbiota’s action through the host’s physiology, research moving forward must expand and become more sophisticated to address causal mechanisms and direct interactions such that the gut microbiota can be leveraged upon to develop useful therapeutic interventions.
This is especially true with studies of the gut-brain-axis. Current research seems to have reached a standstill with the climate focusing on behavioral correlations and general influences of the broad environmental changes of the gut microbiota. Studies using fecal transplants surmise that pathological neurological changes can be transferred into naive mice with a fecal transplant  and could even be used as a therapeutic intervention for Parkinson’s disease . But the questions remain regarding how and why this works? One study by Bravo et al. eloquently showed that Lactobacillus rhamnosus can innervate the vagus nerve to influence emotional behavioral and GABA expression , which demonstrates that causal mechanisms exist—we just need to find them.
Translational research from mice to humans also forms a barrier to pushing the boundaries of gut microbiota research, which requires the creativity and innovation of the current generation of researchers. Studying artificial systems like heavy antibiotic treatment and germ-free animals does not have translatable potential to human studies as these are artificial environments. Studies understanding the causality of the gut microbiota need to use current tools but must also evolve to develop new tools to gain insight into the causal mechanisms linking the gut microbiota and its metabolome to human disease. Especially for studies of probiotic, prebiotic, or synbiotic interventions, translation to human utility requires pharmacokinetic understanding of metabolite production and the dissection of common molecular pathways.
Collectively, this Handbook contains four broad sections, each covering a pertinent research area pertaining to the overall literature on the gut-brain-axis and its relationship with cognitive functioning and AD. We hope that future research will be able to cohesively build upon the current foundation of rigorous studies by developing innovative and novel approaches that will progress our understanding of these complex, multi-variable biological mechanisms, particularly in the context of cognitive functioning and AD.
 Westfall S, Pasinetti GM (2019) The gut microbiota links dietary polyphenols with management of psychiatric mood disorders. Front Neurosci 13, 1196.
 Westfall S, Iqbal U, Sebastian M, Pasinetti GM (2019) Gut microbiota mediated allostasis prevents stress-induced neuroinflammatory risk factors of Alzheimer’s disease. Prog Mol Biol Transl Sci 168, 147-181.
 Neufeld KM, Kang N, Bienenstock J, Foster JA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23, 255-264, e119.
 Luczynski P, McVey Neufeld KA, Oriach CS, Clarke G, Dinan TG, Cryan JF (2016) Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol 19, pyw020.
 Li N, Wang Q, Wang Y, Sun A, Lin Y, Jin Y, Li X (2019) Fecal microbiota transplantation from chronic unpredictable mild stress mice donors affects anxiety-like and depression-like behavior in recipient mice via the gut microbiota-inflammation-brain axis. Stress 22, 592-602.
 Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q, Cui C, Shen YQ (2018) Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: Gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav Immun 70, 48-60.
 Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF (2011) Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 108, 16050-16055.