Dietary Fiber Modulates the Release of Gut Bacterial Products Preventing Cognitive Decline in an Alzheimer’s Mouse Model

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.…”

“…These, in turn, target AD- or related-disease-associated mRNAs, which ultimately down-regulate critically pathologically relevant gene expression programs, resulting in the initiation, development and/or propagation of human disease [ 21 , 29 , 34 , 49 , 50 , 56 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 72 , 73 , 74 , 75 ]. For example, the LPS-mediated, ROS- and NF-kB-regulated up-regulation of microRNAs miRNA-30b, miRNA-146a and miRNA-155 in transgenic murine models of AD and in AD are now known to target and down-regulate the expression of important neuron-specific neurofilament and synaptic elements important in supporting and maintaining homeostasis in brain cells and neural signaling capabilities [ 51 , 52 , 57 , 58 , 59 , 60 , 71 ] ( Figure 2 ). An improved understanding of molecular–genetic signaling along the GI-tract-microbiome–CNS/PNS axis in healthy aging and in AD has significant potential for the development of new diagnostic, prognostic and therapeutic strategies and response-to-treatment efficacy monitoring for the more effective clinical management of AD and other types of progressive, age-related and ultimately lethal neurodegenerative disorders in which LPSs and other microbiome-derived neurotoxins appear to be involved.…”

“…For example, targeting and/or modulating GI-tract-microbiome-LPS-mediated, miRNA-30b-regulated NF-L pathways and other miRNA-mediated gene expression circuitry could be valuable in the design of future therapeutic strategies that: (i) could support and maintain cytoarchitectural components essential for neuronal shape, axonal caliber, inter-neuronal signaling and synaptic plasticity; and (ii) may more effectively manage the many neurological diseases in which NF-L gene expression and abundance play a defining and/or determinant role [ 29 , 39 , 55 , 56 , 57 ]. Recent emerging evidence on dietary-based modifications of microbial dysbiosis may also be an attractive means to alter the abundance, speciation and complexity of enterotoxigenic forms of AD-relevant microbes such as B. fragilis and their potential for their long-term pathological discharge of highly neurotoxic microbial-derived glycolipid/lipoglycan secretions such as LPS [ 51 , 52 , 58 , 59 , 60 ] ( Figure 2 ).…”

Short-Chain Fatty Acids in the Microbiota–Gut–Brain Axis: Role in Neurodegenerative Disorders and Viral Infections

“…The relationship of propionate/propionic acid and neurological disease has been controversial with the SCFA shown to be imparting deleterious effects in a majority of studies. − Neuroprotective role of propionate was demonstrated in an Alzheimer’s model in vitro where it prevented neuronal damage and reduced proinflammatory cytokine production and restored tissue damage in an in vivo model of spinal cord injury (SCI) . In another study, a mouse model of nitroglycerine (NTG)-induced migraine benefited from oral administration of sodium propionate and sodium butyrate.…”

High-fiber-diet-related metabolites improve neurodegenerative symptoms in patients with obesity with diabetes mellitus by modulating the hippocampal–hypothalamic endocrine axis

“…Moreover, high-fiber diet is essentially a low-calorie diet and consuming foods rich in fiber increases satiety and hence reduces caloric intake ( 35 ). In addition, a high fiber intake is associated with a reduced risk of Alzheimer's disease (AD) ( 36 ). Metabolites associated with high-fiber diet are blood markers that target key genes and suppress obesity.…”