Diet-Related Metabolic Perturbations of Gut Microbial Shikimate Pathway-Tryptamine-tRNA Aminoacylation-Protein Synthesis in Human Health and Disease

Abstract

Human gut bacterial Na(+)-transporting NADH:ubiquinone reductase (NQR) sequence is associated with Alzheimer disease (AD). Here, Alzheimer disease-associated sequence (ADAS) is further characterized in cultured spore-forming Clostridium sp. Tryptophan and NQR substrate ubiquinone have common precursor chorismate in microbial shikimate pathway. Tryptophan-derived tryptamine presents in human diet and gut microbiome. Tryptamine inhibits tryptophanyl-tRNA synthetase (TrpRS) with consequent neurodegeneration in cell and animal models. Tryptophanyl-tRNA synthetase inhibition causes protein biosynthesis impairment similar to that revealed in AD. Tryptamine-induced TrpRS gene-dose reduction is associated with TrpRS protein deficiency and cell death. In animals, tryptamine treatment results in toxicity, weight gain, and prediabetes-related hypoglycemia. Sequence analysis of gut microbiome database reveals 89% to 100% ADAS nucleotide identity in American Indian (Cheyenne and Arapaho [C&A]) Oklahomans, of which ~93% being overweight or obese and 50% self-reporting type 2 diabetes (T2D). Alzheimer disease-associated sequence occurs in 10.8% of C&A vs 1.3% of healthy American population. This observation is of considerable interest because T2D links to AD and obesity. Alzheimer disease-associated sequence prevails in gut microbiome of colorectal cancer, which linked to AD. Metabolomics revealed that tryptamine, chorismate precursor quinate, and chorismate product 4-hydroxybenzoate (ubiquinone precursor) are significantly higher, while tryptophan-containing dipeptides are lower due to tRNA aminoacylation deficiency in C&A compared with non-native Oklahoman who showed no ADAS. Thus, gut microbial tryptamine overproduction correlates with ADAS occurrence. Antibiotic and diet additives induce ADAS and tryptamine. Mitogenic/cytotoxic tryptamine cause microbial and human cell death, gut dysbiosis, and consequent disruption of host-microbe homeostasis. Present analysis of 1246 participants from 17 human gut metagenomics studies revealed ADAS in cell death diseases.

Antibiotic-Induced Changes in Microbiome-Related Metabolites and Bile Acids in Rat Plasma

“…The shikimate pathway was discovered to be the biosynthetic pathway present in plants and microorganisms that forms the aromatic acids phenylalanine, tyrosine and tryptophan via their precursor chorismate [ 26 ]. Mammals were considered to lack this pathway, but recent studies have indicated the formation of metabolites derived from the shikimate pathway by the gut microbiome [ 27 ]. The products of the shikimate pathway can give rise to indoles, which fulfill many functions in microbial communities, such as quorum sensing, intercellular communication and signaling pathways [ 28 ].…”

“…HA is a well-known urinary metabolite of host-microbial origin. Its precursor benzoate is derived from the microbial degradation of polyphenols from the diet or synthesized via the shikimate pathway [ 27 , 31 ]. Chorismate can be converted directly into benzoate or with phenylalanine as an intermediate [ 26 ].…”

Various theranostics and immunization strategies based on nanotechnology against Covid-19 pandemic: An interdisciplinary view

“…By using a machine learning model with 20 blood parametric of 366 Covid-19 patients depicted severity of patients with a proteomic risk score and that correlated with gut microbiota, which resembles to pro-inflammatory cytokines [ 198 ]. Metabolomics analysis of some potent amino acid related pathways like aminoacyl-tRNA biosynthesis pathway, arginine biosynthesis pathway, valine, leucine and isoleucine biosynthesis pathways from fecal samples of 987 patients revealed a pattern that harmonized with disease extremity [ 199 ]. Hence, Gau et al predicted intestinal microbiota and associated metabolites may be used as further analysis and characterized as an indicator to forecast susceptibility of SARS-Cov-2 with an individual or entire population [ 200 ].…”

Cross-Study Analyses of Gut Microbiomes from Healthy and Obese Individuals

“…The shikimate pathway is found exclusively in microorganisms and plants and is mainly dedicated to the production of aromatic amino acids (phenylalanine, tyrosine, and tryptophan) in bacteria [77]. Evidence has also shown that perturbation in the shikimate pathway is diet-related [78].…”