Microbiota and the gut-brain-axis: Implications for new therapeutic design in the CNS

Abstract

The recent revelation that the gut microbiome, home to approximately 100 trillion microorganisms, is implicated in the development of both health and disease has spurred an exponential increase in interdisciplinary research involving gut microbiology. In all this hype, there is a need to better understand and contextualize the emerging evidence for the role of the gut microbiota in neurodegenerative and neurodevelopmental diseases, including central nervous system (CNS) malignancies. In this review, we aim to unravel the complex interactions of the microbiota-gut-brain-axis to pave a better understanding of microbiota-mediated pathogenesis, avenues for noninvasive prognosis, and therapeutic possibilities leveraging microbiota-gut-brain-axis modulations. We further provide insights of the ongoing transition from bench to bedside and discuss limitations of current approaches. Ultimately, we urge the continued development of synergistic therapeutic models with considerable consideration of the many gut-resident bacteria that will enable significant progress for the treatment of many neurological diseases.

Keywords: CNS diseases; Glioblastoma; Gut microbiome; Gut-brain-axis; Therapy.

Figure 1

The microbiota-gut-brain axis. The bidirectional communication between the brain and gut microbiota is mediated by several pathways including the immune system, neuroendocrine system, enteric nervous system (ENS), circulatory system, and vagus nerve. The routes of these pathways contain various neuroactive compounds including microbial-derived metabolites, microbial-derived products, peptides, gut hormones, and neuroactive substances. Upon entering the brain, metabolites can subsequently influence neurodevelopment and neurodegeneration of numerous conditions, such as multiple sclerosis, Parkinson's Disease, Alzheimer's Disease, CNS malignancies, stroke, autism spectrum disorder, depression, anxiety, stress, and schizophrenia.

Figure 2

Mechanisms for bacteria crossing the blood brain barrier. The mechanisms for four common meningitis-causing bacteria have been elucidated in recent years through a mixture of largely in vitro and in vivo data. While a pre-requisite for these bacteria is the survival in the bloodstream long enough to interact with brain endothelial cells, the mechanisms and pathways differ. N. meningitidis is known to use a paracellular pathway that involves the bacteria adhering the endothelial cells through the binding of type IV pili to the CD147-β2-adrenergic receptor (β2AR) complex. This interaction activates the complex and induces membrane protrusions to form that allows increased bacterial resistance to the forces of blood flow and subsequently enables vascular colonization. Moreover, the activation induces signaling events that lead to a disrupted cellular junction, allowing bacteria to cross paracellularly. E. coli K1 has been documented to possess mechanisms that enable them to enter the BBB both paracellularly and transcellularly. E. coli bacteria can cross paracellularly through a cell necrosis event that is induced by the bacterial secretion of haemolysin co-regulated protein 1 (Hcp1), which causes apoptosis in endothelial cells. Alternatively, bacterial transcytosis across the endothelium can occur through the adhesin bindings of OmPA (Outer membrane protein A) and IbeA to the receptors Ecgp96 and CaspR1, respectively. Group B Streptococcus (GBS) are predominately documented to possess paracellular mechanisms for entry. The bacterial serin rich repeat protein 2 (Srr2), for example, can promote cell wall degradation through interactions with plasminogen and plasmin, and ultimately result in endothelial monolayer disruption. Alternatively, the production of β-haemolysin is cytolytic to brain endothelial cells and can form pores in the BBB that ultimately also lead to cell necrosis. Lastly, Streptococcus pneumoniae can either enter paracellularly through endothelial monolayer disruptions caused by the bacterial production of pneumolysin and H₂O₂ or transcellularly via several interactions: PCho (bacterial phosphorylcholine) with PAFr (platelet-activating factor receptor); CbpA (choline-binding protein A) to LR (laminin receptor); NanA (neuraminidase A) to LR and PECAM-1 (platelet endothelial cell adhesion molecule-1); and RrgA to PECAM-1 and plgR (poly immunoglobulin receptor)., ,

Figure 3

Microbials modulate the development and treatment of CNS disorders. Microorganisms can promote production of essential metabolites, neurotransmitters, and other neuroactive compounds that influence the progression or treatment of various CNS diseases. In the setting of dysbiosis, increased prevalence of Helicobacter pylori and Escherichia coli, for example, was shown to induce the progression of many neurological disorders and symptoms including the hyperphosphorylation of tau protein and amyloid-Beta load (indicative of Alzheimer's disease), α-Synuclein aggregation and decrease motor performance (indicative of Parkinson's disease), and increased proinflammatory toxins and genotoxic metabolites (indicative of CNS malignancies). Conversely, probiotic administration of beneficial strains such as Bifidobacterium and Lactobacillus, for example, have been shown to alleviate many neurological symptoms through increase GABA levels and expression of neurotrophic factors. Effects include decreased anxiety and depressive-like behaviors, decrease episodes of seizures, decreased spatial memory & learning deficits, and decrease motor dysfunction & dopaminergic neurodegeneration.