Human gastrointestinal (GI) tract microbiome-derived pro-inflammatory neurotoxins from Bacteroides fragilis: Effects of low fiber diets and environmental and lifestyle factors

Abstract

Homo sapiens harbor a complex and dynamic community of microorganisms, collectively known as 'the microbiome' , that together constitute the largest 'dispersed organ system' on and within the body, cumulatively more massive, more metabolically active, and much more genetically complex than all of the multiple cell types of the human liver. Together with host cells and their genes, the microbiome constitutes the 'metaorganism' , defined as an assemblage of interacting biological entities with significant commensal or symbiotic benefit to the entire lifeform. The human GI-tract microbiome's dynamic complexity of different microbial species is largely dependent on diet, dietary fiber, environmental and lifestyle-factors, and the most recent evidence suggests that this in turn contributes to human behavior and immunological and neurological health and disease. This communication-perspectives article will briefly discuss the relatively recent research advances at the intersection of human GI-tract microbiome-derived pro-inflammatory neurotoxins and the effects of low-fiber diets, and environmental and lifestyle factors on microbial abundance and speciation. In addition to the nutrients obtained from our diet it is becoming increasingly clear that beneficial dietary effects on the maintenance of a healthy GI-tract microbiome may also reduce the abundance of pro-inflammatory neurotoxins with gastric, immunological and neurological implications. This paper will further focus on current research developments: (i) of one of the human GI-tract's most abundant Gram-negative bacterial species Bacteroides fragilis (of the phylum Bacteriodetes); (ii) discuss recent advances in our understanding of the contribution of B. fragilis-derived pro-inflammatory neurotoxins and their noteworthy contribution to biophysical barrier disruption and systemic effects; and (iii) evaluate their potential influences on progressive, age-related inflammatory neurodegenerative disease such as those associated with the Alzheimer's disease (AD) process.

Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

“…While commensal GI-tract microbes are beneficial and essential to human health, the enterotoxigenic forms of these same microorganisms have considerable potential to secrete highly neurotoxic biopolymers, including multiple varieties of Gram-negative bacterial-derived glycolipids such as LPSs, which are extremely potent inducers of pro-inflammatory and altered innate-immune and immunological signaling in infection, aging and diseases from AD to cancer [ 36 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. One major characterized pathogenic role of LPSs appears to be the stimulation of cytokine-, chemokine- and/or ROS-mediated pathological signaling programs that drive the induction of pro-inflammatory transcription factor NF-kB (p50/p65), which subsequently promotes the transcriptional up-regulation of NF-kB-sensitive microRNAs.…”

Downregulation of Neurofilament Light Chain Expression in Human Neuronal-Glial Cell Co-Cultures by a Microbiome-Derived Lipopolysaccharide-Induced miRNA-30b-5p

“…It has also been appreciated for some time that the toxins that include LPS drive pathological pro-inflammatory signaling programs in neurons in large part via the induction of NF-kB and the upregulation of NF-kB-sensitive miRNAs. However, the details of the molecular-genetic mechanisms and signaling pathways involved still require a more thorough investigation (4, 40,46,47,50,[52][53][54].…”

“…Previously, microbial-derived LPS has been shown to induce NF-kB and NF-kB-sensitive miRNA-30b signaling (42,(45)(46)(47) and pathologically miRNA-30b is robustly upregulated in the brains of both patients with AD and in Aβ-peptide over-expressing transgenic murine models of AD (TgAD), while expression of its multiple mRNA FIGURE 2 | LPS, present in brain cells affected with AD, has an inhibitory effect on NF-L expression; a human microbiome-derived lipopolysaccharide (LPS)-NF-kB-miRNA-30b-NF-L pathological signaling pathway may be in part responsible for driving altered cytoskeletal dynamics, neuronal atrophy and altered trans-synaptic signaling in stressed human neuronal-glial (HNG) cells in primary culture and in Alzheimer's disease (AD) brain. LPSs are neurotoxic glycolipids derived from the outer cell wall of non-capsulated Gram-negative bacteria; normally they contribute to the integrity of the outer cell wall membrane and protect the cell against the action of bile salts and lipophilic antibiotics (50,52,53). Both microbial infection and LPS are strong inducers of NF-kB signaling in neurons and other human cell types.…”

“…The overall goals of these strategies are that the support and maintenance of cytoskeletal structures essential for synaptic plasticity may more effectively manage the many neurological diseases in which NF-L gene expression and abundance play a determinant and defining role. Lastly, dietarybased modifications of microbial dysbiosis may be an attractive means to modify the abundance, speciation, and complexity of enterotoxigenic forms of AD-relevant microbes and their potential for the pathological discharge of highly neurotoxic microbial-derived secretions that include LPS (4, 50,[53][54][55][56][57].…”

“…The results suggest a (Continued) FIGURE 1 | physiologically relevant miRNA-30b-NF-L-mRNA-3 ′ -UTR interaction and a miRNA-30b-mediated downregulation of NF-L expression in HNG cells. This pathogenic interaction may be related to the downregulation of other immune, inflammatory, and synaptic system genes by upregulated miRNAs in the CNS resulting in a deficit in cytoskeletal and synaptic organization and trans-synaptic signaling (7,21,26,27,31,32,36,(38)(39)(40)50).…”