Dupilumab therapy improves gut microbiome dysbiosis and tryptophan metabolism in Chinese patients with atopic dermatitis.

BACKGROUND: Dupilumab has demonstrate its potential to orchestrate inflammatory skin microenvironment, enhance skin barrier and shift skin microbiome dysbiosis, collectively contributing to clinical improvement in patients with atopic dermatitis (AD). As the second genome of human body, growing evidence suggests that the gut microbiome might relate to the host response to treatments. Little is known about the association between dupilumab treatment and gut microbiome in AD patients. OBJECTIVE: We aimed to characterize the gut microbiome among Chinese subjects with or without AD and determine the potential effect of dupilumab on the gut microbiome. RESULTS: The 16 s rRNA gene sequencing was conducted on 48 healthy controls (HC), 44 AD patients and 27 AD patients who received dupilumab for 16 weeks. Prior to treatment, we identified the changed beta-diversity, increased Firmicutes/Bacteroidetes ratio, decreased Bifidobacterium and expanded Faecalibacterium among the AD patients compared to HC. After 16 weeks of dupilumab treatment, gut microbiome dysbiosis of the AD patients improved with reversed beta-diversity, closer bacterial connections, increased colonization of Bifidobacterium, Ruminococcus gnavus, and Coprococcus, which were negatively correlated with disease severity indicators. This shift was largely independent of the degree of clinical improvement. Bacterial function analysis revealed further metabolic alterations following dupilumab treatment, including up-regulated expression of genes involved in the indole pathway of tryptophan metabolism, corroborated by quantitative UHPLC-MS/MS analysis. CONCLUSION: Dupilumab treatment tends to help shift the gut microbial dysbiosis in AD patients to a healthier state, along with improved intestinal tryptophan metabolism, suggesting the gut flora and its metabolites may mediate part of the synergistic therapeutic effects on the host.

Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis.

OBJECTIVES: Alterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question. METHODS: Targeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model. RESULTS: Differential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model. CONCLUSIONS: Altogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue.

Untargeted and Targeted Metabolomics Reveal the Active Peptide of Eupolyphaga sinensis Walker against Hyperlipidemia by Modulating Imbalance in Amino Acid Metabolism.

The active peptide (APE) of Eupolyphaga sinensis Walker, which is prepared by bioenzymatic digestion, has significant antihyperlipidemic effects in vivo, but its mechanism of action on hyperlipidemia is not clear. Recent studies on amino acid metabolism suggested a possible link between it and hyperlipidemia. In this study, we first characterized the composition of APE using various methods. Then, the therapeutic effects of APE on hyperlipidemic rats were evaluated, including lipid levels, the inflammatory response, and oxidative stress. Finally, the metabolism-regulating mechanisms of APE on hyperlipidemic rats were analyzed using untargeted and targeted metabolomic approaches. The results showed that APE significantly reduced the accumulation of fat, oxidative stress levels, and serum pro-inflammatory cytokine levels. Untargeted metabolomic analysis showed that the mechanism of the hypolipidemic effect of APE was mainly related to tryptophan metabolism, phenylalanine metabolism, arginine biosynthesis, and purine metabolism. Amino-acid-targeted metabolomic analysis showed that significant differences in the levels of eight amino acids occurred after APE treatment. Among them, the expression of tryptophan, alanine, glutamate, threonine, valine, and phenylalanine was upregulated, and that of arginine and proline was downregulated in APE-treated rats. In addition, APE significantly downregulated the mRNA expression of SREBP-1, SREBP-2, and HMGCR. Taking these points together, we hypothesize that APE ameliorates hyperlipidemia by modulating amino acid metabolism in the metabolome of the serum and feces, mediating the SREBP/HMGCR signaling pathway, and reducing oxidative stress and inflammation levels.

Rosa laevigata Michx. Polysaccharide Ameliorates Diabetic Nephropathy in Mice through Inhibiting Ferroptosis and PI3K/AKT Pathway-Mediated Apoptosis and Modulating Tryptophan Metabolism.

Diabetic nephropathy (DN) is a metabolic disease wherein chronic hyperglycemia triggers various renal cell dysfunctions, eventually leading to progressive kidney failure. Rosa laevigata Michx. is a traditional Chinese herbal medicine. Many studies have confirmed its antioxidative, anti-inflammatory, and renoprotective effects. However, the effects and mechanisms of Rosa laevigata Michx. polysaccharide (RLP) in DN remain unclear. In this study, a DN mouse model was established to investigate the therapeutic effect of RLP on DN mice. Then, nontargeted metabolomics was used to analyze the potential mechanism of RLP in the treatment of DN. Finally, the effects of RLP on ferroptosis and the PI3K/AKT pathway were investigated. The results demonstrated that RLP effectively alleviated renal injury and reduced inflammation and oxidative stress in the kidney. In addition, nontargeted metabolomic analysis indicated that RLP could modulate riboflavin metabolism and tryptophan metabolism in DN mice. Notably, ferroptosis and PI3K/AKT pathway-mediated apoptosis in the kidney were also ameliorated following RLP treatment. In conclusion, this study confirmed that RLP had a significant therapeutic effect on DN mice. Furthermore, RLP treatment modulated tryptophan metabolism and inhibited ferroptosis and PI3K/AKT pathway-mediated apoptosis in the kidney.

Integration of metabolomics and machine learning revealed tryptophan metabolites are sensitive biomarkers of pemetrexed efficacy in non-small cell lung cancer.

BACKGROUND: Anti-folate drug pemetrexed is a vital chemotherapy medication for non-small cell lung cancer (NSCLC). Its response varies widely and often develops resistance to the treatment. Therefore, it is urgent to identify biomarkers and establish models for drug efficacy evaluation and prediction for rational drug use. METHODS: A total of 360 subjects were screened and 323 subjects were recruited. Using metabolomics in combination with machine learning methods, we are trying to select potential biomarkers to diagnose NSCLC and evaluate the efficacy of pemetrexed in treating NSCLC. Furtherly, we measured the concentration of eight metabolites in the tryptophan metabolism pathway in the validation set containing 201 subjects using a targeted metabolomics method with UPLC-MS/MS. RESULTS: In the discovery set containing 122 subjects, the metabolic profile of healthy controls (H), newly diagnosed NSCLC patients (ND), patients who responded well to pemetrexed treatment (S) and pemetrexed-resistant patients (R) differed significantly on the PLS-DA scores plot. Pathway analysis showed that glycine, serine and threonine metabolism occurred in every two group comparisons. TCA cycle, pyruvate metabolism and glycerolipid metabolism are the most significantly changed pathways between ND and H group, pyruvate metabolism was the most altered pathway between S and ND group, and tryptophan metabolism was the most changed pathway between S and R group. We found Random forest method had the maximum area under the curve (AUC) and can be easily interpreted. The AUC is 0.981 for diagnosing patients with NSCLC and 0.954 for evaluating pemetrexed efficiency. CONCLUSION: We compared eight mathematical models to evaluate pemetrexed efficiency for treating NSCLC. The Random forest model established with metabolic markers tryptophan, kynurenine and xanthurenic acidcan accurately diagnose NSCLC and evaluate the response of pemetrexed.

The role of cytokines and Indolamine-2.3 dioxygenase in experiencing a psycho-neurological symptom cluster in hematological cancer patients: IL-1alpha, IL-1beta, IL-4, IL-6, TNF-alpha, kynurenine, and tryptophan.

OBJECTIVE: This study examined (a) whether there are a subgroup of cancer patients experiencing the selected psycho-neurological symptoms as a cluster (depression, cognitive impairment, fatigue, sleep disturbance, and pain); (b) whether demographic and clinical characteristics and pro-inflammatory cytokines (IL-1α, IL-1ß, IL-4, IL-6, TNF-alpha) are associated with subgroup membership; and (c) whether the activity of indolamine-2.3 dioxygenase(IDO) is associated with pro-inflammatory cytokine activity and psycho-neurological symptom cluster experience. METHODS: This was a prospective cohort study where 149 hematologic patients were recruited from a university hospital and 65 healthy volunteers provided control data. Latent profile analyses were conducted to identify subgroups at two time points: the last day of chemotherapy and 1 week after chemotherapy completion. Influencing factors of subgroup membership were examined by logistic regression. RESULTS: A substantial number of patients (33%, 34% at each time point) experienced the selected psycho-neurological symptoms as a cluster. Older age and elevated IL-1α and IL-6 were associated with experiencing the psycho-neurological symptom cluster. IDO activity was higher in the patients experiencing psycho-neurological symptom cluster; and was positively associated with IL-6. Symptom severity, IL-1α, IL-6, and IDO activity were all significantly higher in cancer patients than in the healthy controls. The findings were preserved across time points. CONCLUSIONS: The activation of pro-inflammatory cytokines and their cross-talk with IDO may be a common biological mechanism, underlying a psycho-neurological symptom cluster experience. The novel approaches for symptom assessment and management can be developed by assessing multiple psycho-neurological symptoms as a cluster and by targeting their common biological pathway.

Aqueous extract of Polygala japonica Houtt. ameliorated nonalcoholic steatohepatitis in mice through restoring the gut microbiota disorders and affecting the metabolites in feces and liver.

BACKGROUND: Polygala japonica Houtt. (PJ) has been demonstrated with several biological potentials such as lipid-lowering and anti-inflammatory effects. However, the effects and mechanisms of PJ on nonalcoholic steatohepatitis (NASH) remain unclear. PURPOSE: The aim of this study was to evaluate the effects of PJ on NASH and illustrate the mechanism based on modulating gut microbiota and host metabolism. MATERIALS AND METHODS: NASH mouse model was induced using methionine and choline deficient (MCD) diet and orally treated with PJ. The therapeutic, anti-inflammatory, and anti-oxidative effects of PJ on mice with NASH were firstly assessed. Then, the gut microbiota of mice was analyzed using 16S rRNA sequencing to assess the changes. Finally, the effects of PJ on the metabolites in liver and feces were explored by untargeted metabolomics. RESULTS: The results indicated that PJ could improve hepatic steatosis, liver injury, inflammatory response, and oxidative stress in NASH mice. PJ treatment also affected the diversity of gut microbiota and changed the relative abundances of Faecalibaculum. Lactobacillus, Muribaculaceae, Dubosiella, Akkermansia, Lachnospiraceae_NK4A136_group, and Turicibacter in NASH mice. In addition, PJ treatment modulated 59 metabolites both in liver and feces. Metabolites involved in histidine, and tryptophan metabolism pathways were identified as the key metabolites according to the correlation analysis between differential gut microbiota and metabolites. CONCLUSION: Our study demonstrated the therapeutic, anti-inflammatory and anti-oxidative potentials of PJ on NASH. The mechanisms of PJ treatment were related to the improvement of gut microbiota dysbiosis and the regulation of histidine and tryptophan metabolism.

[Repair stimulator alpha-glutamyl-tryptophan in the complex therapy of chronic atrophic gastritis: results of histological examination]. / Stimulyator reparatsii al'fa-glutamil-triptofan v kompleksnoi terapii khronicheskogo atroficheskogo gastrita: rezul'taty gistologicheskogo issledovaniya.

OBJECTIVE: To study the effect of the repair stimulator alpha-glutamyl-tryptophan on the morphological characteristics of the gastric mucosa and the expression of CXCL-12 and CDX-2 in chronic atrophic gastritis associated with Helicobacter pylori. MATERIAL AND METHODS: Biopsy samples of 116 patients with a verified diagnosis of chronic atrophic gastritis associated with Helicobacter pylori were analyzed in a multicenter double-blind randomized placebo-controlled study. During the morphological study, the parameters characterizing the process of atrophy were evaluated: the number of glands per 1 mm2 of the gastric mucosa, the depth of the gastric mucosa glands, the number of parietal cells per 100 epithelial cells of the gastric mucosa, and the presence of signs of intestinal metaplasia. Primary antibodies Anti-CXCL-12 (MA5-23759) and Anti-CDX-2 (EP25) were used to set up immunohistochemical reactions to verify the expression of CXCL-12 and CDX-2. RESULTS: In patients taking the studied drug, a statistically significant increase in the number of glands per 1 mm2 of the gastric mucosa was revealed when compared with the initial screening indicators by 26.1% (p=0.028) and with the placebo group (p=0.026), a tendency to decrease the signs of intestinal metaplasia was determined. There was a statistically significant increase in the expression in the relative area of CXCL-12 expression in patients taking placebo when compared with the parameters of the initial data (p=0.045) and the absence of statistically significant changes in the main group. A statistically significant increase in the relative area of the CDX-2 expression was revealed in the group taking alpha-glutamyl-tryptophan in comparison with the baseline data (p=0.015), no statistically significant dynamics of this indicator was found in the placebo group. CONCLUSION: A statistically significant positive effect of the study drug on regenerative mechanisms leading to stabilization and/or improvement of the histological picture in the atrophic area of the gastric mucosa was found in comparison with the control of the initial state and with placebo. The results of an immunohistochemical study to increase CDX-2 expression while taking the study drug can also be regarded as an indicator of improvement in reparative processes.

Expression of Tryptophan Metabolism Enzymes in Patients with Diffuse Large B-cell Lymphoma and NK/T-cell Lymphoma.

BACKGROUND: Metabolites of tryptophan (Trp) metabolism in the tumor microenvironment play crucial immunosuppressive roles in various cancers. However, the role of Trp metabolism in diffuse large B-cell lymphoma (DLBCL) or natural killer/T-cell lymphoma (NK/TCL) remains unelucidated. METHODS: We investigated the potential role of Trp metabolism in a cohort of 43 patients with DLBCL and 23 with NK/TCL. We constructed tissue microarrays and performed in situ staining of Trp-catabolizing enzymes and PD-L1 using immunohistochemistry (IHC). RESULTS: We observed 14.0% positive staining of IDO1 in DCBCL and 60.9% in NK/TCL; 55.8% of IDO2 in DCBCL and 95.7% in NK/TCL; 79.1% of TDO2 in DCBCL and 43.5% in NK/TCL; 29.7% of IL4I1 in DCBCL and 39.1% in NK/TCL. However, IDO1, IDO2, TDO2, and IL4I1 positivity did not significantly differ between PD-L1+ and PD-L1- biopsy tissue samples of NK/TCL; nonetheless, a positive correlation of IDO1 (r = 0.87, p < 0.001), IDO2 (r = 0.70, p < 0.001), TDO2 (r = 0.63, p < 0.001), and IL4I1 (r = 0.53, p < 0.05) with PD-L1 expression was observed in the TCGA-DLBCL dataset. Finally, immunohistochemical (IHC) analysis revealed the lack of superior prognostic effect with higher expression of Trp enzymes in DLBCL and NK/TCL. Furthermore, IDO1, IDO2, TDO2, and IL4I1 expression, as well as survival rates, did not significantly differ across all groups in the TCGA-DLBCL cohort. CONCLUSION: Collectively, our findings provide novel insights into the enzymes involved in Trp metabolism in DLBCL and NK/TCL and their association with PD-L1 expression, which offers potential strategies to combine Trp-metabolism enzyme inhibitors with anti-PD-L1 or other immunotherapeutic strategies in clinical DLBCL or NK/TCL treatment.

Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment1,2. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy3,4, and genetic alterations alone cannot explain this5. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.

Tryptophan-tyrosine dipeptide improves tau-related symptoms in tauopathy mice.

Neurodegenerative diseases involving pathological tau protein aggregation are collectively known as tauopathies and include Alzheimer's disease and Pick's disease. Recent studies show that the intake of tryptophan-tyrosine (Trp-Tyr)-related ß-lactopeptides, including ß-lactolin, attenuates cognitive decline in the elderly and prevents the amyloid pathology in mouse models of Alzheimer's disease. However, the effects of Trp-Tyr-related ß-lactopeptides on tau-related pathology have not been investigated. In the present study, we examined the effects of Trp-Tyr dipeptide intake on tauopathy in PS19 transgenic mice, a well-established tauopathy model. Intake of Trp-Tyr dipeptide improved the behavioral deficits observed in the open field test, prevented tau phosphorylation, and increased the dopamine turnover and synaptophysin expression in the frontal cortex. Levels of short-chain fatty acids in the cecum were lower in PS19 mice than those in wild-type mice and were increased by treatment with Trp-Tyr dipeptide. In addition, intake of Trp-Tyr dipeptide extended the lifespan of PS19 mice. These findings suggest that the intake of Trp-Tyr-related peptides improves tauopathy symptoms, resulting in improvements in behavioral deficits and longevity. Hence, the intake of Trp-Tyr-related peptides, including ß-lactolin, may be beneficial for preventing dementia.

Expression of PD-L1 and YWHAZ in Patients with Diffuse Large B Cell Lymphoma: A Possible Association with the Prognosis of Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common pathological subtype of non-Hodgkin lymphoma (NHL) and is the most common type of adult lymphoma. Due to the poor prognosis of relapsed/refractory DLBCL, new drug targets and therapeutic methods are urgently needed. We investigated the expression of programmed death ligand 1 (PD-L1) and 3-monooxygenase/tryptophan 5-monooxygenase activating protein zeta (14-3-3ζ or YWHAZ) in patients with DLBCL. The purpose was to verify the expression levels of YWHAZ and PD-L1 and their relationships with the prognosis of DLBCL and to lay a foundation for further study on the role of YWHAZ and PD-L1 in DLBCL. Immunohistochemistry was used in 140 patients with DLBCL to test protein expression levels of YWHAZ and PD-L1. All patients were followed up in the hospital or by telephone or via WeChat. The positive expression rate of YWHAZ was 62.14% (87/140). The expression was negatively correlated with the positive expression of BAD (r = -0.177, P = 0.036) and positively correlated with the positive expression of BCL-2 (r = 0.180, P = 0.033). When the cut-off value for PD-L1 was established at 5%, 10%, 15%, and 20%, the corresponding positive expression rates of PD-L1 were 79.66% (94/118), 51.69% (61/118), 40.68% (48/118), and 36.44% (43/118). YWHAZ significantly affected the OS of DLBCL (P ≤ 0.001). The prognosis of the patients was related to the positive expression of PD-L1 when the cut-off value of PD-L1 was 5% (P = 0.033). However, positive expression of PD-L1 was not associated with the prognosis when the cut-off values of PD-L1 were 10% (P = 0.404), 15% (P = 0.208), and 20% (P = 0.408). The positive expression of YWHAZ (hazard ratio 6.215; 95% confidence interval 3.214-12.017; P < 0.05) was an independent adverse prognostic factor for OS. YWHAZ may be an important oncogene in the occurrence and development of DLBCL and may be used as a therapeutic target. PD-L1 may be an oncogene or tumor suppressor gene in the occurrence and development of DLBCL. Different cut-off values of PD-L1 may affect the prognosis of DLBCL.

Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled Trial.

BACKGROUND & AIMS: Fatigue is highly prevalent among patients with inflammatory bowel disease (IBD), and only limited treatment options are available. Based on the hypothetical link between low serum tryptophan concentrations and fatigue, we determined the effect of 5-hydroxytryptophan supplementation on fatigue in patients with inactive IBD. METHODS: A multicenter randomized controlled trial was performed at 13 Belgian hospitals, including 166 patients with IBD in remission but experiencing fatigue, defined by a fatigue visual analog scale (fVAS) score of ≥5. Patients were treated in a crossover manner with 100 mg oral 5-hydroxytryptophan or placebo twice daily for 2 consecutive periods of 8 weeks. The primary end point was the proportion of patients reaching a ≥20% reduction in fVAS after 8 weeks of intervention. Secondary outcomes included changes in serum tryptophan metabolites, Functional Assessment of Chronic Illness Therapy Fatigue scale, and scores for depression, anxiety, and stress. The effect of the intervention on the outcomes was evaluated by linear mixed modeling. RESULTS: During 5-hydroxytryptophan treatment, a significant increase in serum 5-hydroxytryptophan (estimated mean difference, 52.66 ng/mL; 95% confidence interval [CI], 39.34-65.98 ng/mL; P < .001) and serotonin (3.0 ng/mL; 95 CI, 1.97-4.03 ng/mL; P < .001) levels was observed compared with placebo. The proportion of patients reaching ≥20% reduction in fVAS was similar in placebo- (37.6%) and 5-hydroxytryptophan (35.6%)-treated patients (P = .830). The fVAS reduction (-0.18; 95% CI, -0.81 to 0.46; P = .581) and Functional Assessment of Chronic Illness Therapy Fatigue scale increase (0.68; 95% CI, -2.37 to 3.73; P = .660) were both comparable between 5-hydroxytryptophan and placebo treatment as well as changes in depression, anxiety, and stress scores. CONCLUSIONS: Despite a significant increase in serum 5-hydroxytryptophan and serotonin levels, oral 5-hydroxytryptophan did not modulate IBD-related fatigue better than placebo. (Trial Registration: Belgian Federal Agency for Medication and Health Products, EudraCT number: 2017-005059-10 and ClinicalTrials.gov: NCT03574948, https://clinicaltrials.gov/ct2/show/NCT03574948.).

Potential role of tryptophan catabolism in cancer-related cognitive impairment.

Oncology may be the most rapidly expanding field in medicine, with several innovative diagnostic and therapeutic procedures appearing daily. Advances in oncology have improved the survival rate for patients with cancer and promoting quality of life is now one of the goals in the care of these patients. Patients face a variety of disease- and treatment-related side effects, including anorexia, nausea, vomiting, recurring infections, and sleep difficulties. Cancer-related cognitive impairment (CRCI) is an overlooked clinical condition found in oncologic practice, particularly in patients with breast cancer. Although several potential mechanisms for CRCI have been hypothesized, to our knowledge, the exact mechanism is still unknown. Alterations in the tryptophan kynurenine pathway have been shown to impair cognitive skills in several mental illnesses. However, its possible function in CRCI has yet to be investigated. The aim of this was to examine the possible interactions between tryptophan catabolism and CRCI.

Synthesis of smart carriers based on tryptophan-functionalized magnetic nanoparticles and its application in 5-fluorouracil delivery.

Multifunctional nanocarriers, specifically for tumor targeting and traceable features, have been increasingly considered in cancer therapies. Herein, a novel targeting agent (TA), tryptophan (TRP), was proposed for the synthesis of functionalized (3-aminopropyl) triethoxysilane-iron oxide nanoparticles using two methods, creating a smart drug delivery system (DDS). In one method, two-step, glutaraldehyde (GA) as a linker, bonded TRP and amino-functionalized magnetite, and in the second method, one step, TRP binding was carried out by (3-dimethyl aminopropyl)-N'-ethyl carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide ester. The synthesis yield of the second method was 7% higher than the first method. After synthesizing DDS, 5-fluorouracil (5-FU) was loaded on nanocarriers and was observed TRP functionalized nanoparticles by GA have better loading efficiency, which was 50% greater than the product from the one-step method. A pH-sensitive release profile was also studied for 5-FU/DDS with the release of almost 75% and 50% at pH 5.5 and 7.4, respectively. To analyze the biological aspects of nanocarriers, human breast cancer, MCF-7, and embryonic kidney, HEK293, cell lines were used for cellular uptake and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays.In vitrostudies confirmed that TRP can act as a TA as its cellular uptake through cancerous cells was 40% greater than normal cells, and the MTT assay confirmed that using DDS can increase and decrease the cell viability of normal cells and cancerous cells, respectively, compared to free drug. Therefore, it was concluded that advanced nano-assembly is a great candidate for breast cancer cell-targeted delivery.

Quinolinic Acid, a Tryptophan Metabolite of the Skin Microbiota, Negatively Regulates NLRP3 Inflammasome through AhR in Psoriasis.

Psoriasis is a chronic inflammatory skin disease whose pathogenesis involves skin microbiota dysbiosis. Multiple studies have revealed the changes in microbiota abundances between psoriatic lesions and healthy skin. However, the metabolic pathways of skin microbiota (especially tryptophan metabolism, which is closely related to immunosuppression) are far less understood. In this study, we first detected the major microbial metabolites of tryptophan on the skin surfaces, finding that the quinolinic acid was significantly lower in the lesional skin of patients with psoriasis than in that of healthy subjects and correlated negatively with the severity of psoriasis. In vitro and in vivo, applying quinolinic acid significantly alleviated skin inflammation in an AhR-dependent manner, resulting in inhibition of the NLRP3 inflammasome activation. Furthermore, in mice with imiquimod-induced psoriasis-like dermatitis, topical application of Ahr-targeted small interfering RNA substantially exacerbated the disease severity, with increased NLRP3 inflammasome activation. Collectively, our data suggest that quinolinic acid, a skin microbiota-derived metabolite, negatively regulates aryl hydrocarbon receptor-NLRP3 inflammasome signaling activation in patients with psoriasis, providing an insight into the correlation between microbiota metabolism and the host skin in individuals with psoriasis.

Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis.

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system.

Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.

Gut Microbiome-Derived Uremic Toxin Levels in Hemodialysis Patients on Different Phosphate Binder Therapies.

INTRODUCTION: Constipation is prevalent in patients with kidney failure partly due to the use of medication, such as phosphate binders. We hypothesized that serum levels of gut microbiome-derived uremic toxins (UTOX) may be affected by the choice of phosphate binder putatively through its impact on colonic transit time. We investigated two commonly prescribed phosphate binders, sevelamer carbonate (SEV) and sucroferric oxyhydroxide (SFO), and their association with gut microbiome-derived UTOX levels in hemodialysis (HD) patients. METHODS: Weekly blood samples were collected from 16 anuric HD participants during the 5-week observational period. All participants were on active phosphate binder monotherapy with either SFO or SEV for at least 4 weeks prior to enrollment. Eight UTOX (7 gut microbiome-derived) and tryptophan were quantified using liquid chromatography-mass spectrometry. Serum phosphorus, nutritional, and liver function markers were also measured. For each substance, weekly individual levels, the median concentration per participant, and differences between SFO and SEV groups were reported. Patient-reported bowel movements, by the Bristol Stool Scale (BSS), and pill usage were assessed weekly. RESULTS: The SEV group reported a 3.3-fold higher frequency of BSS stool types 1 and 2 (more likely constipated, p < 0.05), whereas the SFO group reported a 1.5-fold higher frequency of BSS stool types 5-7 (more likely loose stool and diarrhea, not significant). Participants in the SFO group showed a trend toward better adherence to phosphate binder therapy (SFO: 87.6% vs. SEV: 66.6%, not significant). UTOX, serum phosphorus, nutritional and liver function markers, and tryptophan were not different between the two groups. CONCLUSION: There was no difference in the gut microbiome-derived UTOX levels between phosphate binders (SFO vs. SEV), despite SFO therapy resulting in fewer constipated participants. This pilot study may inform study design of future clinical trials and highlights the importance of including factors beyond bowel habits and their association with UTOX levels.