Gastrointestinal (GI) Tract Microbiome-Derived Neurotoxins—Potent Neuro-Inflammatory Signals From the GI Tract via the Systemic Circulation Into the Brain

SARS-CoV-2 Infectivity and Neurological Targets in the Brain

“…ACE2 therefore plays a key regulatory role in the classical axis of the renin-angiotensin system (RAS), a hormonal system that regulates not only systemic vascular resistance to blood flow and blood pressure but also fluid and electrolyte balance (Kehoe et al 2016;Wang et al 2016;Datta et al 2020). ACE2 has also been reported to have ancillary physiological roles: (i) in the regulation of membrane trafficking of the sodium-dependent neutral amino acid transporter SLC6A19 that has been implicated in Hartnup's disease (a disorder of amino acid homeostasis and translocation; Gheblawi et al 2020); (ii) in the interaction with other vasoactive peptides such as Apelin that regulate blood pressure and myocardial contractility (Kuba et al 2013); and (iii) in GI-tract inflammation and the regulation of the complexity and speciation of the GI-tract microbiome (Kuba et al 2013;Gheblawi et al 2020;Lukiw 2020; The highest expression of the SARS-CoV-2 receptor ACE-2 was found in the amygdala, pons and medulla oblongata; the later two regions contain the respiratory control centers of the brain; considerable expression of ACE2 in the brain, temporal lobe and hippocampus may in part explain neurological disruption and cognitive dysfunction associated with SARS-CoV-2 infection; note difference of scale in the Y-axis (ordinate) compared to Fig. 2; to obtain maximal signal quantitation hybridized and washed membranes were overlaid on the MTE template (Fig.…”

“…ACE2 therefore plays a key regulatory role in the classical axis of the renin-angiotensin system (RAS), a hormonal system that regulates not only systemic vascular resistance to blood flow and blood pressure but also fluid and electrolyte balance (Kehoe et al 2016 ; Wang et al 2016 ; Datta et al 2020 ). ACE2 has also been reported to have ancillary physiological roles: (i) in the regulation of membrane trafficking of the sodium-dependent neutral amino acid transporter SLC6A19 that has been implicated in Hartnup's disease (a disorder of amino acid homeostasis and translocation; Gheblawi et al 2020 ); (ii) in the interaction with other vasoactive peptides such as Apelin that regulate blood pressure and myocardial contractility (Kuba et al 2013 ); and (iii) in GI-tract inflammation and the regulation of the complexity and speciation of the GI-tract microbiome (Kuba et al 2013 ; Gheblawi et al 2020 ; Lukiw 2020 ; Zuo et al 2020 ; unpublished observation). Other important contributory factors associated with variable ACE2 receptor expression (and hence potential for SARS-CoV-2 infection and CoV-19 severity) include age, sex, ethnicity, medication and several co-morbidities, such as cardiovascular disease, metabolic syndrome and obesity, and dementia and cognitive decline (Baig and Sanders 2020 ; Gheblawi et al 2020 ).…”

Biomarkers for Alzheimer’s Disease (AD) and the Application of Precision Medicine

“…There is a wealth of data indicating that neurotropic microbes including both DNA and RNA viruses (such as Herpes simplex 1 or SARS-CoV-2 ) or bacterial Phyla such as Proteobacteria , Verrucomicrobia , Fusobacteria , Cyanobacteria , Actinobacteria , and Spirochetes or microbe-derived viral, fungal, or prokaryotic cellular components or microbial neurotoxins have high affinity for neural cells of the human brain and CNS [ 24 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Multiple independent laboratories continue to report the detection of viral, bacterial, fungal, protozoal, or other microbially-derived nucleic acid sequences or neurotoxins, such as highly inflammatory bacterial amyloid peptides, lipopolysaccharide (LPS), and many microbe-derived endotoxins within AD affected brain tissues [ 24 , 29 , 34 , 36 , 39 , 40 ]. Microbial biomarkers and systems biology approaches to understand host–microbiome interactions have been suggested by multiple AD researchers that both: ( i ) predict the risk of developing AD well before the onset of cognitive decline; and ( ii ) stimulate and/or accelerate the development of classical AD neuropathology [ 24 , 34 , 39 , 41 , 42 , 43 , 44 ].…”

“…Multiple independent laboratories continue to report the detection of viral, bacterial, fungal, protozoal, or other microbially-derived nucleic acid sequences or neurotoxins, such as highly inflammatory bacterial amyloid peptides, lipopolysaccharide (LPS), and many microbe-derived endotoxins within AD affected brain tissues [ 24 , 29 , 34 , 36 , 39 , 40 ]. Microbial biomarkers and systems biology approaches to understand host–microbiome interactions have been suggested by multiple AD researchers that both: ( i ) predict the risk of developing AD well before the onset of cognitive decline; and ( ii ) stimulate and/or accelerate the development of classical AD neuropathology [ 24 , 34 , 39 , 41 , 42 , 43 , 44 ].…”

“…Whether these viral, bacterial, or other microbial DNA- or RNA-based nucleic acids or associated lipoproteins, liposaccharides, peptidoglycans, bacterial-derived amyloids, and/or neurotoxins originate from the gastrointestinal (GI) tract microbiome, a potential brain microbiome, or some dormant pathological microbiome is currently not well understood [ 24 , 35 , 36 , 40 , 43 , 45 ]. Since 1978, at least ~4400 peer-reviewed research articles provide convincing evidence that multiple species of microbes, including viruses, bacteria (especially Gram-negative bacteria), and other microorganisms or their secreted components are strongly associated with the onset and/or the development of AD-type change [ 24 , 29 , 33 , 34 , 41 , 42 , 43 , 46 ]. If microbial presence in the brain is involved in the early initiation or propagation of AD, as currently suspected, then specialized RNA-sequencing applications or nucleic acid-containing gene chips, electrochemical biosensors, or panels of microbial-derived 16S ribosomal RNA (rRNA) interrogated with nucleic acid probes derived from AD biofluids might be useful as novel AD biomarkers in the detection of microbial patterns of expression from human brain tissues at any stage or degree of AD neuropathology.…”