Browsing by Author "Dicks, Leon Milner Theodore"

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    Interactions between gut microbiota and the central nervous system, with emphasis on quorum sensing between commensal lactic acid bacteria and human cells
    (Stellenbosch : Stellenbosch University, 2023-03) Dicks, Leon Milner Theodore; Botha, Alfred; Stellenbosch University. Faculty of Science. Dept. of Microbiology.
    ENGLISH ABSTRACT: The human gut hosts close to 4 trillion microorganisms, which is nearly equivalent to the estimated 3.0×1013 human cells in a 70 kg body. Although the composition of gut microbiota changes with age, variation in diet, medication, hormone levels, stress and other environmental factors, a core group of autochthonous bacteria, between 400 and 500 species, are always present. More than 90% of the gut microbiome is represented by Proteobacteria, Actinobacteria, Bacteroidetes and Firmicutes, with the latter in the majority. Fusobacteria and Verrucomicrobia make up the remaining 10% of the gut microbiome. The human gut microbiome supersedes the number of cells in our bodies ten-fold. Since lactic acid bacteria (LAB) are the predominant gut microbiota, it is safe to conclude that changes in this group will affect the entire microbiome, ultimately leading to adjustments in the behaviour of intestinal epithelial cells (IECs). Changes in the immune system and quorum sensing (QS) signals instigated by an altering gut environment trigger a cascade of hormonal and neurological reactions. Activation of Toll-like receptors, for instance, induce strong immune and inflammatory reactions, but at the same time stimulate the secretion of hormones such as 5-hydroxytryptamine (5-HT, or serotonin), glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), glucose-dependent insulinotropic peptide (GIP), cholecystokinin (CCK), ghrelin, leptin, pancreatic polypeptide (PP), oxyntomodulin and neurotensin. Serotonin act as neurotransmitter but also regulates diverse functions such as platelet aggregation, bone development, immune response, cardiac function and gut homeostasis, and control enteric motor and secretory reflex. Gut bacteria also synthesize, or regulate, the production of serotonin and other neurotransmitters such as glutamine (Glu), gamma-amino butyric acid (GABA), dopamine (DA), norepinephrine and histamine. These molecules communicate with the central nervous system (CNS) via afferent fibers in the Vagus nerve (VN), autonomic sympathetic and parasympathetic nervous systems, but also the hypothalamic-pituitary-adrenal axis (HPA). Intermediate compounds such as short-chain fatty acids (SCFAs), tryptophan and secondary bile acids produced by gut bacteria also communicate with the CNS. Signals received from the brain are sent back to entero-epithelial cells (EECs) via the HPA and efferent VN fibers to complete the circle of communication referred to as the gut-brain axis (GBA). The modulation, development, and renewal of neurons in the enteric nervous system (ENS) are controlled by gut microbiota, especially those with the ability to produce and metabolize hormones. Minor activation of the ENS and VN results in drastic changes in the production of neurotransmitters, which also affects digestion, intestinal permeability, gastric motility, and immune regulation. GABA, in addition to other metabolites, play an important role in anti-inflammatory responses and help alleviate psychiatric symptoms stemming from inflammation. Treatment of schizophrenic and bipolar patients with probiotics alleviated symptoms associated with irritable bowel disease (IBD), and autistic children benefitted from probiotic treatment. Obsessive compulsive disorder (OCD)-like behavior could also be controlled by treatment with LAB. Inter- and intra-species signalling systems have been well studied, but far less is known about interkingdom quorum sensing (QS), especially between gut bacteria and intestinal epithelial cells (IECs). Although the auto-inducer 3 (AI-3)/epinephrine (Epi)/norepinephrine (NE) QS signalling system described for pathogenic Escherichia coli, Salmonella typhimurium and Ctirobacter rodentium are widely used by Gram-negative pathogenic bacteria, not all species have receptors that recognize these signals. Instead, they have developed “broad-range” “solo” LuxR-type receptors such as SdiA (a LuxR homolog) and QscR to improve their communication abilities. Despite our knowledge on QS, the effect of these signalling molecules on the CNS is ill-researched. Several QS peptides (QSPs) have the ability to diffuse through the intestinal mucosa and enter the circulatory system, from where they may penetrate the blood-brain barrier (BBB). It may be that LAB communicate with the CNS using small linear or cyclized oligopeptides (QS peptides, QSPs) of 5 to 17 amino acids long, as reported for other Gram-positive bacteria. In our own research we have shown that bacteriocins can indeed transverse epithelial (Caco-2) and endothelial (HUVECs) monolayers without changing the integrity of the membranes and with no toxic effect. Once in the blood stream, bacteriocins may cross the BBB, similar to that reported for the heptapeptide PapRIV produced by Bacillus. Our understanding of exactly how gut microorganisms control cognitive behavior, mood, and neuropsychiatric disorders remains limited. However, the more we discover about the gut microbiome, QS, neurotransmitters and the GBA, the greater the chance of developing novel therapeutics, probiotics and psychobiotics to treat gastro-intestinal disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), but also improve cognitive functions and prevent or treat mental disorders. This calls for in-depth deciphering of the complex, everchanging network between cells and neurons. Research on the quenching of QS signals need to be prioritised. We need to understand how quorum quenching (QQ) therapy will affect beneficial gut microbiota. Biomarkers need to be developed to identify differences in the gut microbiome of individuals suffering from psychological disorders. Interactions between drugs used in treatment and gut microbiota need to be studied in greater depth. We need to understand the effect psychiatric medication may have on the composition of the gut microbiome. Are intestinal microbiota able to metabolise these drugs? Studies should include multi-omics of gut and oral microbiota to have a better understanding of the mutual interplay between phyla. Will it be possible to develop probiotics to treat dysbiosis and neuropsychiatric abnormalities?