Colloidal Nanoparticles of a ß-Cyclodextrin/L-Tryptophan Inclusion Complex for Use as Pickering Emulsion Stabilizers.

Inclusion complexes of ß-cyclodextrin (ß-CD) and tryptophan (Trp) were synthesized using an antisolvent approach, and fully characterized. Scanning electron microscope images proved the formation of the ß-CD/Trp NPs and the powder X-ray diffraction pattern indicated the formation of a crystalline channel-like structure for the ß-CD/Trp nanoparticles (NPs). The NPs of a ß-CD/Trp inclusion complex were used as a natural stabilizer at the oil/water interface of a Pickering emulsion. Pickering emulsions with an oil to water ratio of 1:1 (v:v) were obtained under high-speed homogenization and different mass ratios of the ß-CD to Trp (1:0, 1:0.1, 1:0.25, 1:0.5, 1:1), and at different pH levels (3, 5, 7, 9). At pH 9, when the ß-CD:Trp mass ratio was 1:0.1, the ß-CD/Trp NPs were hydrophilic, and the oil-in-water Pickering emulsions stabilized by those nanoparticles showed the highest storage stability: 180 days at room temperature. In contrast, when the emulsions were prepared at pH 5 with the weight ratios of either 1:0.1 or 1:1, ß-CD:Trp, the nanoparticles were hydrophobic and could be used to stabilize water-in-oil Pickering emulsions.

De novo Design of Tryptophan containing Broad-Spectrum Cationic Antimicrobial Octapeptides.

With the advent of antibiotic resistant organisms, development of alternate classes of molecules other than antibiotics to combat microbial infections, have become extremely important. In this context, antimicrobial peptides have taken center stage of antimicrobial therapeutic research. In this work, we have reported two cationic antimicrobial octapeptides WRL and LWRF, with broad spectrum antimicrobial activities against several strains of ESKAPE pathogens. Both the peptides were membrane associative and induced microbial cell death through membranolysis, being selective towards microbial membranes over mammalian membranes. The AMPs were unstructured in water, adopting partial helical conformation in the presence of microbial membrane mimics. Electrostatic interaction formed the primary basis of peptide-membrane interactions. WRL was more potent, salt tolerant and faster acting of the two AMPs, owing to the presence of two tryptophan residues against that of one in LWRF. Increased tryptophan number in WRL enhanced its membrane association ability, resulting in higher antimicrobial potency but lower selectivity. This experimental and computational work, established that an optimum number of tryptophan residues and their position is critical for obtaining high antimicrobial potency and selectivity simultaneously in cationic AMPs. Understanding the peptide membrane interactions in atomistic details can lead to development of better antimicrobial therapeutics in future.

Antibacterial Efficacy of Tryptophan Coordinated Silver Nanoparticles Against E. coli: Spectroscopic and Microscopic Evaluation of Bacterial Cell Death.

The capability of conventional fluorescence spectroscopy and right-angled synchronous fluorescence spectroscopy (SFS) was evaluated to quantify the antibacterial potential of chemically synthesized Tryptophan coordinated silver nanoparticles (Ag-TrpNPs). Silver nanoparticles have gained significant importance as a material of interest due to their diverse assemblies in the nanoscale range and their potent antibacterial activity. But due to toxicity of silver nanoparticles there is a dire need to coordinate these materials with some biocompatible and biodegradable molecules. The study has been focused on chemical synthesis of functional fluorescence nanomaterials based on Tryptophan molecules coordinated with silver nanoparticles (Ag-TrpNPs). The antibacterial activity of Ag-TrpNPs was assessed in bacteria due to their functional characteristics such as tuneability, biocompatibility, and bioavailability. We employed optical characterization techniques such as Ultraviolet-visible spectroscopy, dynamic light scattering (DLS), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), fluorescence spectroscopy, and confocal microscopy to ensure the particles formation in aqueous suspension. DLS analysis confirmed the hydrodynamic size of the nanoparticles of approximately 100 nm. SEM images revealed the spherical morphology and size distribution of the Ag-TrpNPs. Escherichia coli bacterial strains were used to assess the antibacterial efficacy of the Ag-TrpNPs using fluorescence spectroscopy and imaging. Initially, the agar well plate method was employed to evaluate the antimicrobial activity of the Ag-TrpNPs. The significant zones of inhibition of size 37 mm at 500 µg/mL and 27 mm at 15.5 µg/mL were reported which indicated the efficiency of Ag-TrpNPs from higher to lower concentration. Conventional and synchronous fluorescence spectra provided evidence of bacterial cell death in aqueous suspensions to ensure the interaction of Ag-TrpNPs with E. coli bacteria at different times and concentrations. SEM was employed to investigate the interaction mechanism between Ag-TrpNPs and bacterial cells. The images revealed cell wall disintegration, leading to the leakage of cellular contents, and eventually cell death occurred.

Engineering the L-tryptophan metabolism for efficient de novo biosynthesis of tryptophol in Saccharomyces cerevisiae.

Tryptophol (IET) is a metabolite derived from L-tryptophan that can be isolated from plants, bacteria, and fungi and has a wide range of biological activities in living systems. Despite the fact that IET biosynthesis pathways exist naturally in living organisms, industrial-scale production of IET and its derivatives is solely based on environmentally unfriendly chemical conversion. With diminishing petroleum reserves and a significant increase in global demand in all major commercial segments, it becomes essential to develop new technologies to produce chemicals from renewable resources and under mild conditions, such as microbial fermentation. Here we characterized and engineered the less-studied L-tryptophan pathway and IET biosynthesis in the baker's yeast Saccharomyces cerevisiae, with the goal of investigating microbial fermentation as an alternative/green strategy to produce IET. In detail, we divided the aromatic amino acids (AAAs) metabolism related to IET synthesis into the shikimate pathway, the L-tryptophan pathway, the competing L-tyrosine/L-phenylalanine pathways, and the Ehrlich pathway based on a modular engineering concept. Through stepwise engineering of these modules, we obtained a yeast mutant capable of producing IET up to 1.04 g/L through fed-batch fermentation, a ~ 650-fold improvement over the wild-type strain. Besides, our engineering process also revealed many insights about the regulation of AAAs metabolism in S. cerevisiae. Finally, during our engineering process, we also discovered yeast mutants that accumulate anthranilate and L-tryptophan, both of which are precursors of various valuable secondary metabolites from fungi and plants. These strains could be developed to the chassis for natural product biosynthesis upon introducing heterologous pathways.

Branched-chain amino acids alleviate NAFLD via inhibiting de novo lipogenesis and activating fatty acid ß-oxidation in laying hens.

The adverse metabolic impacts of branched-chain amino acids (BCAA) have been elucidated are mediated by isoleucine and valine. Dietary restriction of isoleucine promotes metabolic health and increases lifespan. However, a high protein diet enriched in BCAA is presently the most useful therapeutic strategy for nonalcoholic fatty liver disease (NAFLD), yet, its underlying mechanism remains largely unknown. Fatty liver hemorrhagic syndrome (FLHS), a specialized laying hen NAFLD model, can spontaneously develop fatty liver and hepatic steatosis under a high-energy and high-protein dietary background that the pathogenesis of FLHS is similar to human NAFLD. The mechanism underlying dietary BCAA control of NAFLD development in laying hens remains unclear. Herein, we demonstrate that dietary supplementation with 67 % High BCAA has unique mitigative impacts on NAFLD in laying hens. A High BCAA diet alleviates NAFLD, by inhibiting the tryptophan-ILA-AHR axis and MAPK9-mediated de novo lipogenesis (DNL), promoting ketogenesis and energy metabolism, and activating PPAR-RXR and pexophagy to promote fatty acid ß-oxidation. Furthermore, we uncover that High BCAA strongly activates ubiquitin-proteasome autophagy via downregulating UFMylation to trigger MAPK9-mediated DNL, fatty acid elongation and lipid droplet formation-related proteins ubiquitination degradation, activating PPAR-RXR and pexophagy mediated fatty acid ß-oxidation and lipolysis. Together, our data highlight moderating intake of high BCAA by inhibiting the AHR/MAPK9 are promising new strategies in NAFLD and FLHS treatment.

Melatonin: A novel and beneficial substance in sweet potatoes through selenium application.

The effects of foliar Se (selenium) fertilizer on melatonin and its biosynthesis in four different colored sweet potatoes were studied. Solutions containing 1.25 mg Se/plant of inorganic selenium (ISe) and organic selenium (OSe) and a control check (CK) were applied three times during the swelling stage. Except for ISe in purple variety, both types of Se applications significantly increased melatonin in four colored varieties. The effect of OSe was greater than that of ISe, mainly because of higher concentration of tryptophan and activities of tryptophan decarboxylase, tryptamine-5 hydroxylase, 5-hydroxytryptamine N-acetyltransferase and N-acetyl-5-hydroxytryptamine methyltransferase. The orange variety had highest melatonin with the application of ISe and OSe, and highest melatonin among all applications was achieved by OSe in orange variety, followed by OSe in purple variety. These findings revealed that melatonin with extremely strong health benefits could be found and significantly increased in sweet potatoes through Se applications.

Association between tryptophan concentrations and the risk of developing cardiovascular diseases: a systematic review and meta-analysis.

BACKGROUND: Metabolic regulation of various amino acids have been proven to be effective in preventing cardiovascular disease (CVD). The impact of tryptophan, an essential amino acid, on the risk of developing CVD has not been fully elucidated. AIMS: The aim of this meta-analysis was to systematically review evidence of the effects of tryptophan on CVD risk. METHODS: The PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched to collect relevant trials from inception to August 2024. The means and hazard ratios (HRs) were extracted and pooled. Subgroup analysis was performed to identify pooled effect estimates, and sensitivity analysis was conducted to assess the robustness of the pooled estimates. RESULTS: Data were collected from 34,370 people under follow-up for CVD events in 13 studies, including cohort studies and case-control studies. They were categorized into three groups on the basis of sample type and indicators: the plasma tryptophan level group, the plasma tryptophan CVD hazard group, and the urinary tryptophan CVD hazard group. The CVD included in this study were coronary artery disease, heart failure, and peripheral artery disease. Twelve studies on plasma tryptophan were meta-analyzed. The plasma tryptophan levels in CVD patients were generally lower than those in individuals without CVD (SMD = -8.57, 95%CI (-15.77, -1.37), P = 0.02). Decreased circulating tryptophan levels are associated with cardiovascular disease risk (HR = 0.85, 95%CI (0.78, 0.92), P < 0.00001). CONCLUSIONS: Decreased circulating tryptophan levels are associated with an increased risk of CVD events. Intervention in circulating tryptophan levels may be indicated to help prevent CVD.

Tryptophan Metabolism Disorder-Triggered Diseases, Mechanisms, and Therapeutic Strategies: A Scientometric Review.

BACKGROUND: Tryptophan is widely present in foods such as peanuts, milk, and bananas, playing a crucial role in maintaining metabolic homeostasis in health and disease. Tryptophan metabolism is involved in the development and progression of immune, nervous, and digestive system diseases. Although some excellent reviews on tryptophan metabolism exist, there has been no systematic scientometric study as of yet. METHODS: This review provides and summarizes research hotspots and potential future directions by analyzing annual publications, topics, keywords, and highly cited papers sourced from Web of Science spanning 1964 to 2022. RESULTS: This review provides a scientometric overview of tryptophan metabolism disorder-triggered diseases, mechanisms, and therapeutic strategies. CONCLUSIONS: The gut microbiota regulates gut permeability, inflammation, and host immunity by directly converting tryptophan to indole and its derivatives. Gut microbial metabolites regulate tryptophan metabolism by activating specific receptors or enzymes. Additionally, the kynurenine (KYN) pathway, activated by indoleamine-2, 3-dioxygenase (IDO) and tryptophan 2, 3-dioxygenase, affects the migration and invasion of glioma cells and the development of COVID-19 and depression. The research and development of IDO inhibitors help to improve the effectiveness of immunotherapy. Tryptophan metabolites as potential markers are used for disease therapy, guiding clinical decision-making. Tryptophan metabolites serve as targets to provide a new promising strategy for neuroprotective/neurotoxic imbalance affecting brain structure and function. In summary, this review provides valuable guidance for the basic research and clinical application of tryptophan metabolism.

Stability of the Glycated Amino Acid 6-(2-Formyl-5-hydroxymethyl-1-pyrrolyl)-l-norleucine (Pyrraline) During Oxidation.

Food proteins may be modified during processing and storage through reactions with reducing sugars (Maillard reaction, glycation) or by reactive oxygen species (protein oxidation). Little is known about particular reactions at the interface of glycation and oxidation. In the present study, the glycated amino acid pyrraline (6-(2-formyl-5-hydroxymethyl-1-pyrrolyl)-l-norleucine) and the proteinogenic amino acids tyrosine and tryptophan were subjected to different types of oxidation. The stability of the amino acids was assessed by HPLC with UV detection, whereas oxidation products were assigned by HPLC with triple quadrupole or time-of-flight mass spectrometric detection. Conditions that lead to oxidation of aromatic proteinogenic amino acids can also lead to oxidation of pyrraline. Pyrraline was particularly unstable in the presence of permanganate, hypochlorite, and under hydroxyl radical-generating conditions (iron, ethylenediaminetetraacetic acid, ascorbic acid). Evidence obtained by high-resolution mass spectrometry revealed the oxidation of pyrraline to 6-(2,5-diformyl-1-pyrrolyl)-l-norleucine, 6-(2-carboxy-5-hydroxymethyl-1-pyrrolyl)-l-norleucine, 6-(2-formyl-5-carboxy-1-pyrrolyl)-l-norleucine, and 6-(2,5-dicarboxy-1-pyrrolyl)-l-norleucine in the presence of potassium permanganate. The latter product was isolated by semipreparative HPLC and characterized by NMR. Under hydroxyl radical-generating conditions, pyrraline is hydroxylated at the ring under formation of 6-(2-formyl-4-hydroxy-5-hydroxymethyl-1-pyrrolyl)-l-norleucine or 6-(2-formyl-3-hydroxy-5-hydroxymethyl-1-pyrrolyl)-l-norleucine. This study shows that the so-called "advanced glycation end products" are no end products of the Maillard reaction, but may undergo further chemical degradation reactions.

Kynurenine-AhR reduces T-cell infiltration and induces a delayed T-cell immune response by suppressing the STAT1-CXCL9/CXCL10 axis in tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a critical global health issue that is complicated by the ability of the pathogen to delay the host's T-cell immune response. This delay in T-cell recruitment to the site of infection is a pivotal survival strategy for Mtb, allowing it to establish a persistent chronic infection. To investigate the underlying mechanisms, this study focused on Mtb's exploitation of host tryptophan metabolism. Mtb upregulates indoleamine 2,3-dioxygenase 1 (IDO1) in inflammatory macrophages, thereby increasing kynurenine (Kyn) production. Kyn then activates the aryl hydrocarbon receptor (AhR), leading to the upregulation of suppressor of cytokine signaling 3 and subsequent inhibition of the JAK-STAT1 signaling pathway. This results in reduced secretion of the chemokines CXCL9 and CXCL10, which are crucial for T-cell recruitment to the lungs. Supported by in vivo mouse models, our findings reveal that disrupting this pathway through AhR knockout significantly enhances T-cell infiltration and activity, thereby undermining Mtb-induced immunosuppression. In contrast, additional Kyn injection obviously inhibited T-cell infiltration and activity. These results highlight potential therapeutic targets of AhR and IDO1, offering new avenues for enhancing the host immune response against tuberculosis and guiding future vaccine development efforts.

The effect of prebiotic supplementation on serum levels of tryptophan and kynurenine in obese women with major depressive disorder: a double-blinded placebo-controlled randomized clinical trial.

OBJECTIVE: The objective of the present study was to examine the effect of calorie restricted diet (CRD) plus inulin supplementation on serum levels of tryptophan (Trp), kynurenine (Kyn) and Trp/Kyn ratio in obese women with major depressive disorder (MDD). RESULTS: In this double-blind placebo-controlled randomized clinical trial, 51 obese women (BMI = 30-40 kg/m2) with mild MDD were assessed for depression level using Hamilton depression rating scale (HDRS). The patients were randomly allocated into either "Prebiotic group" (received 10 g/day inulin) or "Placebo group" (received 10 g/day maltodextrin). All participants also received individualized CRD. Fasting serum levels of Trp, Kyn, and Trp/Kyn ratio were assessed at baseline and after 8 weeks. Results showed slightly greater increases in serum levels of Trp and Trp/Kyn ratio as well as reductions in serum level of Kyn and HDRS score in prebiotic group than placebo group. However, between group differences in these parameters as well as HDRS score were not statistically significant after adjusting for baseline variables at the end of the trial. Results indicates that CRD accompanied by inulin supplementation (10 g/day) did not influence serum levels of Trp, Kyn and Trp/Kyn ratio as well as HDRS score after 8 weeks. TRIAL REGISTRATION: The trial was registered in the Iranian registry of clinical trials at 2018-08-02 ( https://www.irct.ir/ ; registration number: IRCT20100209003320N15).

Activation of aryl hydrocarbon receptor protein promotes testosterone synthesis to alleviate abnormal spermatogenesis caused by cholestasis.

In this study, we have investigated potential roles of cholestasis played in spermatogenesis in the cholestatic animal model generated by giving the mice DDC diet. The data showed that cholestasis jeopardized the testicular structure and function by downregulating the expressions of genes related to the androgen's synthesis. Mechanistically, the cholestasis disturbers the liver's tryptophan metabolism and its metabolites. These tryptophan metabolites including serotonin, 5-Hydroxyindoleacetic acid, 4-(2-Aminophenyl)-2,4-dioxobutanoic acid and Quinoline-4,8-diol were significantly reduced in the cholestatic mice model compared to their controlled counterparts. These tryptophan metabolites are the endogenous ligands of AHR and their levels are positively correlated to the expressions of genes related to the androgen's synthesis and AHR. Notably, supplementation of AHR ligand ITE promoted the expression of genes related to the testosterone synthesis and alleviated abnormal spermatogenesis. In addition, the bacteria that disturbed the tryptophan metabolism in cholestatic mice were identified by 16S rDNA sequencing and Spearman correlation analysis. Briefly, we have identified a cholestasis associated gut microbiota-testis axis. This axis is responsible for the cholestasis induced abnormal spermatogenesis and male reproductive dysfunction. Breaking vicious cycle of this axis may be a suitable strategy to prevent and treat the cholestasis associated male infertility.

Pediatric migraine is characterized by traits of ecological and metabolic dysbiosis and inflammation.

BACKGROUND: Recently, there has been increasing interest in the possible role of the gut microbiota (GM) in the onset of migraine. Our aim was to verify whether bacterial populations associated with intestinal dysbiosis are found in pediatric patients with migraine. We looked for which metabolic pathways, these bacteria were involved and whether they might be associated with gut inflammation and increased intestinal permeability. METHODS: Patients aged between 6 and 17 years were recruited. The GM profiling was performed by the 16S rRNA metataxonomics of faecal samples from 98 patients with migraine and 98 healthy subjects. Alpha and beta diversity analyses and multivariate and univariate analyses were applied to compare the gut microbiota profiles between the two group. To predict functional metabolic pathways, we used phylogenetic analysis of communities. The level of indican in urine was analyzed to investigate the presence of metabolic dysbiosis. To assess gut inflammation, increased intestinal permeability and the mucosal immune activation, we measured the plasmatic levels of lipopolysaccharide, occludin and IgA, respectively. RESULTS: The α-diversity analysis revealed a significant increase of bacterial richness in the migraine group. The ß-diversity analysis showed significant differences between the two groups indicating gut dysbiosis in patients with migraine. Thirty-seven metabolic pathways were increased in the migraine group, which includes changes in tryptophan and phenylalanine metabolism. The presence of metabolic dysbiosis was confirmed by the increased level of indican in urine. Increased levels of plasmatic occludin and IgA indicated the presence of intestinal permeability and mucosal immune activation. The plasmatic LPS levels showed a low intestinal inflammation in patients with migraine. CONCLUSIONS: Pediatric patients with migraine present GM profiles different from healthy subjects, associated with metabolic pathways important in migraine.

α-Amino-ß-Carboxymuconate-ε-Semialdehyde Decarboxylase Catalyzes Enol/Keto Tautomerization of Oxaloacetate.

ACMSD (α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase) is a key metalloenzyme critical for regulating de novo endogenous NAD+/NADH biosynthesis through the tryptophan-kynurenine pathway. This decarboxylase is a recognized target implicated in mitochondrial diseases and neurodegenerative disorders. However, unraveling its enzyme-substrate complex has been challenging due to its high catalytic efficiency. Here, we present a combined biochemical and structural study wherein we determined the crystal structure of ACMSD in complex with malonate. Our analysis revealed significant rearrangements in the active site, particularly in residues crucial for ACMS decarboxylation, including Arg51, Arg239* (a residue from an adjacent subunit), His228, and Trp194. Docking modeling studies proposed a putative ACMS binding mode. Additionally, we found that ACMSD catalyzes oxaloacetic acid (OAA) tautomerization at a rate of 6.51 ± 0.42 s-1 but not decarboxylation. The isomerase activity of ACMSD on OAA warrants further investigation in future biological studies. Subsequent mutagenesis studies and crystallographic analysis of W194A variant shed light on the roles of specific second-coordination sphere residues. Our findings indicate that Arg51 and Arg239* are crucial for OAA tautomerization. Moreover, our comparative analysis with related isomerase superfamily members underscores a general strategy employing arginine residues to promote OAA isomerization. Given the observed isomerase activity of ACMSD on OAA and its structural similarity to ACMS, we propose that ACMSD may facilitate isomerization to ensure ACMS is in the optimal tautomeric form for subsequent decarboxylation initiated by the zinc-bound hydroxide ion. Overall, these findings deepen the understanding of the structure and function of ACMSD, offering insights into potential therapeutic interventions.

Fruit-specific effects of tryptophan and melatonin as active components to extend the functionality of red fruits during post-harvest processing.

Preserving quality attributes in the distribution chain is a challenging task, particularly in fruits with a brief shelf life. The application of melatonin in cherries, raspberries, strawberries and blueberries stored at room temperature was evaluated, as well as the effects of its precursor (tryptophan) to determine their specificity and interchangeable feasibility for post-harvest applications. The results demonstrated that melatonin is effective in all tested fruits, reducing deterioration rate and its severity, preserving fruit firmness and reducing darkening and weight loss. Furthermore, tryptophan applications incremented melatonin contents in strawberries and blueberries and delayed decay in both fruits. Melatonin reduced postharvest losses in all studied fruits related to its antisenescent properties, while the beneficial impact of tryptophan in extending shelf life was fruit-specific and appeared to be partly mediated by melatonin. Melatonin and tryptophan must be considered as active components of new formulations for extending the shelf life of red fruits during post-harvest processing.

The role of microbial indole metabolites in tumor.

The gut microbiota can produce a variety of microbial-derived metabolites to influence tumor development. Tryptophan, an essential amino acid in the human body, can be converted by microorganisms via the indole pathway to indole metabolites such as Indole-3-Lactic Acid (ILA), Indole-3-Propionic Acid (IPA), Indole Acetic Acid (IAA) and Indole-3-Aldehyde (IAld). Recent studies have shown that indole metabolites play key roles in tumor progression, and they can be used as adjuvant regimens for tumor immunotherapy or chemotherapy. Here, we summarize recent findings on the common microbial indole metabolites and provide a review of the mechanisms of different indole metabolites in the tumor microenvironment. We further discuss the limitations of current indole metabolite research and future possibilities. It is expected that microbial indole metabolites will provide new strategies for clinical therapy.

Kiwifruit Polysaccharides Alleviate Ulcerative Colitis via Regulating Gut Microbiota-Dependent Tryptophan Metabolism and Promoting Colon Fucosylation.

A previous study showed that kiwifruit polysaccharide (KFP) has benefits in relieving intestinal inflammation, while the underlying mechanism remains unresolved. The objective of this study was to investigate the regulatory effect of KFP on the gut microbiota metabolism and intestinal barrier of ulcerative colitis (UC) mice induced by dextran sulfate sodium (DSS). KFP significantly improved the UC symptoms including weight loss, shortened colon length, splenomegaly, diarrhea, hematochezia, and colon inflammation of mice. In addition, KFP could alleviate DSS-caused gut microbiota dysbiosis and increase the levels of short-chain fatty acids in the cecal contents of mice. Furthermore, the results of nontargeted and targeted metabolomics analysis combined with antibiotic treatment revealed that KFP could regulate gut microbiota-dependent tryptophan metabolism, activate the aryl hydrocarbon receptor (AhR) in colon cells, and enhance interleukin-22 production and tight junction proteins' (ZO-1, occludin, and claudin3) expression to repair the intestinal barrier in UC mice. Immunofluorescence results showed that KFP significantly upregulated the conjunction of lectin WGA and UEA1 in the UC mouse colon, implying that KFP promoted fucosylation in the colon. These results suggest that KFP alleviates UC primarily via targeting the gut microbiota involved in the AhR pathway and upregulating colon fucosylation.

Microbiota-derived tryptophan metabolism and AMPK/mTOR pathway mediate antidepressant-like effect of Shugan Hewei Decoction.

Introduction: Depression is a common psychological disorder, accompanied by a disturbance of the gut microbiota and its metabolites. Recently, microbiota-derived tryptophan metabolism and AMPK/mTOR pathway were found to be strongly linked to the development of depression. Shugan Hewei Decoction (SHD) is a classical anti-depression traditional Chinese medicine formula. Although, we have shown that SHD exerted antidepressant effects via cecal microbiota and cecum NLRP3 inflammasome, the specific mechanism of SHD on metabolism driven by gut microbiota is unknown. In this study, we focus on the tryptophan metabolism and AMPK/mTOR pathway to elucidate the multifaceted mechanisms of SHD. Methods: Male rats were established to the chronic unpredictable stress (CUS)/social isolation for 6 weeks, and SHD-L (7.34 g/kg/d), SHD-H (14.68 g/kg/d), Fructooligosaccharide (FOS) (3.15 g/kg/d) were given by intragastric administration once daily during the last 2 weeks. Behavioral experiments were carried out to evaluate the model. The colonic content was taken out for shotgun metagenomic sequencing combined with the untargeted metabolomics, the targeted tryptophan metabolomics. ELISA was used to detect the levels of zonula occludens 1 (ZO-1), Occludin in colon, as well as lipopolysaccharide (LPS), diamine oxidase (DAO), D-lactate (DLA) in serum. The expressions of mRNA and proteins of adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway of autophagy were examined using RT-qPCR and Western blot in colon. Results: SHD modulated gut microbiota function and biological pathways, which were related to tryptophan metabolism. In addition, SHD could regulate microbiota-derived tryptophan production (such as reduction of 3-HK, 3-HAA etc., increment of ILA, IAA etc.), which metabolites belong to kynurenine (KYN) and indole derivatives. Further, SHD reduced intestinal permeability and enhanced the intestinal barrier function. Moreover, SHD could upregulate the levels of AMPK, microtubule associated protein light chain 3 (LC3), autophagy related protein 5 (ATG5) and Beclin1, downregulate the levels of mTOR, p62, promoted autophagy in colon. Spearman's analysis illustrated the close correlation between tryptophan metabolites and intestinal barrier, AMPK/mTOR pathway. Conclusion: SHD may exert antidepressant-like effects by regulating microbiota-derived tryptophan metabolism, and triggering the AMPK/mTOR pathway of autophagy, enhancing the intestinal barrier function.

Microbes and mood: innovative biomarker approaches in depression.

Although the field of psychiatry has made gains in biomarker discovery, our ability to change long-term outcomes remains inadequate. Matching individuals to the best treatment for them is a persistent clinical challenge. Moreover, the development of novel treatments has been hampered in part due to a limited understanding of the biological mechanisms underlying individual differences that contribute to clinical heterogeneity. The gut microbiome has become an area of intensive research in conditions ranging from metabolic disorders to cancer. Innovation in these spaces has led to translational breakthroughs, offering novel microbiome-informed approaches that may improve patient outcomes. In this review we examine how translational microbiome research is poised to advance biomarker discovery in mental health, with a focus on depression.

Vinegar-processed Schisandra Chinensis enhanced therapeutic effects on colitis-induced depression through tryptophan metabolism.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by its incurable nature and undefined etiology, which is often accompanied by a high prevalence of comorbid depression. The gut-brain axis has emerged as a promising treatment target in recent years. PURPOSE: This study aimed to investigate how vinegar-processed Schisandra Chinensis (VSC) enhances therapeutic effects on depressive behavior in chronic UC mice. METHODS: A chronic UC model was induced in mice using dextran sulfate sodium. The therapeutic effects of both raw and vinegar-processed Schisandra Chinensis on UC and associated depressive symptoms were assessed. Colonic mucosal damage was evaluated using hematoxylin and eosin (H&E) and Alcian blue staining. The integrity of the blood-brain barrier (BBB) and synaptic structures was visualized via transmission electron microscopy (TEM). Enzyme-linked immunosorbent assay (ELISA) was employed to quantify inflammatory cytokine levels in the colon, serum, and brain, while western blotting was performed for protein expression analysis. Additionally, metagenomic analysis was conducted to investigate gut microbiota composition. Nissl staining and immunofluorescence were used to assess hippocampal neuronal damage, and behavioral assessments including the morris water maze, open field test, forced swimming test and tail suspension test, were implemented to evaluate depressive states. Serum metabolites were analyzed using UPLC-MS/MS. RESULTS: Both raw and vinegar-processed Schisandra Chinensis significantly upregulated aryl hydrocarbon receptor (AhR), inhibited NF-κB p-p65 activation, and reduced levels of pro-inflammatory cytokine. These treatments also enhanced the expression of tight junction proteins, restored colonic mucosal and BBB integrity, alleviated damage to hippocampal neurons, and improved synaptic structure. Behavioral assessments indicated that VSC was particularly effective in ameliorating depressive-like behaviors in chronic UC mice. In the gut, both treatments reshaped the gut microbial composition, restoring the relative abundance of Duncaniella, Candidatus_Amulumruptor, Alistipes, Parabacteroides, Lachnospiraceae_bacterium, uncultured_Bacteroides_sp., Candidatus_Amulumruptor_caecigallinarius, with VSC showing more pronounced effects. Serum metabolomics revealed an increase in tryptophan levels and a decrease in kynurenine and xanthurenic acid levels with VSC, indicating that tryptophan metabolism shifted from the kynurenine pathway to the 5-HT or indole pathway. However, this phenomenon did not occur with Schisandra Chinensis (SC). CONCLUSION: This study demonstrated that the disruption of tryptophan metabolic balance served as a biological mechanism underlying the occurrence of depressive behaviors induced by UC. The application of SC following vinegar processing enhanced its regulatory effects on gut microbiota and tryptophan metabolism. This findings provided a new insight for the clinical management of gut-brain comorbidities.