Microbial Metabolism and Disease

By Elena L. Paley

Microbiome Metabolic Pathways and Disease provides insight into the interaction of microbial metabolic pathways in the human body and the impact these can have on a variety of diseases. By analyzing these pathways the book seeks to investigate how these metabolic processes can be targeted and manipulated in order to treat various disorders and diseases. Topics covered in the book include microbial shikimate pathways, protein biosynthesis, tryptophan metabolites, microbiome metabolic engineering, fecal microbiota transplantation, and virulence factors. Additionally, a variety of conditions are covered, such as disorders associated with metabolic syndromes, serotonin syndromes, Alzheimer’s disease, and Covid-19, providing a detailed overview of how metabolic pathways of microbiome can impact health and disease in the human body.

• Explores microbial metabolic pathways in the human body and implications for disease
• Investigates specific steps involved in metabolic reactions in the human microbiome, including shikimate pathways and tryptophan pathways
• Considers a variety of diseases and disorders, such as Alzheimer’s disease, metabolic syndromes, Crohn’s disease and Covid-19
• Includes analysis of various amino acids and enzymes in microbial and human cells and how these can impact health

• Language: English
• Publisher: Academic Press
• Release date: Mar 13, 2021
• ISBN: 9780323884464

Elena L. Paley

Dr. Paley is Cofounder of the nonprofit Stop Alzheimers Corp and Founder of Expert Biomed, Inc. She holds a PhD degree in biology with specialization in molecular biology from the Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences in the Laboratory of Lev L. Kisselev. Dr. Paley’s research focuses mainly on protein biosynthesis in biology and diseases and is conducted in collaboration with Harvard University, Brandeis University, the University of Miami, Tel Aviv University, the Institut des Vaisseaux et du Sang (Paris, France), and the University of Texas at San Antonio. She is Adjunct Professor at Nova Southeastern University, FL, United States, and is inventor in patents issued and pending.

Book preview

Microbial Metabolism and Disease

Elena L. Paley, Ph.D. M.Sc.

Expert BioMed, Inc., Miami, FL, United States

Stop Alzheimers Corp., Miami, FL, United States

Table of Contents

Cover image

Title page

Copyright

Chapter 1. Naturally occurring affectors of tRNA aminoacylation in transition from health to disease: interference in the initial step of protein biosynthesis

1.1. Introduction

1.2. Experimental evidences supporting the concept

1.3. Conclusions

Chapter 2. Physicochemical, biochemical, and cell biology properties and byproducts of tryptamine and other trace amines

Chapter 3. Tryptophan metabolites and biogenic amines in physical exercises and metabolic syndrome

Chapter 4. Tryptamine in inflammation and regulation of gene transcription

Chapter 5. Genes encoding mammalian, plant, and microbial aromatic amino acid decarboxylase

5.1. Mammalian aromatic acid decarboxylase

5.2. Bacterial aromatic l-amino acid decarboxylases

5.3. Fungal pyridoxal-dependent aromatic-l-amino-acid decarboxylase

5.4. Plant tryptophan decarboxylase

5.5. Conclusion

Chapter 6. Decarboxylases producing tryptamine and other biogenic amines in the human microbiome

6.1. Conclusion

Chapter 7. Microbial shikimate pathway in diseases

7.1. Apicomplexan parasites

7.2. Effect of tryptamine and other tryptophan-related compounds on shikimate pathway enzymes

7.3. Pyridoxal phosphate-dependent enzymes

7.4. Metabolic engineering

7.5. Inhibitors of shikimate pathway enzymes

7.6. Conclusion

Chapter 8. Biogenic amines in fasting, feeding, and stress conditions

8.1. Fasting, starvation, and feeding

8.2. Anorectic effect

8.3. Stress factors

8.4. Stress and mucus

8.5. Irritable bowel syndrome: poor sleep

8.6. Conclusions

Chapter 9. Metabolites of shikimate and tryptophan pathways in coronavirus disease (COVID-19)

9.1. Comparison of statistics for age-related diseases COVID-19 and Alzheimer disease

9.2. Proteomic and metabolomic profiling of sera from COVID-19 patients and further discussion

9.3. Postmortem studies of COVID-19 patients in different countries

9.4. Conclusions

Chapter 10. Virulence factors

10.1. Bacteria and virus interactions in influenza

10.2. Decarboxylase and viral infection

10.3. Emerging data suggest that microbial tryptophan catabolites resulting from shikimate pathway, diet, and human proteolysis are influencing host health

10.4. Toxicologic effects of biogenic amines and postmortem examinations of serotonin syndrome cases

10.5. Biogenic amines and amino acid decarboxylases as virulence factors

Chapter 11. Relation of human gut Alzheimer disease associated sequence (ADAS) with shikimate pathway metabolites

11.1. Alterations in human gut microbiome shikimate pathway and metabolites of aromatic amino acids linked to Alzheimer disease and associated metabolic disorders

11.2. Ubiquinone, a substrate of Na(+)-transporting NADH:ubiquinone reductase (NQR) related to ADAS

11.3. Shikimate pathway metabolites 4-hydroxybenzoate, 3–hydroxybenzoate, benzoate, and quinate in human fecal samples

11.4. Meta-analysis of aromatic amino acids and biogenic amines derived from aromatic amino acids in human gut

Chapter 12. Benefits of using fecal microbiota transplantation (FMT) as treatment have been controversial

Chapter 13. Shikimate pathway enzymes in human microbiome. Putative gene candidates for gene knockout in diseases caused by infections

13.1. Shikimate pathway and its inhibitor pesticide glyphosate in general human population and in diseases

13.2. Human microbial metabolic capacity for production of shikimate pathway metabolites

13.3. Conclusions

Chapter 14. Tryptophan biosynthesis pathway in human microbiome and disease

14.1. Enzymes of microbial tryptophan biosynthesis

14.2. Tryptophan metabolism in disease-associated bacteria Pseudomonas putida

14.3. Inhibitors of tryptophan biosynthesis pathway for potential therapy of diseases associated with dysbiosis

Chapter 15. Antibodies to tryptamine and other biogenic amines: potential usage for human diagnostics and immunotherapy

15.1. Antibodies to tryptamine and other biogenic amines

15.2. Monoclonal antibodies toward small molecules for diagnostic and therapeutic use

15.3. Exploring tryptamine conjugates

15.4. Enzymatic and nonenzymatic oxidative decarboxylation of amino acids

15.5. Conclusions

Chapter 16. Cell death in Alzheimer disease brain and tryptamine-treated cells: microscopy

16.1. Tryptamine localization: immunohistochemistry and electron microscopy

16.2. Tryptamine role in cytotoxicity: necrosis, apoptosis, autophagy, and vesicles

16.3. Tryptamine links to inositol phosphate, acetylcholine, and acetylcholinesterase

16.4. Scientific opinion on risk-based control of biogenic amine formation in fermented foods

16.5. Growth inhibition of yeast species by tryptamine: glucose or ethanol as the carbon source

16.6. Manifestations of cell death pathways in human brain and tryptamine-treated cells

16.7. Tryptamine in systemic sclerosis (scleroderma)

16.8. Conclusion

Chapter 17. Microbial metabolism in etiology of neurodegenerative and related diseases

Chapter 18. Tryptamine produced by human microbiome as an inhibitor of microbial and mammalian enzymes and a ligand of receptors

18.1. Biogenic amines in the human microbiome: enzymes inhibited by tryptamine

18.2. Physiologic effects of tryptamine and other biogenic amines

18.3. Tryptamine and other biogenic amines in Clostridium bifermentans, a role in necrotizing pneumonia

18.4. COVID-19 and bacterial coinfections: biogenic amines in Staphylococcus aureus, necrotizing pneumonia

18.5. Blood–brain barrier: AD and human microbial biogenic amines

18.6. Conclusions

References

Index

Copyright

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Chapter 1: Naturally occurring affectors of tRNA aminoacylation in transition from health to disease

interference in the initial step of protein biosynthesis

Abstract

Here, a new unifying concept states that excessive death of cells and particularly neurons due to the interference in the initial step of protein biosynthesis contributes significantly to the pathogenesis of Alzheimer disease (AD), diabetes, and other cell death diseases. This concept based on experimental data obtained by the author, coauthors, and other researchers. Here, I analyze several natural factors interfering with tRNA aminoacylation, the initial step of protein biosynthesis catalyzed by a family of aminoacyl-tRNA synthetases (ARS). The vital enzymes ARSs catalyze attachment of amino acids to their cognate tRNAs with formation of aminoacyl-tRNAs. Correspondingly, molecules interfering with tRNA aminoacylation can induce cell death or cell proliferation depending on the nature of specific effectors. As corollaries to this concept, the following topics are considered: (1) experimental cell and animal models of cell death and neurodegeneration induced by naturally occurring biogenic amine (BA) tryptamine inhibiting tryptophanyl-tRNA synthetase (TrpRS) thus causing tryptophanyl-tRNAtrp deficiency, (2) TrpRS presence in cell compartments associated with AD, (3) alterations in human gut microbiome of AD patients revealed by human gut microbiome analysis targeting tryptophan-tryptamine pathway, (4) tryptamine content in human food, (5) tryptamine production by human microbiomes, (6) mutations in genes encoding cytoplasmic or mitochondrial TrpRS causing TrpRS deficiency, Parkinsonism, and cognitive impairment, (7) ability of tryptamine and TrpRS to form helixes, (8) BA as modifiable and degradable factors, (9) diet-induced alterations in BA content, and (10) the potential use of tryptamine-degradable factors for disease prevention.

Keywords

Animal model; Biogenic amines; Cell model; Cell death; Diet; Gene mutations; Gut microbiome; Neurodegeneration; Protein biosynthesis; tRNA aminoacylation

1.1. Introduction

In 1981, Sporn and Harris published a unifying concept that excessive proliferation of cells and turnover of cellular matrix contribute significantly to the pathogenesis of several diseases, including cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, and cirrhosis of the liver [1]. Interestingly, at least a part of the diseases with excessive cell proliferation is associated with Alzheimer disease (AD) [2], which is rather an opposite disease of cell death considering the neuronal loss as one of the main characteristics of AD brain. Here, the new unifying concept of cell excessive proliferation and cell death derived from the protein biosynthesis interference in disease pathogenesis is presented (Fig. 1.1).

As corollaries to this concept, the following topics are included in Fig. 1.1 and considered in this work: (1) inhibition of aminoacyl-tRNA synthetases (ARSs) by the naturally occurring biogenic amine (BA), the products of amino acids decarboxylation; (2) BA presence in the human food and microbiome; (3) mutations of genes encoding cytoplasmic or mitochondrial TrpRS; (4) the naturally occurring antibodies against cytoplasmic TrpRS epitopes and mimotopes; (5) posttranslational modification and phosphorylation of TrpRS by different protein kinases; (6) inductions of cytoplasmic TrpRS by interferons and by different infections; (7) multiprotein complexes of ARSs; and (8) TrpRS oligomerization and aggregation.

The unifying concept states that protein biosynthesis interference is linked to both proliferative and neurodegenerative diseases supported by experimental evidence on protein biosynthesis reduction in AD and increase in cancer.

The fidelity of protein biosynthesis in any cell rests on the accuracy of aminoacylation of tRNA. The exquisite specificity of this reaction is critically dependent on the correct recognition of tRNA by ARSs. In 1988, Swanson et al. published in Science that the relative concentrations of a tRNA and its cognate ARS are normally well balanced and crucial for maintenance of accurate aminoacylation [3]. These data indicate that the presence of ARS and the cognate tRNAs in complexed form, which requires the proper balance of the two macromolecules, is critical in maintaining the fidelity of protein biosynthesis. Thus, limits exist on the relative levels of tRNAs and ARSs within a cell. In this regard, it is worth mentioning that only one enzyme of the ARS family, a cytoplasmic TrpRS, is dramatically induced by interferons. Moreover, the data show that TrpRS is induced by a number of microbial pathogens and overexpressed or reduced in cancer [2]. Therefore, the fidelity of protein biosynthesis can be compromised when TrpRS is overproduced in human cells with no cognate tRNAtrp overproduction. It means that overproduced TrpRS can incorrectly acylate the noncognate tRNA with Trp. The stabilities of four correctly acylated and 12 misacylated tRNAs in the ribosomal A site were determined in the study of Dale and Uhlenbeck [4]. Surprisingly, all 16 aminoacyl-tRNAs displayed similar dissociation rate constants from the A site. Therefore, the aberrant proteins might be synthesized due to TrpRS protein overexpression and consequent misacylation.

Figure 1.1 Natural effectors of protein biosynthesis in transition from health to disease: interference in the initial step of protein biosynthesis.

In addition to TrpRS inhibition [5], tryptamine that readily crosses the blood–brain barrier [6] can metabolize in the brain into monoamine oxidase inhibitor (MAOI) to prevent its own degradation [7]. Furthermore the microbial BA tryptamine, tyramine, and phenylethylamine produced from the corresponding aromatic amino acids are encoded by the same gene for aromatic amino acid decarboxylase and are able to inhibit amine oxidases catalyzing BA metabolism including metabolism of histamine [8] implicated in allergic reactions and inflammation. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, and it does so with the full complexity of local peripheral inflammatory responses. Animal models and clinical studies strongly suggest that AD inflammation significantly contributes to AD pathogenesis [9].

In discussions of the etiological factors leading to neurodegeneration of AD type, it is usually assumed that the factors must be related to amyloid-beta and tau, the components of senile plaques and neurofibrillary tangles, respectively. Because significant differences in the levels of BA/polyamines putrescine, spermine, and spermidine originated from precursor amino acid ornithine were identified using S-plot, mass spectra, databases, and standards in metabolic profiling (ultra-performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis) of AD brains [10] the BA can be involved in AD pathology. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD control groups. Furthermore, increased metabolites such as methionine sulfoxide, 3-methoxy-anthranilate, cadaverine, guanine, and histamine were observed on 2018 by widely targeted metabolomics of postmortem cerebrospinal fluid (CSF) from the AD subjects [11]. In the study reported by Mahajan et al. of National Institute on Aging, National Institutes of Health on 2020, dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways was revealed in AD in a targeted metabolomic and transcriptomic study [12]. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus and middle frontal gyrus), the associations between brain tissue concentrations of 26 metabolites and the following primary outcomes—group differences, Consortium to Establish a Registry for AD (neuritic plaque burden), and Braak (neurofibrillary pathology) scores—was tested. Polyamine synthesis and catabolism alteration (spermidine: higher in AD relative to control, P   =   .004) were detected [12].

The metabolomics data on increased BA in brain and CSF of AD patients [10–12] are consistent with our data on the increase of fecal putrescine, spermidine, cadaverine, and histamine in the human population with a high prevalence of Alzheimer disease associated sequence (ADAS) in the human population with a high prevalence of obesity and type 2 diabetes [13]. ADAS was discovered by the human gut microbiome analysis that targeted the tryptophan-tryptamine pathway [14]. Currently the ADAS carriers at different ages including infants led to ADAS-comprising human sample size of 2830 from 27 studies of four continents (North America, Australia, Asia, and Europe) [13].

In mice, fecal tryptamine was significantly increased in steatohepatitis, a liver damage developed during alcohol consumption for 20 days [15]. ADAS was revealed in patients with nonalcoholic fatty liver disease (NAFLD) [16]. Fecal tryptamine and putrescine were significantly elevated in patients with irritable bowel syndrome (IBS) compared to controls [17]. Recent meta-analysis suggests that Parkinson disease (PD) and AD are significantly associated with intestinal disorders including IBS [18]. Urine tryptamine elevated (3.31-fold) in PD patients [19]. Table 1.1 includes data on tryptamine alterations associated with some cases of ADAS presence in different medical conditions.

Tryptamine undergoes a methylation process, generating the intermediate product N-methyltryptamine (NMT). NMT is in turn transmethylated to form the final product psychedelic hallucinogen N,N-dimethyl tryptamine (DMT). DMT binds several serotonin receptors, acting as a partial agonist in particular on the 5-HT2A and 5-HT2C receptors. It has also been shown to possess affinity for the α1- and α2-adrenergic receptors, dopamine D1, and sigma-1 [44]. Tryptamine itself is also regularly observed as a putrefactive compound following the psychedelic ingestion [45]. According to the National Program on Substance Deaths Abuse Annual Report, from January to December 2012 in the United Kingdom by Corkery et al., tryptamine was reported as a cause of death after postmortem toxicology testing (2009) [46]. Tryptamine IC50 values (μg/mL) for human lymphoma cancer cells BC1 and human cervix carcinoma (derivative of HELA) KB-V1, a multidrug-resistant (mdr) subclone are 14.2 and 13.3, respectively [47]. The present article is concerned with experiments attempting to determine a mechanism linking tryptamine, other naturally occurring BAs, ARSs and related compounds to AD and associated diseases. A detailed development of this hypothesis has been presented elsewhere [2,5,13,14,16,48–52].

Table 1.1

Tryptamine level ↑increase; ↓decrease compared to controls; FC, fold change; NA, not available.

Data on ADAS in human fecal samples are available [2,13,14,16].

Level (2   mM or 320   μg/g) detected in liver of mice fed with low-fat diet [34].

a  Both a set of obesity-enriched enzymes and set of inflammatory bowel disease (IBD)-enriched enzymes include aromatic-L-amino-acid decarboxylase [EC:4.1.1.28] (5.217-fold increase in obesity and 7.772-fold increase in IBD) [20] that can catalyze the tryptamine production from tryptophan. Arginine decarboxylase [EC:4.1.1.19] catalyzing production of agmatine is also higher in obesity (4.783-fold) and in IBD (2.462-fold) [20]. IBS: irritable bowel syndrome.

b  Pancreatic cancer: five cases of pancreatic ductal adenocarcinoma, early stage without clinical evidence of distant metastasis, controls of three chronic pancreatitis, two normal, P value 0.016 [28]. C&A: Cheyenne and Arapaho Native American tribes, ICC: invasive cervical carcinoma, RAU: recurrent aphthous ulcer, NAFLD: nonalcoholic fatty liver disease, LSIL: low-grade squamous intraepithelial lesions, IAA: indoleacetic acid. This table is an update of the Supplementary Table S4 [16].

c  Formula-fed/breast-fed infants.

d  Tryptamine is lower (~0.5-fold) in liver of mice fed with high-fat diet compared to tryptamine.

1.2. Experimental evidences supporting the concept

1.2.1. Tryptamine-induced neurodegeneration in cell and animal models

The naturally occurring BA tryptamine present in the human diet and produced by the human microbiome is in the μg/gram range. The detailed analysis of tryptamine in food and in microbiome was reported recently [2]. Tryptamine is a competitive inhibitor of TrpRS, the enzyme of initial step of protein biosynthesis. Tryptamine induces neuronal loss, amyloidosis, and formation of neurofibrillary tangles of helical filaments in the mouse brain and neuronal cells [48]. Tryptamine-induced formation of tangles of filaments is also found in bovine kidney cells [5]. Tryptamine induces axonopathy, mitochondriopathy, and vesicle formation [50,51]. TrpRS is a human autoantigen [53] revealed with specific monoclonal antibodies in extracellular plaque-like aggregates in the hippocampus of AD brain [49]. Tryptamine metabolizes by monoamine oxidases (MAO) and self-assembles in a twofold helix with its metabolite indole-3-acetic acid (IAA) in vitro. The crystal chirality is generated by the formation of a twofold helix in only one direction between the two molecules through the salt interaction and hydrogen bonding in the lattice [54].

1.2.2. Alzheimer disease is a systemic widespread disease

The full autopsy studies suggest that AD is not strictly a brain disease but a disease of many organs and systems [2]. In a recent report, Paley examined 54 articles published in peer-reviewed journals from 1986 to 2020 with PubMed citations that use different approaches for analysis of AD and dementia in human subjects: complete autopsy, partial autopsy, analysis of death certificates, population-based cross-sectional survey, case-control studies, case reports, follow-up examinations, meta-analysis, multivariable analysis, reviews, retrospective cohort studies, screening of patients, and analysis of the prospective data from the National Health and Nutrition Examination Survey and the Linked Mortality File [2]. Altogether, the different approaches support the concept of AD as a widespread systemic disorder. The following three studies exemplify this analysis [2]. Hospital admission rates for some major neurologic diseases among members of the Danish Religious Societies Health Study comprising 6532 Seventh-day Adventists and 3720 Baptists were compared with the general Danish population. Standardized incidence ratios of dementia or AD were significantly decreased for members of both religious communities [55]. Seventh-day Adventists do not consume tobacco, alcohol, or pork, and many adhere to lacto-ovo-vegetarian diet, and Baptists discourage excessive use of alcohol and tobacco. Cross-sectional study of 72,815 patients over 64 seen in the 19 Spanish primary care centers during 2008 is reported in an article of 2014 of the Aragon Health Sciences Institute [56]. Among the patients with dementia, 12.34% had dementia as the only diagnosis. The total of both sexes of ≥65 had ≥6 disease in 5.55% patients without dementia and in 16.44% patients with dementia. A total of 43 different comorbidities with a prevalence of ≥1% were identified in the population with dementia (41 different comorbidities in men and 36 in women). The 10 diseases with the highest prevalence for both sexes were hypertension, anxiety and neurosis, degenerative joint disease, lipid metabolism disorders, lower back pain, diabetes, anemia, thyroid disease, cataracts and aphakia, and cardiac arrhythmia. The two most frequent comorbidities both for men and women with dementia were hypertension and diabetes. In 2011, Maarouf and coauthors reported that some nonagenarian individuals, suggested as high pathology controls, remain cognitively intact while enduring high amyloid plaque loads for decades [57]. Included in the study was a cohort of eight individuals with a mean age of 92.8 years (range: 90–100 years) that were clinically assessed as nondemented. On neuropathologic examination, these oldest-old cases contained sufficient AD amyloid plaque and neurofibrillary tangle density to meet at least NIA-Reagan ‘‘intermediate’’ neuropathologic criteria for AD.

1.2.3. Seizures and myoclonus in Alzheimer disease and in tryptamine-treated animals

In 1959, Tedeschi et al. described a pharmacologic procedure by which drugs were tested for their ability to potentiate or antagonize convulsions induced by the intravenous injection of tryptamine [58]. Tryptamine induces seizures, convulsions, tremors, and myoclonus in monkeys, rabbits, guinea pigs, rats, and mice (details in the legend to Fig. 1.2) [2,6,48,58,59].

Microbiome: In the study of Sridharan et al. reported in 2014, tryptamine was quantified among the bioactive microbiota metabolites in the mouse gut [81]. Researchers utilized two independent mass spectrometry methods to quantify the levels of the predicted metabolites in cecum contents from conventionally raised specific pathogen-free (SPF) and germ-free (GF) mice. In cecum luminal contents, tryptamine was detected at 0.07   μM in SPF mice and no tryptamine was detected in GF mice [81]. In the study of Jin et al. the entire cecum (tissue with luminal contents) and fecal pellets were used to detect tryptamine at 10–20   μM in the common laboratory female C57BL/6 mice maintained in a pathogen-free animal facility located at the Texas A&M University [82]. SPF mice are mice that are demonstrated to be free of a specific list of pathogens by routine testing. The list of organisms assessed typically includes disease-causing pathogens that can affect mouse health and research outcomes, as well as opportunistic and commensal organisms that typically do not cause illness in normal, healthy mice. Apparently, the common laboratory mice contain tryptamine-producing microorganism/s, which are not included in the list of specific pathogens. The planar lipid bilayer membrane permeability was higher for nonionic tryptamine (1.8   ×   10 −¹   cm/s) than for nonionic histamine (3.5   ×   10 −⁵   cm/s) [83]. Moreover the pH-dependent chemical reaction with bilayer membrane composing of egg phosphatidylcholine plus cholesterol (1:1   mol ratio) in tetradecane is important in the transport of tryptamine but not histamine [83]. The uptake of tryptamine by liposomes (large unilamellar vesicles), which contained various amounts of dipalmitoylphosphatidylserine (DPPS), was also examined [84]. The uptake of tryptamine decreased with a decrease of DPPS content in the liposomes. Moreover, the uptake of tryptamine by intestinal brush-border membrane vesicles was inhibited by the local anesthetic tetracaine and antidepressant imipramine [84]. Imipramine is an MAOI [85]. Trace amines readily crossed synthetic lipid bilayer fluorosome membranes by simple diffusion, with p-tyramine (P   =   .01) and tryptamine (P   =   .0004) showing significantly faster diffusion than dopamine (35.9   ±   7.0   s) and 5-HT (48.2   ±   5.9   s), respectively, with diffusion half-lives of 13.5 ± 4.1 (p-tyramine) and 6.8 ± 0.7   s (tryptamine) [86].

Figure 1.2 Multiple effects of tryptamine. Cell death and anticancer effects: tryptamine IC50 values (μg/mL) for human lymphoma cancer cells BC1 and human cervix carcinoma (derivative of HELA) KB-V1, a multidrug-resistant (mdr) subclone, are 14.2 and 13.3, respectively [47]. TrpRS: tryptophanyl-tRNA synthetase; tryptamine inhibits IDO (indoleamine-2,3-dioxygenase), tryptophan metabolizing enzyme in the kynurenine (Kyn) pathway [60]; tryptamine inhibits histamine metabolizing enzymes HMT (histamine-N-methyltransferase) and DAO (diamine oxidase) [61]; tryptamine binds to HSA (human serum albumin) [62]; 5-HT syndrome (serotonin syndrome) [63–65]; tryptamine displaced serotonin at 5-HT1 and 5-HT2 binding sites in the rat cortex of rat brain [66]. 5-HT antibodies increased during mild dementia and plateaued thereafter [67]; mitosis: tryptamine is a mitogen for smooth muscle cells [68]; seizures, myoclonus: tryptamine-induced bilateral convulsions and tremors [69], bilateral clonic seizure of forepaws [70], forepaw clonus [59] in rats, convulsions in mice [48], myoclonus in guinea pigs [71,72]. Tedeschi et al. published in 1959 that in Macaca mulatta monkeys, 10   mg/kg tryptamine HCl i.v. caused asymmetrical clonic convulsions followed by intermittent tremors. When 5   mg/kg (calculated by probits to induce 3   s of uninterrupted clonic seizure in 1% of animals) was given 5   h after 100   mg/kg iproniazid phosphate po, 4/4 monkeys exhibited convulsions. This doze of monoamine oxidase inhibitor (MAOI) iproniazid alone produced no overt effects [58]. Mydriasis (dilated pupils) and decreased locomotor activity occurred in rabbits (N   ≥   4 group) after i.v. infusion of 1.5   mg/kg/min tryptamine HCl; at 2–3   mg/kg/min, clonic convulsive movement of forepaws was seen after 5–10   min [58]. In Sprague–Dawley and Wistar albino rats (N   =   8–10 dose), tremors were seen after 10   mg/kg [58]. Tryptamine (40   mg/kg) induced clonus of the forepaws in 100% of the female Sprague–Dawley rats [59]. MAOIs can be consumed as dietary compounds or as antidepressants [2]. AADH (aromatic amine dehydrogenase) catalyzes tryptamine oxidation [73,74]. A large variety of naturally occurring substances have been tested for spasmogenic activity in cerebral arteries, partly to identify possible pathologic spasmogenes. Tryptamine produced Cmax tension comparable to serotonin for the cerebral arterial spasm in dog basilar artery [75]. Both 5-HT and tryptamine caused dose-dependent contractions of the isolated pulmonary artery over a range of 5–20   μg [76]. Mesentery vasopressor: involvement of the Rho-kinase pathway in the tryptamine-evoked vasoconstriction was indicated by its reduction by the Rho-kinase inhibitors, Y-27,632 and fasudil. The tryptamine vasoconstriction is modulated by the coreleased endothelial vasodilator, nitric oxide. Thus, circulating tryptamine can regulate mesenteric blood flow through a cascade of signaling pathways secondary to stimulation of 5-HT(2A) receptors [77,78]. Amino-guanidine and tryptamine inhibit nitric oxide synthase (NOS) [79]. Heart: cardiac effects, dose-dependent negative inotropic effect as shown by reduced cardiac output, potentiated by the dietary MAOI genistein [80]. ADAS: AD-associated bacterial sequence from human gut microbiome [14,16]. Currently the ADAS-carriers at different ages including infants led to ADAS-comprising human sample size of 2830 from 27 studies of four continents (North America, Australia, Asia, and Europe) [13]. CRC (colorectal cancer), associated with ADAS [13,16]. ICC (invasive cervical carcinoma) [26], BC (bladder cancer), levels of tryptamine (0.1-fold) and histamine (0.58-fold) in BC are lower than in the normal tissues [27], PC (pancreatic cancer) [28].

Patients with AD are more prone to seizures and myoclonus. In 1986, Hauser et al. published the study conducted in the United States on 81 patients with dementia and autopsy findings of AD that were reviewed to identify patients with seizures or myoclonus after onset of dementia [87]. Eight (10%) had seizures, and eight others (10%) had myoclonus. The incidence of seizures was 10 times more than expected in a reference population. Seizures occurred in any stage of AD, but myoclonus was often a late manifestation. Both seizures and myoclonus, individually or together, are manifestations of AD and may be seen at any time in the course of the illness.

In the study reported in 2017 by Beagle et al. electronic medical records at the UCSF Memory and Aging Center were reviewed for patients evaluated between January 1, 2007 to December 31, 2013 (n   =   7925) and who met diagnostic criteria for AD, frontotemporal dementia (FTD), or dementia with Lewy bodies (DLB) (n   =   2408) at their most recent clinical evaluation. The cumulative probability of developing seizures after disease onset was 11.5% overall, with the highest in AD (13.4%) and DLB (14.7%) and lowest in FTD (3.0%). The cumulative probability of developing myoclonus was 42.1% overall, with the highest in DLB (58.1%). The seizure incidence rates, relative to control populations, were nearly 10-fold in AD and DLB, and sixfold in FTD. Relative seizure rates increased with earlier age at onset in AD (age <50, 127-fold; 50–69, 21-fold; 70+, twofold) and FTD (age <50, 53-fold; 50–69, ninefold), and relative myoclonus rates increased with earlier age at onset in all groups. Seizures began an average of 3.9 years after the onset of cognitive or motor decline, and myoclonus began 5.4 years after onset [88]. Intriguing, patients with seizure risk factors were excluded, including those with remote history of seizures (defined as seizure onset at least 10 years prior to symptoms of neurodegenerative disease; n   =   16) or those with previous seizures provoked by cortical lesions, acute metabolic disorders, or subdural hematomas (n   =   25). This approach corresponds with exclusion criteria in similar studies investigating seizures in dementia patients [88]. With regard to the present concept, the exclusion subjects with remote history of seizures defined as seizure onset at least 10 years prior to overt symptoms of neurodegenerative disease or those with acute metabolic disorders represent the group of a special interest. Particularly, the exclusion group with remote seizures might demonstrate the manifest of the elevated tryptamine production at least 10 years prior to overt symptoms of neurodegenerative disease.

Sleep plays an intricate role in epilepsy and can affect the frequency and occurrence of seizures. With nearly 35% of US adults failing to obtain the recommended 7   h of sleep every night, understanding the complex relationship between sleep and epilepsy is of utmost relevance. Sleep deprivation is a common trigger of seizures in many persons with epilepsy, and sleep patterns play a role in the occurrence of seizures [89]. In the study published in 2020, a total of 179 children (5–14 years of age) were examined. Blood samples were drawn at 20:00 and 09:00   h, and urine was collected between blood draws. Levels and daily fluctuations of metabolites were measured by tandem mass spectrometer. Tryptamine exhibited higher evening values (P   <   .0001) in this study [90]. Therefore, seizures and myoclonus are manifestations of both AD and tryptamine activity.

1.2.4. Serotonin (5-HT) or tryptamine syndrome

The first cases of serotonin syndrome were reported in 1960 [91] when patients were on potent MAOI and tryptophan [92]. Several of these patients became altered as though they had undergone ethanol intoxication. The clinical hallmarks of serotonin (5-HT) syndrome are altered mental status, fever, myoclonus, clonic tremors, hyperreflexia, seizures, mood alterations, unsteady gait, dizziness, and nausea. Urinary tryptamine indicated MAO inhibition in these patients, whereas no tryptophan effect was observed without MAOI [91]. The MAOI plus tryptophan neurologic effects currently coined as serotonin syndrome attribute these effects in seven patients to alterations in the metabolism of tryptamine and serotonin [91]. Tryptamine displaced serotonin at 5-HT1 and 5-HT2 binding sites in the rat cortex of rat brain [66]. The tryptamine-induced seizure activity could be prevented by 5-HT2 receptor antagonism [6,93]. Clinical manifestations of serotonin (tryptamine) syndrome range from barely perceptible to lethal. MAOI that inhibit MAO-A are strongly associated with severe serotonin syndrome [94], which is similar to the tryptamine-induced 5-HT syndrome in animals [63–65]. Yamada et al. suggest that the 5-HT syndrome and the head twitch responses induced by tryptamine in five strains of mice are linked separately with the 5-HT1 and 5-HT2 receptors, respectively. The strain differences in the tryptamine-induced 5-HT syndrome in mice can be explained by the different levels of brain tryptamine [63]. Tryptamine in a dose greater than 15   mg/kg induced distinct head weaving and hind limb abduction. These behavioral