Open access peer-reviewed chapter
Abstract
Tryptophan is an essential amino acid. It is metabolized through two main pathways: the kynurenine pathway and the methoxyidol pathway. The intestinal microbiota has been identified as a modifier of the metabolism of tryptophan and its derived metabolites. The resulting metabolites can trigger immune, metabolic, and neuronal effects, at the systemic and distant levels, as well as therapeutic specific and nonspecific targets. The reader reviewing this content will learn the importance of tryptophan biotransformation through metabolism and the host-microbiome complex, the formation of serotonin and kynurenine, the pathways of unwinding and the physiological effects of metabolites within the intestinal part, energy metabolism and neurotransmitters. The effects and pathologies that dysregulation may have with this metabolism will be reviewed, as well as the therapeutic targets and related drugs.
Keywords
- gut microbiome
- tryptophan metabolism
- therapeutic strategies
- microbiota-gut-brain axis
- probiotics
1. Introduction
The intestine is an ecosystem harboring a dense and diverse microbial community called “gut microbiota” considered an endocrine organ. Many of the effects are mediated by metabolites that are either produced by microbes from the transformation of environmental or host molecules.
L-tryptophan is an amino acid that has emerged as a critical player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, contributes to the normal grown and health of both animals and humans.
The intestinal microbiota influences the metabolism of tryptophan, specific to microbial control over the kynurenine pathway and the indole pathway, which are important for host physiology. These metabolites participate in processes such as immune system regulations, regulations of metabolism, gastrointestinal motility, inflammation, and oxidative and anti-oxidative effects. Deciphering the complex equilibrium between intestinal microbiota and tryptophan metabolism will facilitate the understanding of the diversity of pathogenesis of human diseases and new therapeutic opportunities.
2. Microbiota-gut-brain axis: tryptophan metabolism
The human gut microbiota plays an essential role in host health and physiology. Its colonization begins in the earliest moments of life after birth. It is composed of microorganisms such as bacteria, viruses, fungi, yeasts, and bacteriophages [1, 2]. Throughout one’s lifespan, the composition of the microbiota can be influenced by various factors, starting with the type of birth delivery, nutrition, antibiotic exposure, inflammation, aging, psychological stress, and lifestyle [1, 3].
As mentioned earlier, the gut microbiota influences multiple physiological processes, including digestion, metabolism, the balance between host defense and immune tolerance, pathogen resistance, epithelial cell proliferation and differentiation, insulin resistance, as well as the behavioral and neurological functions of the host [4, 5]. This last effect is particularly associated with bidirectional gut-brain interactions, better known as the gut-brain axis (GBA). The GBA facilitates communication between the central nervous system (CNS), the enteric nervous system (ENS), and the gastrointestinal (GI) tract (Figure 1) [6, 7]. Given the significance of GBA, numerous studies have been conducted to characterize the molecular and functional connections between the gut and the brain. Currently, the most extensively documented network is between the CNS, ENS, and the hypothalamic-pituitary-adrenal axis. The ENS resides in the intestinal wall, and its communication with the CNS occurs through neuroimmune and neuroendocrine signaling, mediated by the vagus nerve [8, 9].
Figure 1.
The gut-brain axis (GBA). Schematic representation of the bidirectional crosstalk between the central nervous system (CNS), the enteric nervous system (ENS), and the gastrointestinal (GI) tract. Vagal efferent and afferent nerves send signals reciprocally between the brain and the gut. Enterochromaffin cells produce and release serotonin (5-HT- 5-hydroxytryptamine) into the gut. Created with BioRender.com.
The vagus nerve is the longest cranial nerve and is considered the main component of the parasympathetic nervous system; it sends information about the state of the inner organs to the brain and is involved in the control of multiple functions such as immune response, digestion, heart rate, endocrine functions, the mood, among others. The vagus nerve is crucial to the brain-gut axis since establishes the connections between the brain and the gastrointestinal tract; vagal efferents send the signals from the brain to the gut and the vagal afferents from the intestinal wall to the brain. The vagal afferent pathways are involved in the regulation of the hypothalamic-pituitaryadrenal (HPA) axis, and in conjunction allow the brain to influence the activities of intestinal functional effector cells (immune cells, epithelial cells, enteric neurons, smooth muscle cells, interstitial cells of Cajal, and enterochromaffin cells) [9, 10, 11]. Enterochromaffin cells (ECs) are the most abundant enteroendocrine cell type in the intestinal epithelium, their arrangement in the colon lets them be in direct contact with gut microbiota, as well as with the afferent and efferent nerve endings (Figure 1). Its importance resides in its ability to produce, store, and release serotonin in the gut. They produce 90% of the serotonin in the body, which is essential for intestinal motility, platelet function, immune response, and bone development [11, 12, 13]. Recently, Dodds et al. [13] developed an
2.1 Tryptophan
Tryptophan (Trp) is an aromatic amino acid that in humans is obtained exclusively by the diet since its biosynthesis is performed in bacteria and plant cells. Although Trp can be metabolized in mammals, microorganisms, and plants, they use different metabolic pathways and produce a vast diversity of metabolites. In mammals, the kynurenine pathway is the most used to degrade it, and only a small proportion is metabolized into serotonin (5-HT, 5-hydroxytryptamine); as the precursor of these metabolites, Trp is considered a key player in the microbiota-gut-brain axis since these neuroactive compounds are involved in depression and other neuropsychiatric disorders [14, 15].
2.2 Kynurenine pathway
Almost 90% of total tryptophan is oxidized to kynurenine across the kynurenine pathway. The initial enzymes of this pathway are the indoleamine-2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) both of which are responsible for converting tryptophan into kynurenine (Figure 2). IDO is present in various organs (brain, GI tract, and liver), and it is typically activated in response to immune stimuli. In contrast, TDO is predominantly expressed in the liver, and its activity depends on tryptophan’s availability. Inflammation plays a central role in IDO and TDO activation since IDO is stimulated by proinflammatory cytokines, particularly interferon gamma, and TDO is stimulated by glucocorticoids. On the other hand, kynurenine can be transformed into two different precursors: kynurenic acid and quinolinic acid. These metabolites are neuroactive and stimulate N-methyl D-aspartate (NMDA) and alpha-7 nicotinic receptors. Its effects are contrasting, whereas kynurenic acid may act as an anti-inflammatory molecule with neuroprotective features, quinolinic acid is excitotoxic [6, 16].
Figure 2.
Tryptophan metabolism host and microbial tryptophan catabolites. Modified from Roth et al. [14]. Overview of the different tryptophan pathways. Microbes degrade tryptophan in the human gut. CNS, central nervous system; EC, Enterochromaffin cells; 5HIAA, 5-Hydroxyindolacetic acid; MAO, monoamine oxidase; IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; 3HAA, 3-Hydroxyanthranilic acid; 3HK, 3-Hydroxykynurenine; XA, Xanthurenic acid; NAD, nicotinamide adenine dinucleotide; IPYA, indole-3-pyurvic acid; ILA, indole-3-lactic acid; IA, indole acrylic acid; IPA, indolic-3-propionic acid; IAM, indole-3-acetamide; IAA, indole-3-acetic acid; IAld, indole-3-aldehyde; IAAld, indole-3-acetaldehyde. Created with BioRender.com.
2.3 Serotonin pathway (CNS and enterochromaffin cells)
The serotonin or 5-HT pathway is also crucial to human physiology as this neurotransmitter influences physiological and behavioral functions such as cognitive and emotional processes, autonomic control, and circadian rhythm. 5-HT acts not only in the CNS but also has various effects externally. For example, it regulates GI and heart rate regulation and mammary gland development, and more recently, potential roles beyond being a neurotransmitter have been reported. The latest studies have revealed that 5-HT can regulate neuronal growth and differentiation during early brain development. Additionally, it has been reported that 5-HT can undergo serotonylation, a mechanism in which covalent bonds are formed with certain substrate proteins, such as histones, giving rise to a class of histone posttranslational modifications that play important roles in regulating neuronal transcriptional programs [15, 17].
5-HT is a monoamine that can be synthesized in the brain and gut by two isoforms of Trp hydroxylase (TPH). In the brain, TPH2 catalyzes 5-HT conversion in monoaminergic neurons (central 5-HT); it represents only a small proportion of the body’s total 5-HT. In contrast, peripheral 5-HT (the most abundant) is produced by ECs across TPH1. After 5-HT synthesis, it can be metabolized to form melatonin or 5-hydroxyindoleacetic acid (5-HIAA) and the major 5-HT metabolite (Figure 2). Normally, 5-HT cannot cross the blood-brain barrier, so there are differences in the availability of serotonin along the GBA [6, 17].
2.4 Indole pathway and microbial tryptophan catabolites
Most proteins are digested and absorbed in the small intestine; however, increased protein intake lets a significant amount of these proteins and amino acids reach the colon, where a wide range of commensal bacteria triggers their catabolism. Trp is metabolized into indole and indole derivatives (indole-3-aldehyde (IAld), indole3-acetic-acid (IAA), and indole-3-propionic acid (IPA)) (Figure 2). Gram-negative and Gram-positive bacterial species, such as
Recent advances have suggested that microbiota-derived tryptophan catabolites are crucial for maintaining intestinal homeostasis, and several mechanisms have been described (Figure 3). Indole, IPA, and IA can influence gut cells, reducing intestinal permeability and thus affecting mucosal homeostasis. On the other hand, indole induces enteroendocrine L-cells to release glucagon-like peptide 1 (GLP-1), which triggers effects such as appetite suppression and insulin secretion, and slowed gastric emptying. Additionally, some catabolites stimulate intestinal immune cells
Figure 3.
Microbial tryptophan catabolites host effects. Modified from Roager and Licht [19]. IA, indole acrylic acid; IPA, indolic-3-propionic acid; IAA, indole-3-acetic acid; IAld, indole-3-aldehyde; 5-HT, 5-hydroxytryptamine; GLP-1, glucagon-like peptide 1; AHR, aryl hydrocarbon receptor; IS, indoxyl sulfate. Created with BioRender.com.
3. Physiological effects (hunger and satiety, intestinal health, mental health, and insulin sensitivity)
The gut-brain axis is a bidirectional complex that maintains communication between the central nervous system and the digestive tract. The brain integrates it, the spinal cord, the autonomic nervous system (sympathetic, parasympathetic, and enteric nervous systems), and the neuroendocrine and neurohumoral systems [19, 22].
The intestinal microbiota is composed of 1013–1014 microbial cells. Its distribution is 90% bacteria, predominantly Firmicutes and Bacteroidetes; the other 10% between Actinobacteria and Proteobacteria and in smaller proportion between Verrucomicrobes, Fusobacteria, Cyanobacteria, and nonbacterial microorganisms, such as archaea and yeasts [23, 24].
The microbiota has four main functions:
Metabolic function is related to the production of short-chain fatty acids (SCFA), the balance between fatty acid oxidation and lipogenesis, and vitamin synthesis [25].
The immunological function is related to the activation of T lymphocytes, the production of immunoglobulins by B production of immunoglobulins by B lymphocytes, the release of proinflammatory and immunoregulatory cytokines, and the secretion of hormones, neuropeptides, and neurotransmitters. These processes are triggered by the recognition of so-called pathogen-associated molecular patterns (PMAPs) by pattern recognition receptors [25, 26].
Physiological and barrier function consists of cell turnover, linked to apoptosis and maintenance of the barrier function, with components of the immune system, hormones, and metabolites from the intestinal lumen into the bloodstream [26, 27].
These functions are important for the production and regulation of the passage of proinflammatory cytokines, toxins, and microorganisms into the bloodstream, which stimulates the release of hormones, immunoglobulins, and the activation of systems, such as the hypothalamic-pituitary-adrenal (HPA) axis with the consequent production of cortisol and the activation of the vagal system [25, 28].
The small intestine has a layer called mucosa, which is the first line of defense, and digests, and absorbs nutrients, electrolytes, and water. The mucosa-associated lymphoid tissue (MALT) and the intestine-associated lymphoid tissue (GALT) are in charge of the immune response, which is formed by lymphoid nodules and isolated lymphocytes that generate their own response and originate innate and adaptive (humoral) immune response and production of inflammatory cytokines, among them tumor necrosis factor-alpha (TNF-α) and interleukin I and 6 regulatory and cooperator T lymphocytes [28, 29].
The large intestine acts as a selective barrier to microorganisms and participates in conjunction with the epithelium, lymphoid tissue, and calciform cells [29].
The microbiome is formed by signaling from the microorganisms themselves and their postbiotics called “quorum sensing,” which participate in physiological processes. This microbiota-brain axis has been related to several homeostatic physiological processes such as digestion, hunger-satiety axis, metabolism, eating behaviors, and neural problems. The three main related axes are immune, neuronal, and metabolic, as seen in Figure 4 [28, 30, 31].
Figure 4.
Effects of the microbiota-gut-axis.
3.1 Metabolic effects
Signals following ingestion are transmitted to the central nervous system (CNS) where the hypothalamus integrates signals emitted from the neuroendocrine cells of the intestinal epithelium that sense the luminal milieu and release glucagon-like peptide and cholecystokinin (CCK), gastric intestinal polypeptide (GIP), and pancreatic polypeptide (PYY) acting in a paracrine manner, which is directed to peripheral organs. These peptides are released near afferent neurons, these send signals to the solitary nucleus and the arcuate nucleus, and this signal is also activated by the enteric nervous system, which is activated by the production of serotonin at the intestinal level, by tryptophan metabolism and intraganglionic laminar endings, also the peptides can go directly to the circulation and arrive directly to the solitary tract [31, 32, 33].
In the arcuate nucleus, the signals emitted by these intestinal peptides can regulate glucose and energy homeostasis, where the orexigenic (hunger) and anoxygenic (satiety) neurons intervene [31, 33].
On the other hand, the vagus nerve transmits information to regulate energy homeostasis and glucose levels. Chronic stimulation of vagal afferent pathways is known to reduce energy intake. Glucose consumption increases this vagal signaling [34].
3.2 Effects on blood glucose
In the intestine, glucose is also formed by gluconeogenesis, which improves insulin sensitivity. Other peptides increase glucose-6-phosphatase. Changes in the microbiota contribute to vagal afferent desensitization. It is known that the consumption of fat in food may also play a role in this desensitization [34, 35].
The enteroendocrine cells of the small and large intestine secrete GLP-1 and GIP, although it is greater in the large intestine and to a greater extent GLP-1 through the action of metabolites secreted from microorganisms (Figure 1). On the other hand, the release of SCFA, which is a product of intestinal microbiota metabolism, induces the release of GLP-1 by G protein-bound receptors in enterocytes [36, 37].
Additionally, GLP-1 release reduces food intake by the aforementioned mechanisms. GIP acts in the pancreas by stimulating the release of insulin and neurons found in the paraventricular nucleus so that an impairment in the production and intestinal permeability or reduction in SCFA has been related to increased body weight, dyslipidemia, and increased appetite signaling as well as leptin resistance [37, 38].
More recent studies have described that tryptophan metabolism
3.3 Brain function
The microbiome can influence brain function by pathways that include the release of neurotransmitters and neurotransmitter metabolites that modulate the immune system and the regulation of the hypothalamic-pituitary-adrenal axis. The enteric nervous system is connected to the central nervous system, and the vagal nerve modulates the release of neurotransmitters such as acetylcholine, dopamine, and norepinephrine, which additionally also affects hormone production [40].
The gut-brain axis has been implicated in brain aging, plasticity, and cognition, and it is known that there are four messengers involved in this brain operation: short-chain fatty acids, branched amino acids, peptides, gut hormones, cytokines and sensory neurons. There are four messengers involved in this brain function: short-chain fatty acids, branched amino acids, peptidoglycans, gut hormones, cytokines and sensory neurons [41].
Short-chain fatty acids are produced by the fermentation of gastrointestinal microorganisms, and these act by regulating neuroplasticity, epigenetic expression, and the immune system. Sodium butyrate improves serotonin production and behavior, for example, in mice, it has decreased depression and intestinal hormones, such as GLP-1, and GIP, not only regulate appetite but also stimulate the colonic vagal system. Amines (such as tryptophan, and tyramine), travel through the blood system and also affect local neurons and cells of the central nervous system and afferent pathways of the vagus nerve [42].
Within the production of neurotransmitters, it is known that Bacteroides, Bifidobacterium, Parabacteroides, and Escherichia spp. produce γ-aminobutyric acid (GABA) and are important in the production of serotonin (5-hydroxytryptamine 5-HT); most of this component is produced in the intestine, and although it does not affect the amount of serotonin in the brain and does not cross the blood-brain barrier, it has been shown that it does have a modulatory role in the 5HT signaling pathways in the brain. The mechanism is not yet fully elucidated; however, it is known that cells of the innate immune system such as dendritic cells, monocytes, and mast cells express serotonin receptors and transporters. Something similar occurs in the adaptive system and any blood cell except erythrocytes. Therefore, 5HT regulates inflammation and chemotaxis, in addition to the fact that practically all organs and cells have one or more serotonin receptors [42, 43].
The microorganisms that can lead to the production of metabolites that interact with the nervous system are:
As mentioned above, this relationship is bidirectional and there are factors such as stress that activate the HPA system, which releases corticotropin-releasing hormone into the bloodstream, or the brain, which releases adrenocorticotropic hormone and cortisol, which affects the intestinal barrier. There are also immunomodulators and neurotransmitters that activate neurons in the intestinal system and the vagus nerve, which in turn changes the composition of the microbiota [43, 45].
4. The intestinal microbiota as a modifier of tryptophan metabolism: dysregulation and associated pathologies
As mentioned earlier, the composition of the microbiota can be influenced by age, sex, genetics, geography, probiotics, race, stress, smoking, diet, medication (especially antibiotics), or gastrointestinal infections. These differences can alter availability and tryptophan metabolism and be associated with various pathologies [14, 46].
The luminal tryptophan availability is influenced by microbial tryptophan metabolism. Restrictive diets, low in protein or essential amino acids, in addition to causing anorexia and weight loss [10, 47, 48], can reduce microbial proliferation (Lactobacillus) and through dietary intake improve microbial metabolism and increase Indol 3-aldehyde (IAld). In animal models, high-fat diets deplete microbial metabolites of indole-3-acetic (IAA) acid and tryptamine, indicating that microbial degradation is diminished. Formula milk alters serotonin to tryptamine metabolism. A diet rich in carbohydrates the microbial metabolism of tryptophan is affected, indigestible carbohydrates (starch) facilitate the production of (SCFAs), and reduce the degradation of tryptophan and Indole compounds, in addition to the increase in tryptophan levels in the large intestine and serum [6].
Oral antibiotics modify the composition and metabolism of the IM, in case of depletion, serotonin levels are reduced, the colon motility is delated, the kynurenine pathway is affected, and the availability of Trp is increased [6, 49]. In addition to the administration antibiotics increase the levels of indol and compounds in the large intestine [49].
4.1 Inflammatory bowel disease and irritable bowel syndrome
Among the diseases mort linked to the IM inflammatory bowel disease, patients with ulcerative colitis and Crohn’s disease, and tryptophan levels in serum are lower than healthy controls, this suggests that changes in metabolism are involved in the etiology of inflammatory bowel disease. Metagenomic analysis of tool samples a reduction of intestinal microorganisms involved in Trp in addition to a lower production of ligands AHR observed [14]. The increase in the catabolism of Typ in intestinal immune cells is associated with impaired ability to degrade Typ limiting the bioavailability of beneficial indole derivatives and contributing to the severity of the disease [50].
Irritable bowel syndrome is characterized by abdominal pain and changes in bowel habits. Kynurenine to Trp levels have been shown to be increased in plasma. The composition of the gut microbiota may play an important role in pathogenesis since bacterial abundance and brain connectivity are different in healthy controls [6].
4.2 Alzheimer disease
There is evidence of the influence of Trp metabolites, the IM, and the neuroinflammatory process associated with Alzheimer’s disease (AD) [51]. In patients with AD, a significant difference has been found in the taxonomy of the intestinal microbiota with a predominance in the decrease of Fermicutes and Actinobacteria in addition to an increase in Bacteroidetes species, compared to agematch control patients. Another study reported that patients with AD had reduced circulating Trp levels and elevated kynurenine/TPH ratios, it is also associated with greater cognitive impairment and elevated proinflammatory cytokines [51].
4.3 Parkinson disease
Current evidence suggests that the microbiota is involved in the pathogenesis through inflammatory neurotoxicity. The abundance of Bacteroidetes in this type of patient correlates with the clinical severity of motor symptoms and high levels of proinflammatory TNFα and INFγ. Verrucomicrobia is associated with higher levels of INFγ and possible interaction with metabolites of IDO and Trp. Parkinson’s disease patients have elevated proportions of kynurenine/TPH in plasma, as well as reduced KAT activity relative to control patients [14].
4.4 Multiple sclerosis
Analysis of stool from multiple sclerosis patients showed an increase in Methanobrevibacter and Akkermansia, as well as a decrease in Butyricimones compared to control patients. Patients have reduced circulation of the aryl hydrocarbon receptor of tryptophan hydrolase metabolites, indicating a metabolic dysregulation in pathogenesis [14].
4.5 Migraine
Clinical studies focusing on intestinal microbial changes in migraine patients have shown that intestinal dysbiosis worsens migraine pain in a TNFa-dependent process. The analysis of fecal samples of elderly women showed elevation of Firmicutes, especially of the Clostridium species, compared to the control group of the same age. In addition, Kynurenine metabolites have also been found to be elevated in this same group of patients [14].
4.6 Anxiety and depression
Serotonin is widely studied in anxiety and depression. In susceptible populations, such as older adults, a decrease in plasma tryptophan concentration may cause mood changes. It has been observed that decreased Trp levels and a higher ratio of kynurenine to Trp in plasma are associated with depression [6]. There is evidence of the role of the intestinal microbiota in the onset and clinical phenotype of this type of disorder. It has been observed that depression affects the HPA axis, neurotransmitter levels, and the inflammatory process are affected [52]. A study in mice revealed that in chronic sleep restriction stress, and these animals had depressive behavior, strong activation of the Kyn pathway, and IDO in the brain and gut. In germ-free mice, more anxious behavior has been observed in contrast to conventionally bred mice. Even with microbial repopulation after weaning, the behavior was not easily reversible, which is why it is described as a critical period during which the gut microbiota can aid psychological development [6]. In addition, children born overweight and overweight mothers have been observed to show higher scores of anxiety, shyness, and depression, correlated with the abundance of Actinobacteria and Fusobacteria [53].
4.7 Autism spectrum disorder
Autism spectrum disorder (ASD) is a disorder characterized by social and behavioral impairment. In addition to neurological symptoms, the patient often suffers from gastrointestinal abnormalities. Some microbial species have been linked to the pathogenesis of this disease; symptoms have been linked to a reduction of
4.8 Cerebrovascular disease
Tryptophan metabolites may influence the development and severity of cerebrovascular disease. It has been observed that in stroke patients, there is a positive correlation between the kyn/Trp ratio and the severity of stroke. Patients with acute ischemic stroke metabolic profiles showed elevated levels of serum lactate, carbonate, and glutamate, in addition to lower levels of Try and other amino acids [14].
The IM has been studied in animal models, such as stroke patients, and the microbial diversity has been observed to collapse after ischemic stroke metabolic in the days after stroke onset. Gut dysbiosis contributes additionally to the pathogenesis of stroke risk factors such as diabetes mellitus, hypertension, obesity, and metabolic syndrome [14].
4.9 Metabolic disorder
The IM plays a fundamental role in the metabolic balance of the host. It is now known that the intestinal IM is involved in the pathogenesis of metabolic disorders [50]. Metabolic disorders represent a group of interrelated pathological conditions that combine obesity, dyslipidemia, glucose intolerance, insulin resistance, hypertension, and diabetes mellitus, which, as mentioned above, increase the incidence of cardiovascular disease and increase mortality [54].
Specific classes where IM-derived metabolites, such as bile acids, branched-chain amino acids, Trp metabolites, and indole derivatives, have been implicated in metabolic disorders [50].
Cross-sectional studies have shown that tryptophan catabolism is altered in individuals with obesity and metabolic syndrome, and kynurenine/tryptophan ratios of blood concentrations are elevated in obese, metabolic syndrome, or hyperuricemia patients compared to healthy controls. In addition, kynurenine/tryptophan ratios correlate positively with BMI, triglyceride, and uric acid levels [50].
In a cohort study of diabetic patients, kynurenine levels were found to be positively associated with BMI and a higher HOMA2 insulin resistance index. Another study focused on alterations in plasma and fecal levels of Trp catabolites found that plasma levels of kynurenine were higher in obese or type 2 diabetic subjects than in control patients. In addition, in feces, a change in Trp catabolism toward kynurenine and lower production of indole-3-acetic acid were observed in obese and diabetic patients without treatment. Rationale suggests increased intestinal IDO1 activity and inhibition of the microbial indole pathway [50, 54].
Alterations in Tpy levels have also been observed in older adults with diabetes mellitus with aging, and the composition and function of adipose tissue changes, leading to insulin resistance. There are also cellular changes such as mitochondrial dysfunction, antioxidant deficiency, inflammation, and decreased immune response, changes that affect the Kyn pathway. It has also been observed that adults over 65 years of age have lower Tpy levels than younger groups [55].
Carcinogenesis is related to immune status and environmental factors, among them the intestinal microbiota and its metabolites, the bacterial metabolites of Trp play a role in the development of several types of cancer [54]. Under physiological conditions and as a defense mechanism, local inflammation depletes Tpy, which limits the growth of microbes and the proliferation of malignant cells. Under tumor conditions, the degradation of Trp and the accumulation of its metabolites increases, suppressing the tumor’s immune response as a defense mechanism [56].
Between 16 and 20% of cancers are the result of pathogenic infections. Patients with Crohn’s disease harbor pathogenic
Trp catabolism exerts immunosuppressive actions in many types of cancer. Aryl hydrocarbon receptor activation in myeloid cells promotes an immunosuppressive tumor microenvironment and facilitates pancreatic ductal adenocarcinoma growth. In gastrointestinal, lung, melanoma, prostate, and pancreatic cancers, over-activation of the Kyn pathway, particularly IDO, predicts a bad prognosis [54].
4.10 Dermatological disorders
The skin and the intestine have similar characteristics with microorganisms that regulate their function and use of metabolites. Of the main related reactions, it has been demonstrated that the immune inflammation is caused by leukocytes, keratinocytes, macrophages, neutrophils, and T cells that increase inflammation and psoriasis by releasing proinflammatory cytokines. The gut axis and gut microbiota are the key elements of the gut-brain-skin axis and play an important role in the association between psoriasis and depression.
It has also been found that abnormal induction of the Kyn pathway is associated with dermal fibroblast infiltration and the release of inflammatory interleukins. Physiologically the skin microbiota degrades host tryptophan to regulate inflammation
5. Therapeutic strategies
The intestinal microbiota IM develops numerous metabolic processes. It needs to maintain an adequate state in its composition and functions (eubiosis) to maintain its state of health [8]. The genetic diversity of microbial communities determines a large number of enzymes and biochemical pathways, which are modified according to the conditions of the host, even in severe pathological states, such as cancer [59]. Its metabolic function makes it a therapeutic target when it is altered (dysbiosis). The advances achieved in the sequencing 16S rRNA, metagenomics, proteomics, and transcriptomics, allow to know its composition and functions, providing criteria with therapies according to the existing pathology [31, 60].
The intestinal microbiota, in our gut, plays a critical role in maintaining our overall health. It is responsible for various metabolic processes and must remain in a healthy state to ensure that we stay healthy. The diversity of microbial communities in our gut determines the many enzymes and biochemical pathways that are present, and these can be altered in response to the host’s condition, even in severe cases such as cancer. When the microbiota is altered, it can become a therapeutic target, and advances in sequencing and analysis have allowed us to better understand its composition and functions. With this knowledge, we can develop targeted therapies that are tailored to the patient’s specific needs [31].
5.1 Intestinal microbiota as a therapeutic target
The therapeutic targets at this level are numerous due to the complexity of existing microorganisms, whose influence and role within MI are increasingly found. This forces us to search for the best possible scenario to acquire knowledge of its importance and role played in health (eubiosis) and an alternative in disease management (dysbiosis), as well as an adequate perspective of its disease preventive capacity [61]. Because the modifications of microorganisms and their genes and enzymes affect the metabolism of the nutrients and substances that enter, they give rise to metabolites in an inappropriate way that leads to multiple pathologies. The relationship between metabolites/products is known as the microbiome since it implies genetic participation [31]. The study of dysbiosis is so important that specific databases have been developed since 2018, where every time new microorganisms, related diseases, or metabolites are registered; they are automatically added to these data [62]. It is expected that the use of microbes in genetic form will achieve disease preventive effects. In studies carried out, some metabolites exhibit the ability to potentiate other drugs by enhancing their beneficial effect, for example, for chemotherapeutic agents in the pancreas and ovary. Every day advances in the knowledge of therapeutic targets to restore not only the alteration of the beneficial and commensal species specific to the individual but also their capacity for participatory microbiome [61, 63].
In dysbiosis, strategies have been applied to restore the native microbiome. These range from fecal microbiota transplantation (FMT), and the use of pre, pro, and synbiotics to the use of new biotechnological drugs with inhibition of enzymes involved in the metabolism of such essential substances as tryptophan [19]. Other alternatives, both natural, traditional, and pharmacological medicines with synthetic biology are also studied [61, 64].
Genetic engineering offers the possibility of generating molecules, antitoxins, bacteriophages, peptides, and microbial metabolites, but most studies have been carried out in rodents. At the moment, the pharmaceutical industry is conducting studies at different phases of research with encouraging results based on well-established knowledge [65]. So, certain bacterial types are found to improve diseases, where
5.2 Increase the amount of gut microbiota
It involves directing the benefits of the host-microbiome interaction by adding strains of microbes that are diminished. They can be individual strains or a group of them. The microbes used can be natural or genetically modified to produce therapeutic molecules. It can be with probiotics or fecal microbiota transplantation (FMT).
FMT, in general, involves the therapeutic administration of healthy microbial populations to replace disease-causing ones. There are different types of selection, preparation, and management for FMT found in the literature. The main diseases that have responded adequately to FMT are listed:
The most used are Lactobacilli, bifidobacteria, and
The main probiotics, both native and modified, make up such an extensive list for the purposes of the book that it is suggested to go to the review done by Yadav and Chauhan [61].
5.3 Reduce gut microbiota
It is intended to reduce the number of pathogenic microbes through bacteriocins and bacteriophages. It is intended to achieve the desired effect without significantly affecting the other members of the IM. Bacteriocins are peptides synthesized in ribosomal form that show antimicrobial activity. Two classes have been identified and the bacteria that produce bacteriocins are Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. There is a long list of bacteriocins that are very helpful in various fields, both medicine and other areas. Resistance to bacteriocins can also be found.
Bacteriophages are viruses that have specificity for a bacterium. It inserts itself into the genome and causes bacterial membrane disintegration. They are considered a suitable alternative to antibiotic-resistant germs. Engineered phages use a CRISPR-cas system to destroy pathogens. Unlike IM and probiotics, their specific targets are pathogenic bacteria [61].
5.4 Modulatory therapy
Includes the modulation of IM or its interactions with the host for therapeutic purposes. It considers the restoration of diminished MI and the transformation of existing flora to achieve a healthier MI. It can be through diet, exercise, and antibiotics. Diet plays a critical role in the use of vitamin D.
Other types of therapeutic targets and beneficial germs that can help have been added to the literature such as psychobiotics (help in improving mental health in mental illness), postbiotics (inanimate microbes or their products that provide benefits), and synbiotics (mixtures of pre- and probiotics).
An important model for understanding therapies for MI is inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis. The disorder of the intestinal flora of this disease is considered to offer the greatest number, both in pharmacological strategies and the use of natural remedies and traditional medicines, and some tested with adequate results. In IBD, the participation of the intestinal microbiota (IM) stands out. Significant growth of proinflammatory microorganisms is found, including
5.5 Pharmacological interventions and possible therapeutic targets on tryptophan metabolism
At the level of the brain, the amino acid tryptophan plays a vital role in the synthesis of important biological molecules. Its metabolites are involved in a large number of processes; many beneficial types, depending on the metabolic pathways it follows, can give rise to malignant types, such as proteins in cancer cells. It also produces the activation of immunity and antitumor effects, which makes it a very complex component to achieve therapeutic interventions, due to the complex management within the host. One component is the administration of D tryptophan as a supplement, but within the body, its therapeutic targets are found in its metabolites and enzymes that intervene according to metabolic pathways. An important marker is the Kyn: Trp ratio, which increases with age causing frailty in adults. The KYNU enzyme is one of the most gene expressed. The main enzymes are tryptophan-2,3-dioxygenase (TDO), indolamine2,3-dioxygenase 1 (IDO1), indolamine-2,3-dioxygenase (IDO2), and KMO. All can be managed with inhibitors, modulators, agonists, and antagonists primarily [68].
6. Conclusions
The knowledge about the interaction between tryptophan metabolism and the gut microbiota has expanded greatly in recent years. Tryptophan and its metabolites modulated through the gut microbiota are involved in several host physiological and pathological processes. Degradation of tryptophan and its metabolites is an important target from a therapeutic perspective; however further. Research is required to refine effective dose ranges and gut microbial species to modulate host physiology.
Conflict of interest
The authors declare that there is no conflict of interest for the publication of this work; no financial or material assistance was received from any company.
References
- 1.
Ratsika A, Codagnone MC, O’mahony S, Stanton C, Cryan JF. Priming for life: Early life nutrition and the microbiota-gut-brain Axis. Nutrients. 2021; 13 (2):1-33. DOI: 10.3390/NU13020423 - 2.
Chen Y, Zhou J, Wang L. Role and mechanism of gut microbiota in human disease. Frontiers in Cellular and Infection Microbiology. 2021; 11 (625913):1-12. DOI: 10.3389/FCIMB.2021.625913/PDF - 3.
Milani C et al. The first microbial colonizers of the human gut: Composition, activities, and health implications of the infant gut microbiota. Microbiology and Molecular Biology Reviews. 2017; 81 (4):e00036-17. DOI: 10.1128/MMBR.00036-17 - 4.
Rowland I et al. Gut microbiota functions: Metabolism of nutrients and other food components. European Journal of Nutrition. 2018; 57 (1):1-24. DOI: 10.1007/S00394-017-1445-8 - 5.
Hasan N, Yang H. Factors affecting the composition of the gut microbiota, and its modulation. PeerJ. 2019; 7 (8):1-31. DOI: 10.7717/PEERJ.7502 - 6.
Gao K, Mu CL, Farzi A, Zhu WY. Tryptophan metabolism: A link between the gut microbiota and brain. Advances in Nutrition. 2020; 11 (3):709-723. DOI: 10.1093/ADVANCES/NMZ127 - 7.
Mayer EA, Nance K, Chen S. The gut-brain Axis. Annual Review of Medicine. 2022; 73 :439-453. DOI: 10.1146/ANNUREV-MED-042320-014032 - 8.
Carloni S, Rescigno M. Unveiling the gut-brain axis: Structural and functional analogies between the gut and the choroid plexus vascular and immune barriers. Seminars in Immunopathology. 2022; 44 (6):869-882. DOI: 10.1007/S00281-022-00955-3 - 9.
Breit S, Kupferberg A, Rogler G, Hasler G. Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Frontiers in Psychiatry. 2018; 9 (44):1-15. DOI: 10.3389/FPSYT.2018.00044/PDF - 10.
Browning KN, Verheijden S, Boeckxstaens GE. The Vagus nerve in appetite regulation, mood, and intestinal inflammation. Gastroenterology. 2017; 152 (4):730-744. DOI: 10.1053/J.GASTRO.2016.10.046 - 11.
Qin HY, Wong HLX, Zang KH, Li X, Bian ZX. Enterochromaffin cell hyperplasia in the gut: Factors, mechanism and therapeutic clues. Life Sciences. 2019; 239 :116886. DOI: 10.1016/J.LFS.2019.116886 - 12.
Xu X, Chen R, Zhan G, Wang D, Tan X, Xu H. Enterochromaffin cells: Sentinels to gut microbiota in hyperalgesia? Frontiers in Cellular and Infection Microbiology. 2021; 11 (760076):1-14. DOI: 10.3389/FCIMB.2021.760076/PDF - 13.
Dodds KN, Travis L, Kyloh MA, Jones LA, Keating DJ, Spencer NJ. The gut-brain axis: Spatial relationship between spinal afferent nerves and 5-HT-containing enterochromaffin cells in mucosa of mouse colon. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2022; 322 (5):G523-G533. DOI: 10.1152/AJPGI.00019.2022 - 14.
Roth W, Zadeh K, Vekariya R, Ge Y, Mohamadzadeh M. Tryptophan metabolism and gut-brain homeostasis. International Journal of Molecular Sciences. 2021; 22 (6):1-23. DOI: 10.3390/IJMS22062973 - 15.
Correia AS, Vale N. Tryptophan metabolism in depression: A narrative review with a focus on serotonin and kynurenine pathways. International Journal of Molecular Sciences. 2022; 23 (15):8493. DOI: 10.3390/IJMS23158493 - 16.
Kim YK. Anxiety disorders: Rethinking and understanding recent discoveries. 2020;p. 566 - 17.
Al-Kachak A et al. Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior. bioRxiv. 2023; 05 (04):539464, 1-71. DOI: 10.1101/2023.05.04.539464 - 18.
Höglund E, Øverli Ø, Winberg S. Tryptophan metabolic pathways and brain serotonergic activity: A comparative review. Frontiers in Endocrinology (Lausanne). 2019; 10 (158):1-11. DOI: 10.3389/FENDO.2019.00158 - 19.
Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nature Communications. 2018; 9 (1):1-10. DOI: 10.1038/S41467-018-05470-4 - 20.
Ismael S et al. IPA and its precursors differently modulate the proliferation, differentiation, and integrity of intestinal epithelial cells. Nutrition Research and Practice. 2023; 17 (4):616-630. DOI: 10.4162/NRP.2023.17.4.616 - 21.
Tan YQ et al. Host/microbiota interactions-derived tryptophan metabolites modulate oxidative stress and inflammation via aryl hydrocarbon receptor signaling. Free Radical Biology & Medicine. 2022; 184 :30-41. DOI: 10.1016/J.FREERADBIOMED.2022.03.025 - 22.
Carlos Pineda-Cortes J, Carlos Pineda J. El Microbioma y las enfermedades neurodegenerativas del Sistema Nervioso Central Autor para correspondencia. Revista biomédica. 2017; 1 :28 - 23.
Rodriguez-Valera F et al. Explaining microbial population genomics through phage predation. Nature Precedings. 2009; 07 (11):828-836. DOI: 10.1038/npre.2009.3489.1 - 24.
Rooks MG et al. Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission. The ISME Journal. 2014; 8 (7):1403. DOI: 10.1038/ISMEJ.2014.3 - 25.
Cryan JF et al. The microbiota-gut-brain Axis. Physiological Reviews. 2019; 99 (4):1877-2013. DOI: 10.1152/PHYSREV.00018.2018 - 26.
Fernandez-Real JM et al. Gut microbiota interacts with brain microstructure and function. The Journal of Clinical Endocrinology and Metabolism. 2015; 100 (12):4505-4513. DOI: 10.1210/JC.2015-3076 - 27.
Zhou H, Wang L, Liu F. Immunological impact of intestinal T cells on metabolic diseases. Frontiers in Immunology. 2021; 12 (639902):1-13. DOI: 10.3389/FIMMU.2021.639902 - 28.
Taleb S. Tryptophan dietary impacts gut barrier and metabolic diseases. Frontiers in Immunology. 2019; 10 (2113):1-7. DOI: 10.3389/FIMMU.2019.02113 - 29.
Valle-Noguera A, Ochoa-Ramos A, Gomez-Sánchez MJ, Cruz-Adalia A. Type 3 innate lymphoid cells as regulators of the host-pathogen interaction. Frontiers in Immunology. 2021; 12 (748851):1-19. DOI: 10.3389/FIMMU.2021.748851 - 30.
Jostins L et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491 (7422):119-124. DOI: 10.1038/NATURE11582 - 31.
Falà AK, Álvarez-Ordóñez A, Filloux A, Gahan CGM, Cotter PD. Quorum sensing in human gut and food microbiomes: Significance and potential for therapeutic targeting. Frontiers in Microbiology. 2022; 13 :1002185. DOI: 10.3389/FMICB.2022.1002185/BIBTEX - 32.
Moser B, Milligan MA, Dao MC. The microbiota-gut-brain Axis: Clinical applications in obesity and type 2 diabetes. Revista de Investigación Clínica. 2022; 74 (6):302-313. DOI: 10.24875/RIC.22000197 - 33.
Wachsmuth HR, Weninger SN, Duca FA. Role of the gut–brain axis in energy and glucose metabolism. Experimental & Molecular Medicine. 2022; 54 (4):377-392. DOI: 10.1038/s12276-021-00677-w - 34.
Christensen LW, Kuhre RE, Janus C, Svendsen B, Holst JJ. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. Physiological Reports. 2015; 3 (9):e12551, 1-13. DOI: 10.14814/PHY2.12551 - 35.
Müller M et al. Circulating but not faecal short-chain fatty acids are related to insulin sensitivity, lipolysis and GLP-1 concentrations in humans. Scientific Reports. 2019; 9 (1):1-9. DOI: 10.1038/s41598-019-48775-0 - 36.
Palmnäs-Bedard MSA et al. The human gut microbiota and glucose metabolism: A scoping review of key bacteria and the potential role of SCFAs. The American Journal of Clinical Nutrition. 2022; 116 (4):862-874. DOI: 10.1093/AJCN/NQAC217 - 37.
Müller TD et al. Glucagon-like peptide 1 (GLP-1). Molecular Metabolism. 2019; 30 :72-130. DOI: 10.1016/J.MOLMET.2019.09.010 - 38.
He J et al. Short-chain fatty acids and their association with Signalling pathways in inflammation, glucose and lipid metabolism. International Journal of Molecular Sciences. 2020; 21 (17):1-16. DOI: 10.3390/IJMS21176356 - 39.
Qi Q et al. Host and gut microbial tryptophan metabolism and type 2 diabetes: An integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies. Gut. 2022; 71 (6):1095. DOI: 10.1136/GUTJNL-2021-324053 - 40.
Muller PA et al. Microbiota modulate sympathetic neurons via a gut–brain circuit. Nature. 2020; 583 (7816):441-446. DOI: 10.1038/s41586-020-2474-7 - 41.
Pang S, Wen-Yi J, Zi W. The interplay between the gut microbiome and neurological disorders: Exploring the gut-brain Axis. Neurology Letters. 2023; 2 (1):25-29. DOI: 10.52547/NL.2.1.25 - 42.
Smith PA. The tantalizing links between gut microbes and the brain. Nature. 2015; 526 (7573):312-314. DOI: 10.1038/526312A - 43.
Sarubbo F, Moranta D, Tejada S, Jiménez M, Esteban S. Impact of gut microbiota in brain ageing: Polyphenols as beneficial modulators. Antioxidants. 2023; 12 (4):1-19. DOI: 10.3390/ANTIOX12040812 - 44.
Morais LH, Schreiber HL, Mazmanian SK. The gut microbiota-brain axis in behaviour and brain disorders. Nature Reviews. Microbiology. 2021; 19 (4):241-255. DOI: 10.1038/S41579-020-00460-0 - 45.
Blacher E et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature. 2019; 572 (7770):474-480. DOI: 10.1038/S41586-019-1443-5 - 46.
Ortiz GG et al. Gut-brain Axis: Role of microbiota in Parkinson’s disease and multiple sclerosis. Eat, Learn, Remember. 2019:11-30. DOI: 10.5772/INTECHOPEN.79493 - 47.
Zapata RC, Singh A, Ajdari NM, Chelikani PK. Dietary tryptophan restriction dose-dependently modulates energy balance, gut hormones, and microbiota in obesity-prone rats. Obesity. 2018; 26 (4):730-739. DOI: 10.1002/OBY.22136 - 48.
Strasser B, Fuchs D. Diet versus exercise in weight loss and maintenance: Focus on tryptophan. International Journal of Tryptophan Research. 2016; 9 (1):9-16. DOI: 10.4137/IJTR.S33385/ASSET/IMAGES/LARGE/10.4137_IJTR.S33385-FIG2.JPEG - 49.
Zhang C, Yu M, Yang Y, Mu C, Su Y, Zhu W. Differential effect of early antibiotic intervention on bacterial fermentation patterns and mucosal gene expression in the colon of pigs under diets with different protein levels. Applied Microbiology and Biotechnology. 2017; 101 (6):2493-2505. DOI: 10.1007/S00253-016-7985-7 - 50.
Liu M, Nieuwdorp M, de Vos WM, Rampanelli E. Microbial tryptophan metabolism tunes host immunity, metabolism, and Extraintestinal disorders. Metabolites. 2022; 12 (9):1-24. DOI: 10.3390/METABO12090834 - 51.
Savonije K, Weaver DF. The role of tryptophan metabolism in Alzheimer’s disease. Brain Sciences. 2023; 13 (2):1-12. DOI: 10.3390/BRAINSCI13020292 - 52.
Klimova B, Novotny M, Valis M. The impact of nutrition and intestinal microbiome on elderly depression-a systematic review. Nutrients. 2020; 12 (3):1-12. DOI: 10.3390/NU12030710 - 53.
Nieto-Ruiz A et al. Maternal weight, gut microbiota, and the association with early childhood behavior: The PREOBE follow-up study. Child and Adolescent Psychiatry and Mental Health. 2023; 17 (1):2-18. DOI: 10.1186/S13034-023-00589-9 - 54.
Su X, Gao Y, Yang R. Gut microbiota-derived tryptophan metabolites maintain gut and systemic homeostasis. Cells. 2022; 11 (15):2296, 1-20. DOI: 10.3390/CELLS11152296 - 55.
Khoshnevisan K, Chehrehgosha M, Sajjadi-Jazi SM, Meftah AM. Tryptophan and serotonin levels as potent biomarkers in diabetes mellitus complications: A new approach of diagnostic role. Journal of Diabetes and Metabolic Disorders. 2022; 21 (2):1923-1934. DOI: 10.1007/S40200-022-01096-Y - 56.
Ghiboub M, Verburgt CM, Sovran B, Benninga MA, de Jonge WJ, Van Limbergen JE. Nutritional therapy to modulate tryptophan metabolism and aryl hydrocarbon-receptor signaling activation in human diseases. Nutrients. 2020; 12 (9):1-21. DOI: 10.3390/NU12092846 - 57.
Wyatt M, Greathouse KL. Targeting dietary and microbial tryptophan-indole metabolism as therapeutic approaches to colon cancer. Nutrients. 2021; 13 (4):1-23. DOI: 10.3390/NU13041189 - 58.
Guenin-Macé L et al. Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa. JCI Insight. 2020; 5 (20):e140598, 1-15. DOI: 10.1172/JCI.INSIGHT.140598 - 59.
Tintelnot J et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 2023; 615 (7950):168-174. DOI: 10.1038/S41586-023-05728-Y - 60.
Guillot CC. Microbiota intestinal y salud infantil intestinal microbiota and child health. Revista Cubana de Pediatría. 2018; 90 (1):94-110. Available from:http://scielo.sld.cu [Accessed: August 19, 2023] - 61.
Yadav M, Chauhan NS. Microbiome therapeutics: Exploring the present scenario and challenges. 2021; 15 (10):1-19. DOI: 10.1093/gastro/goab046 - 62.
Janssens Y et al. Disbiome database: Linking the microbiome to disease. BMC Microbiology. 2018; 18 (1):1-6. DOI: 10.1186/S12866-018-1197-5 - 63.
Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut. 2021; 70 (6):1174-1182. DOI: 10.1136/GUTJNL-2020-323071 - 64.
Zhu HZ et al. Xiaoyaosan improves depressive-like behavior in rats with chronic immobilization stress through modulation of the gut microbiota. Biomedicine & Pharmacotherapy. 2019; 112 :108621, 1-13. DOI: 10.1016/J.BIOPHA.2019.108621 - 65.
Charbonneau MR, Isabella VM, Li N, Kurtz CB. Developing a new class of engineered live bacterial therapeutics to treat human diseases. 2020; 11 (1):1-11 DOI: 10.1038/s41467-020-15508-1 - 66.
Mimee M, Citorik RJ, Lu TK. Microbiome therapeutics – Advances and challenges. Advanced Drug Delivery Reviews. 2016; 105 (Pt A):44. DOI: 10.1016/J.ADDR.2016.04.032 - 67.
Zhu M, Song Y, Xu Y, Xu H. Manipulating microbiota in inflammatory bowel disease treatment: Clinical and natural product interventions explored. International Journal of Molecular Sciences. 2023; 24 (13):11004. DOI: 10.3390/IJMS241311004 - 68.
Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nature Reviews Drug Discovery. 2019; 18 (5):379-401. DOI: 10.1038/s41573-019-0016-5