In recent years, gut–brain axis signaling has been recognized as an essential factor modifying behavior, mood, cognition, and cellular viability under physiological and pathological conditions. Consequently, the intestinal microbiome has become a potential therapeutic target in neurological and psychiatric disorders. The microbiota-derived metabolite of tryptophan (Trp), indole-3-propionic acid (IPA), was discovered to target a number of molecular processes and to impact brain function. In this review, we outline the key mechanisms by which IPA may affect neuronal activity and survival and provide an update on the evidence supporting the neuroprotective action of the compound in various experimental paradigms. Accumulating data indicates that IPA is a free radical scavenger, a ligand of aryl hydrocarbon receptors (AhR) and pregnane X receptors (PXR), and an anti-inflammatory molecule. IPA decreases the synthesis of the proinflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and other cytokines, reduces the generation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, and enhances the synthesis of neurotrophic factors. Furthermore, produced in the gut, or administered orally, IPA boosts the central levels of kynurenic acid (KYNA), a neuroprotective metabolite of Trp. IPA reduces the release of proinflammatory molecules in the gut, breaking the gut–inflammation–brain vicious cycle, which otherwise leads to neuronal loss. Moreover, as a molecule that easily enters central compartment, IPA may directly impact brain function and cellular survival. Overall, the gathered data confirms neuroprotective features of IPA, and supports its potential use in high-risk populations, in order to delay the onset and ameliorate the course of neurodegenerative disorders and cognitive impairment. Clinical trials evaluating IPA as a promising therapeutic add-on, able to slow down the progress of neurodegenerative disorders such as Alzheimer’s or Parkinson’s disease and to limit the morphological and behavioral consequences of ischemic stroke, are urgently needed.

In the era of a steadily increasing lifespan, neurodegenerative diseases among the elderly present a significant therapeutic and socio-economic challenge. A properly balanced diet and microbiome diversity have been receiving increasing attention as targets for therapeutic interventions in neurodegeneration. Microbiota may affect cognitive function, neuronal survival and death, and gut dysbiosis was identified in Parkinson’s disease (PD). Tryptophan (Trp), an essential amino acid, is degraded by microbiota and hosts numerous compounds with immune- and neuromodulating properties. This broad narrative review presents data supporting the concept that microbiota, the Trp-kynurenine (KYN) pathway and aryl hydrocarbon receptors (AhRs) form a triad involved in PD. A disturbed gut–brain axis allows the bidirectional spread of pro-inflammatory molecules and α-synuclein, which may contribute to the development/progression of the disease. We suggest that the peripheral levels of kynurenines and AhR ligands are strongly linked to the Trp metabolism in the gut and should be studied together with the composition of the microbiota. Such an approach can clearly delineate the sub-populations of PD patients manifesting with a disturbed microbiota–Trp-KYN–brain triad, who would benefit from modifications in the Trp metabolism. Analyses of the microbiome, Trp-KYN pathway metabolites and AhR signaling may shed light on the mechanisms of intestinal distress and identify new targets for the diagnosis and treatment in early-stage PD. Therapeutic interventions based on the combination of a well-defined food regimen, Trp and probiotics seem of potential benefit and require further experimental and clinical research.

Overactive bladder syndrome (OAB) is a prevalent condition that affects the elderly population in particular and significantly impairs quality of life. Imperatorin, a naturally occurring furocoumarin, possesses diverse pharmacological properties that warrant consideration for drug development. The aim of this study was to investigate the potential of imperatorin (IMP) to attenuate the cystometric and biochemical changes typically associated with retinyl acetate-induced overactive bladder (OAB) and to assess its viability as a pharmacological intervention for OAB patients. A total of 60 rats were divided into four groups: I—control, II—rats with rapamycin (RA)-induced OAB, III—rats administered IMP at a dose of 10 mg/kg/day, and IV—rats with RA-induced OAB treated with IMP. IMP or vehicle were injected intraperitoneally for 14 days. The cystometry and assessment of bladder blood flow were performed two days after the last dose of IMP. The rats were then placed in metabolic cages for 24 h. Urothelial thickness measurements and biochemical analyses were performed. Intravesical infusion of RA induced OAB. Notably, intraperitoneal administration of imperatorin had no discernible effect on urinary bladder function and micturition cycles in normal rats. IMP attenuated the severity of RA-induced OAB. RA induced increases in urothelial ATP, calcitonin gene-related peptide (CGRP), organic cation transporter 3 (OCT3), and vesicular acetylcholine transporter (VAChT), as well as significant c-Fos expression in all micturition areas analyzed, which were attenuated by IMP. Furthermore, elevated levels of Rho kinase (ROCK1) and VAChT were observed in the detrusor, which were reversed by IMP in the context of RA-induced OAB in the urothelium, detrusor muscle, and urine. Imperatorin has a mitigating effect on detrusor overactivity. The mechanisms of action of IMP in the bladder appear to be diverse and complex. These findings suggest that IMP may provide protection against RA-induced OAB and could potentially develop into an innovative therapeutic strategy for the treatment of OAB.

Despite the close and clinically confirmed association between depression and overactive bladder, it remains unclear whether this affective disorder is a factor causing overactive bladder or whether overactive bladder is a specific symptom of psychosomatic disorders. This study examined the effects of repeated corticosterone administration on the occurrence of symptoms associated with depression and overactive bladder. Additionally, we examined whether administering TC-G 1008, an antidepressant that selectively activates the GPR39 receptor, could alleviate corticosterone-induced depression-like behavior and detrusor overactivity-related changes in cystometric measurements. We also explored its potential to reverse alterations in various biomarkers associated with both conditions in the serum, urinary bladder, and brain of female rats. The administration of corticosterone (20 mg/kg/day for 14 days) yielded anticipated results, including an increase in the duration of immobility during the forced swim test, alterations in parameters specific to bladder overactivity, a decrease in neurotrophins, and an elevation in pro-inflammatory cytokine levels. Treatment with TC-G 1008 (15 mg/kg/day) alleviated symptoms of both detrusor overactivity and depression, while also restoring the levels of biochemical and cystometric markers to normal ranges. Additionally, antidepressants based on GPR39 agonists could enhance the levels of kynurenic acid in the neuroprotective pathway. These results indicate that the GPR39 agonist receptor might be a promising future therapeutic approach for treating overactive bladder that occurs alongside depression.

In the published manuscript [...].

Kombucha is gaining global popularity for its health benefits. This study explored the use of chestnut honey, a rich source of kynurenic acid (KYNA), to produce kombucha enriched with this metabolite. Five variants were prepared using different green/black tea blends and carbon sources: white sugar or acacia honey (controls) versus chestnut honey. Samples were analyzed for tryptophan metabolites, physicochemical properties, and microbial diversity. Komagataeibacter and Enterobacter were predominant bacterial genera in SCOBY. Candida and Aspergillus were predominated in the single sample analyzed for fungi. During fermentation, tryptophan decreased, while kynurenine increased. KYNA levels remained largely stable during fermentation and were mainly influenced by the fermentation substrate. No melatonin pathway derivatives were detected. On day 7, chestnut honey yielded kombucha with 381.680-739.915 μmol/L KYNA and elevated myricetin. Overall, chestnut honey-based kombucha represents a system in which substrate composition appears to be the main factor influencing KYNA levels in the final beverage.