Metabolic disorders represent a growing worldwide health challenge due to their dramatically increasing prevalence. The gut microbiota is a crucial actor that can interact with the host by the production of a diverse reservoir of metabolites, from exogenous dietary substrates or endogenous host compounds. Metabolic disorders are associated with alterations in the composition and function of the gut microbiota. Specific classes of microbiota-derived metabolites, notably bile acids, short-chain fatty acids, branched-chain amino acids, trimethylamine N-oxide, tryptophan and indole derivatives, have been implicated in the pathogenesis of metabolic disorders. This review aims to define the key classes of microbiota-derived metabolites that are altered in metabolic diseases and their role in pathogenesis. They represent potential biomarkers for early diagnosis and prognosis as well as promising targets for the development of novel therapeutic tools for metabolic disorders.

https://gut.bmj.com/content/gutjnl/70/6/1174.full.pdf

Gut microbiota-derived metabolites as central regulators in metabolic disorders.

Synthetic molecular probes, chemosensors, and nanosensors used in combination with innovative assay protocols hold great potential for the development of robust, low-cost, and fast-responding sensors that are applicable in biofluids (urine, blood, and saliva). Particularly, the development of sensors for metabolites, neurotransmitters, drugs, and inorganic ions is highly desirable due to a lack of suitable biosensors. In addition, the monitoring and analysis of metabolic and signaling networks in cells and organisms by optical probes and chemosensors is becoming increasingly important in molecular biology and medicine. Thus, new perspectives for personalized diagnostics, theranostics, and biochemical/medical research will be unlocked when standing limitations of artificial binders and receptors are overcome. In this review, we survey synthetic sensing systems that have promising (future) application potential for the detection of small molecules, cations, and anions in aqueous media and biofluids. Special attention was given to sensing systems that provide a readily measurable optical signal through dynamic covalent chemistry, supramolecular host–guest interactions, or nanoparticles featuring plasmonic effects. This review shall also enable the reader to evaluate the current performance of molecular probes, chemosensors, and nanosensors in terms of sensitivity and selectivity with respect to practical requirement, and thereby inspiring new ideas for the development of further advanced systems.

/pdf/molecular-probes-chemosensors-and-nanosensors-for-optical-3t6xj63m.pdf

Molecular Probes, Chemosensors, and Nanosensors for Optical Detection of Biorelevant Molecules and Ions in Aqueous Media and Biofluids

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways.

/pdf/tryptophan-metabolism-in-depression-a-narrative-review-with-22u140le.pdf

Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways

Under physiological conditions 95% of the ingested essential amino acid tryptophan is metabolized by the kynurenine pathway (KP) to yield the ubiquitous co-enzyme nicotinamide adenine dinucleotide, fulfilling cellular energy requirements. Importantly, the intermediaries of KP exert crucial effects throughout the body, including the central nervous system. Besides, KP metabolites are implicated in diverse disease processes such as inflammation/immune disorders, endocrine/metabolic conditions, cancers and neuropsychiatric diseases. A burgeoning body of research indicates that the KP plays a pathogenic role in major psychiatric diseases like mood disorders and schizophrenia. Triggered by inflammatory processes, the balance between neurotoxic and neuroprotective branches of the KP is disturbed. In preclinical models these discrepancies result in behaviors reminiscent of depression and psychosis. In clinical samples, recent studies are discovering key kynurenine pathway abnormalities which incriminate it in the pathogenesis of the main psychiatric disorders. Harnessing this knowledge has the potential to find disease biomarkers helpful in identifying and prognosticating neuropsychiatric disorders. Concurrently, earnest research efforts directed towards manipulating the KP hold the promise of discovering novel pharmacological agents that have therapeutic value. In this manuscript, an in-depth appraisal of the extant literature is done to understand the working of KP as this applies to neuropsychiatric disorders. It is concluded that this pathway plays an overarching role in the development of major psychiatric disorders, the KP metabolites have the potential to serve as disease markers and new medications based on KP modulation can bring lasting cures for patients suffering from these intractable conditions.

Kynurenine Pathway of Tryptophan Metabolism in Neuropsychiatric Disorders: Pathophysiologic and Therapeutic Considerations.

Serotonin, also known as 5-hydroxytryptamine (5-HT), is a metabolite of tryptophan and is reported to modulate the development and neurogenesis of the enteric nervous system, gut motility, secretion, inflammation, sensation, and epithelial development. Approximately 95% of 5-HT in the body is synthesized and secreted by enterochromaffin (EC) cells, the most common type of neuroendocrine cells in the gastrointestinal (GI) tract, through sensing signals from the intestinal lumen and the circulatory system. Gut microbiota, nutrients, and hormones are the main factors that play a vital role in regulating 5-HT secretion by EC cells. Apart from being an important neurotransmitter and a paracrine signaling molecule in the gut, gut-derived 5-HT was also shown to exert other biological functions (in autism and depression) far beyond the gut. Moreover, studies conducted on the regulation of 5-HT in the immune system demonstrated that 5-HT exerts anti-inflammatory and proinflammatory effects on the gut by binding to different receptors under intestinal inflammatory conditions. Understanding the regulatory mechanisms through which 5-HT participates in cell metabolism and physiology can provide potential therapeutic strategies for treating intestinal diseases. Herein, we review recent evidence to recapitulate the mechanisms of synthesis, secretion, regulation, and biofunction of 5-HT to improve the nutrition and health of humans.

https://www.mdpi.com/1422-0067/22/15/7931/pdf

The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine.

Tryptophan (TRP), an essential amino acid in mammals, is involved in several physiological processes including neuronal function, immunity, and gut homeostasis. In humans, TRP is metabolized via the kynurenine and serotonin pathways, leading to the generation of biologically active compounds, such as serotonin, melatonin and niacin. In addition to endogenous TRP metabolism, resident gut microbiota also contributes to the production of specific TRP metabolites and indirectly influences host physiology. The variety of physiologic functions regulated by TRP reflects the complex pattern of diseases associated with altered homeostasis. Indeed, an imbalance in the synthesis of TRP metabolites has been associated with pathophysiologic mechanisms occurring in neurologic and psychiatric disorders, in chronic immune activation and in the immune escape of cancer. In this chapter, the role of TRP metabolism in health and disease is presented. Disorders involving the central nervous system, malignancy, inflammatory bowel and cardiovascular disease are discussed.

Tryptophan in health and disease.

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Tryptophan in health and disease.