Epidemiological studies have highlighted an association between periodontitis and osteoporosis.However,the mechanism underlining this association remains unclear.Here,we revealed significant differences in the salivar...Epidemiological studies have highlighted an association between periodontitis and osteoporosis.However,the mechanism underlining this association remains unclear.Here,we revealed significant differences in the salivary microbiota between periodontally healthy individuals and periodontitis patients,with periodontitis patients exhibiting increased salivary microbiota diversity and an elevated abundance of pathogenic bacteria.Using an ovariectomized(OVX) mouse model,we demonstrated that the salivary microbiota from periodontitis patients exacerbated bone destruction by modulating the gut microbiota.Metabolomic analysis revealed that the periodontitis-associated salivary microbiota suppressed tryptophan metabolism.The tryptophan metabolite indole-3-lactic acid(ILA) directly inhibited osteoclast formation and differentiation.In OVX mice treated with periodontitis salivary microbiota,supplementation with ILA effectively suppressed osteoclastogenesis and alleviated the detrimental effects of periodontitis-associated salivary microbiota on systemic bones.In summary,our data demonstrate that periodontitis can affect systemic bone metabolism via the oral-gut axis and that ILA supplementation serves as a potential therapeutic option to mitigate these adverse effects.展开更多
Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In t...Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.展开更多
Background:Tertiary lymphoid structures(TLSs)promote antitumor immunity and predict favorable immunotherapy outcomes in breast cancer.The study aimed to investigate how Tryptophan 2,3-dioxygenase(TDO2)-associated tryp...Background:Tertiary lymphoid structures(TLSs)promote antitumor immunity and predict favorable immunotherapy outcomes in breast cancer.The study aimed to investigate how Tryptophan 2,3-dioxygenase(TDO2)-associated tryptophan metabolism influences TLS maturation and B cell class switching in breast cancer.Methods:Bulk transcriptomic data from The Cancer Genome Atlas-Breast Invasive Carcinoma(TCGA-BRCA,n=1055)were analyzed using Gene Set Variation Analysis(GSVA)-based metabolic scoring,immune deconvolution,and TLS quantification.Single-cell RNA sequencing(scRNA-seq,n=26)and spatial transcriptomics(n=1)were applied to map TDO2 expression and TLS spatial organization.Validation was performed by immunohistochemistry(n=38)and multiplex immunofluorescence(n=12).Results:We identified that elevated tryptophan metabolism was predominantly enriched in the Luminal A subtype and delineates an immune-cold phenotype with less immunogenicity,associated with a distinct immune-dominant cellular microenvironment,particularly enriched in T and plasma cells.High expression of the tryptophan-metabolizing enzyme TDO2 was significantly enriched in TLS-low tumors and negatively correlated with TLS maturation signatures.Functional enrichment revealed suppressed B cell class switching and attenuated C-X-C motif chemokine ligand 9(CXCL9)expression in TLS-deficient tumors.Spatial transcriptomics and hotspot analysis demonstrated an inverse spatial correlation between TDO2 expression and TLS core components.Tumors with high tryptophan metabolism showed decreased cluster of differentiation 20(CD20)^(+)and CXCL9^(+)cell infiltration within TLS zones.Tumors with strong TDO2-kynurenine activity displayed impaired TLS organization and attenuated humoral immunity.Conditional spatial co-occurrence modeling confirmed reduced proximity between tryptophan metabolism hotspots and TLS-related immune features.Conclusion:In conclusion,our findings suggest that TDO2-associated tryptophan metabolism is linked to impaired TLS maturation and suppressed B cell class switching in breast cancer.Targeting the TDO2-kynurenine axis may represent a promising strategy to restore TLS formation and enhance immunotherapy responsiveness in breast cancer.展开更多
Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types...Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.展开更多
Objective:Prenatal depression is one of the most common psychological disorders during pregnancy,with an incidence of approximately 19.7%in China,and the incidence is showing a significant upward trend.Prenatal depres...Objective:Prenatal depression is one of the most common psychological disorders during pregnancy,with an incidence of approximately 19.7%in China,and the incidence is showing a significant upward trend.Prenatal depression seriously endangers maternal and infant health,may lead to self-injury and suicide,and has lasting effects on the health of offspring.Studies have shown that gut microbiota imbalance and disruption of the gutbrain axis can affect brain function and behavior and play an important role in the occurrence and development of depression.Significant changes occur in the gut microbiota of pregnant women during pregnancy,which may influence inflammation and metabolism.Gut microbiota play a key role in tryptophan metabolism;however,the mechanisms by which maternal gut microbiota regulate tryptophan metabolism to affect brain function and mood remain unclear.This study aims to clarify the role of plasma tryptophan in the relationship between gut microbiota and prenatal depression in pregnant women based on the gut-brain axis mechanism.Methods:A total of 73 pregnant women were included in the study.The Edinburgh Postnatal Depression Scale(EPDS)was used for assessment.According to the cutoff score(10 points),participants were divided into a prenatal depression group(pregnant women with prenatal depression)and a control group(pregnant women without prenatal depression).Demographic information,fecal samples,and plasma samples were collected.Gut microbiota sequencing was performed using 16S ribosomal RNA(rRNA)sequencing.Amino acid detection in plasma and feces was conducted using ultrahigh performance liquid chromatography-electrospray ionization tandem mass spectrometry(UHPLC-ESIMS/MS).Data were analyzed using SPSS 26.0 and R software,and mediation model analysis was performed using SPSS PROCESS.Results:There were no statistically significant differences inα-diversity orβ-diversity of gut microbiota between the 2 groups(all P>0.05).Compared with the control group,plasma tryptophan levels were significantly higher in the prenatal depression group(t=−2.964,P<0.05).The abundances of Candidatus_Soleaferrea(β=−19.945,OR<0.001,95%CI<0.001 to 0.002,P=0.004)and Enterococcus(β=−9.074,OR<0.001,95%CI<0.001 to 0.183,P=0.016)were negatively correlated with prenatal depression,whereas the abundance of Lachnospiraceae_NC2004_group was positively correlated with prenatal depression(β=5.870,OR=354.354,95%CI 1.248 to 100619.527,P=0.042).Plasma tryptophan levels played a mediating role between Enterococcus abundance and prenatal depression.Conclusion:Depressive symptoms during pregnancy are associated with the composition of gut microbiota during pregnancy.Tryptophan,as a precursor of serotonin,may play a mediating role in this process,providing new insights for improving prenatal depression through interventions targeting gut microbiota or tryptophan metabolism.展开更多
OBJECTIVE:To investigate the effect of central amino acid metabolic profiles on acupuncture analgesia.METHODS:BALB/c mice were injected with Complete Freund's Adjuvant(CFA)and acupuncture was applied at Zusanli(ST...OBJECTIVE:To investigate the effect of central amino acid metabolic profiles on acupuncture analgesia.METHODS:BALB/c mice were injected with Complete Freund's Adjuvant(CFA)and acupuncture was applied at Zusanli(ST36)for 7 d after modeling.Paw withdrawal thermal latency(PWTL)and paw withdrawal mechanical threshold(PWMT)were tested during the experiment.The level of prostaglandin E2(PGE2)was measured by enzyme-linked immunosorbent assay(ELISA).Using liquid chromatography-mass spectrometry(LC-MS/MS)based on the multiple reaction monitoring(MRM)-targeted metabolomic approach,neurotransmitter in the brain and spinal cord as well as were detected,further tryptophan metabolites in spinal cord were detected,and the data was analyzed using multiquant software.RESULTS:Acupuncture significantly improved the PWTL and PWMT on the modeling side of CFA mice,and simultaneously,decreased the PGE2 level.Based on targeted neurotransmitter analysis,acupuncture increased the expression of phenylethylamine and decreased N-acetyl serotonin in the brain,while significantly up-regulated serotonin,and down-regulated the levels of homovanillic acid,5-hydroxy-L-tryptophan and 3,4-Dihydroxyphenylethylene Glyco in the spinal cord.Further investigation targeted tryptophan metabolism found that acupuncture considerably decreased the content of tryptophan and L-kynurenine,but increased serotonin.CONCLUSIONS:This study aims to assess changes in central neurotransmitters of CFA mice treated with acupuncture,revealing that abnormalities in central neurotransmitter metabolism may be a potential biochemical basis for pain.More importantly,our preliminary study suggests the potential role of tryptophan and its metabolites in acupuncture analgesia,which may provide new insight and direction for the pain management interface of neurometabolism.展开更多
BACKGROUND The tryptophan-kynurenine(TRP-KYN)pathway may be implicated in the pathophysiology of cognitive impairment and pain severity in major depressive disorder(MDD);however,few studies have explored the intricaci...BACKGROUND The tryptophan-kynurenine(TRP-KYN)pathway may be implicated in the pathophysiology of cognitive impairment and pain severity in major depressive disorder(MDD);however,few studies have explored the intricacies of their interaction.AIM To investigate the relationship between the TRP-KYN pathway and cognitive function in MDD patients with and without painful physical symptoms(PPS).METHODS Seventy patients with MDD were recruited,including 33 and 37 with and without PSS,respectively.The Hamilton Depression Scale,the Hamilton Anxiety Scale,and the Short-form of McGill pain questionnaire(SFMPQ)were used to assess clinical symptoms.Cognitive function was assessed by the MATRICS Consensus Cognitive Battery(MCCB)score.TRP-KYN pathway metabolites’serum levels were measured using high-performance liquid chromatography-tandem mass spectrometry.RESULTS The with PPS group exhibited significantly higher TRP-KYN ratios than did the without PPS group;in the former,the SFMPQ scores positively and negatively correlated with the TRP-KYN ratio and total MCCB score,respectively.Regression analysis indicated that body mass index and SFMPQ scores were significantly associated with the TRP-KYN ratio,predicting 30%of the variance.CONCLUSION The TRP-KYN ratio is a potential biomarker for identifying patients with depression accompanied by pain symptoms,and targeting it may represent a novel therapeutic strategy for managing pain in these individuals.Further elucidation of the biological mechanisms underlying cognitive impairment in MDD patients with PPS is warranted.展开更多
Inflammation is often accompanied by glioblastoma cells(GBMs)and is considered a key factor for GBM growth.This feature is believed to be connected with the tryptophan pathway mainly affected by intestinal microbes si...Inflammation is often accompanied by glioblastoma cells(GBMs)and is considered a key factor for GBM growth.This feature is believed to be connected with the tryptophan pathway mainly affected by intestinal microbes since the concept of gut-brain axis(GBA)has been proposed.Here we present a microchip model co-culturing intestinal cells(Caco2),microbes(E.coli),and GBM cells(U87)to study inflammatory responses of GBM by investigating the tryptophan metabolism.E.coli after encapsulating with alginate hydrogel microparticles(AHMPs)was seeded in the microchip where Caco2 was located,forming the simulated system of intestinal physiology and avoiding excessive reproduction of microbes.Continuous flow was applied to maintain the cell viability,induce the morphogenesis,and simulate the tryptophan transportation in GBA.The morphological alterations of Caco2 and U87 were characterized by fluorescence imaging and the tryptophan metabolism,especially the tryptophan-kynurenine pathway,was analyzed by LC-MS.Above these results of molecular analysis and cell behavior,we can conclude that GBM inflammation is induced by tryptophan accumulation.This microchip-based model generally provides an alternative method for in vitro research of interactions in GBA.展开更多
The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s pote...The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s potential in regulating Tph1 gene expression,maintaining 5-HT levels in stressed mice,but its precise mechanisms were unclear.This study used metabolomic techniques to assess probiotic fermentation products,revealing acetate as the crucial element in Bb-CCFM1025’s regulation of gut 5-HT synthesis.Further exploration correlated acetate with Tph1 transcription in intestinal organoids.Transcriptomic methods and quantitative reverse transcription polymerase chain reaction validation demonstrated how acetate facilitated 5-HT synthesis and secretion.It unveiled that acetate orchestrates signaling pathways(phosphoinositide 3-kinase-protein kinase B(PI3K-AKT),phospholipase C-phosphorylated extracellular signal-regulated kinase(PLC-pERK),and PLC-1,4,5-trisphosphate(IP3)-Ca^(2+))within EC,enabling 5-HT production.These findings elucidate the biochemical mechanisms behind specific probiotics’effects,aiding in the targeted selection of similar beneficial strains.This study offers theoretical support for choosing probiotics with analogous functionalities based on their physiological impacts.展开更多
Background Tryptophan is essential for nutrition,immunity and neural activity,but cannot be synthesized endogenously.Certain natural products influence host health by modulating the gut microbiota to promote the produ...Background Tryptophan is essential for nutrition,immunity and neural activity,but cannot be synthesized endogenously.Certain natural products influence host health by modulating the gut microbiota to promote the production of tryptophan metabolites.Sanguinarine(SAN)enhances broiler immunity,however,its low bioavailability and underlying mechanisms remain unclear.This study aimed to decode the mechanisms by which sanguinarine enhances intestinal immune function in broilers.Methods Liquid chromatography-tandem mass spectrometry(LC-MS/MS)was employed to identify the main metabolites of sanguinarine in the intestine.Subsequently,equal concentrations of sanguinarine and its metabolites were separately added to the diets.The effects of sanguinarine and its metabolites on the intestinal immune function of broiler chickens were evaluated using 16S rRNA gene amplicon sequencing and tryptophan metabolomics approaches.Results We determined that dihydrosanguinarine(DHSA)is the main metabolite of sanguinarine in the intestine.Both compounds increased average daily gain and reduced feed efficiency,thereby improving growth performance.They also enhanced ileal villus height and the villus-to-crypt(V/C)ratio while decreasing crypt depth and upregulating the mRNA expression of tight junction proteins ZO-1,occludin and claudin-1.Furthermore,both compounds promoted the proliferation of intestinal Lactobacillus species,a tryptophan-metabolizing bacterium,stimulated short-chain fatty acid production,and lowered intestinal pH.They regulated tryptophan metabolism by increasing the diversity and content of indole tryptophan metabolites,activating the aryl hydrocarbon receptor(AhR)pathway,and elevating the mRNA levels of CYP1A1,CYP1B1,SLC3A1,IDO2 and TPH1.Inflammatory cytokines IL-1β and IL-6 were inhibited,while anti-inflammatory cytokines IL-10 and IL-22,serum SIgA concentration,and intestinal MUC2 expression were increased.Notably,DHSA exhibited a more pronounced effect on enhancing immune function compared to SAN.Conclusions SAN is converted to DHSA in vivo,which increases its bioavailability.DHSA regulates tryptophan metabolism by activating the AhR pathway and modulating immune-related factors through changes in the gut microbiota.Notably,DHSA significantly increases the abundance of Lactobacillus,a key tryptophan-metabolizing bacterium,thereby enhancing intestinal immune function and improving broiler growth performance.展开更多
Background Diets with high inclusion of corn co-products such as corn fermented protein(CFP)may contain excess Leu,which has a negative impact on feed intake and growth performance of pigs due to increased catabolism ...Background Diets with high inclusion of corn co-products such as corn fermented protein(CFP)may contain excess Leu,which has a negative impact on feed intake and growth performance of pigs due to increased catabolism of Val and Ile and reduced availability of Trp in the brain for serotonin synthesis.However,we hypothesized that the negative effect of using CFP in diets for weanling pigs may be overcome if diets are fortified with crystalline sources of Val,Trp,and(or)Ile.Methods Three hundred and twenty weanling pigs were randomly allotted to one of 10 dietary treatments in a com-pletely randomized design,with 4 pigs per pen and 8 replicate pens per treatment.A corn-soybean meal diet and 2 basal diets based on corn and 10%CFP or corn and 20%CFP were formulated.Seven additional diets were formu-lated by fortifying the basal diet with 20%CFP with Ile,Trp,Val,Ile and Val,Ile and Trp,Trp and Val,or Ile,Trp and Val.A two-phase feeding program was used,with d 1 to 14 being phase 1 and d 15 to 28 being phase 2.Fecal scores were recorded every other day.Blood samples were collected on d 14 and 28 from one pig per pen.On d 14,fecal samples were collected from one pig per pen in 3 of the 10 treatments to determine volatile fatty acids,ammonium concen-tration,and microbial protein.These pigs were also euthanized and ileal tissue was collected.Results There were no effects of dietary treatments on any of the parameters evaluated in phase 1.Inclusion of 10%or 20%CFP in diets reduced(P<0.05)final body weight on d 28,and average daily gain(ADG)and average daily feed intake(ADFI)in phase 2 and for the entire experimental period.However,pigs fed the CFP diet supplemented with Val,Ile,and Trp had final body weight,ADFI,ADG and gain to feed ratio in phase 2 and for the entire experiment that was not different from pigs fed the control diet.Fecal scores in phase 2 were reduced(P<0.05)if CFP was used.Conclusions Corn fermented protein may be included by up to 20%in diets for weanling pigs without affecting growth performance,gut health,or hindgut fermentation,if diets are fortified with extra Val,Trp,and Ile.Inclusion of CFP also improved fecal consistency of pigs.展开更多
BACKGROUND Prediabetes mellitus(PDM)is receiving increasing attention as a precursor to type 2 diabetes mellitus.Lifestyle and traditional Chinese medicine(TCM)inter-ventions are effective for PDM prevention and treat...BACKGROUND Prediabetes mellitus(PDM)is receiving increasing attention as a precursor to type 2 diabetes mellitus.Lifestyle and traditional Chinese medicine(TCM)inter-ventions are effective for PDM prevention and treatment.Therefore,we con-ducted a preliminary investigation and an exploratory randomised controlled trial to assess the effects of a combined lifestyle and TCM intervention on PDM indicators.AIM To study the effectiveness of Xiaokeqing granules(XQG)and lifestyle inter-ventions in PDM participants while using metabolomics to identify potential markers.METHODS Forty PDM participants with yin deficiency syndrome with excessive heat were recruited and randomly allocated to the control(Con)group or the XQG group(20 per group).The Con group underwent lifestyle interventions,whereas the XQG group underwent lifestyle and XQG interventions.The follow-up duration was 2 months.Fasting blood glucose,2-hour postprandial glucose(2hPG),gly-cated haemoglobin A1c,fasting insulin,homeostasis model assessment-insulin resistance levels,and serum metabolomics characteristics were compared via liquid chromatography-tandem mass spectrometry analysis.RESULTS There were significant differences in 2hPG between the two groups(P<0.05)in the intention-to-treat analysis and per-protocol analysis.The intervention method used in this study was safe(P>0.05).Groenlandicine,kaempferol,isomangiferin,etc.,are the XQG constituents absorbed in the blood.N-Nervonoyl methionine and 5-hydroxy-L-tryptophan are core potential metabolomic biomarkers for the effectiveness of XQG and lifestyle interventions.HTR1A,HTR2C,SLC6A4,etc.,are the core targets of XQG and lifestyle interventions,as well as the reason for their clinical efficacy.Possible mechanistic pathways include tryptophan metabolism,pantothenate and certificate of analysis biosynthesis,lysine degradation and biosynthesis of cofactors.CONCLUSION This pilot study provides evidence that a combined XQG and lifestyle intervention can improve 2hPG in par-ticipants with PDM.The mechanism of action is related to multiple constituents,targets and pathways.展开更多
Obesity is a major focus of researchers due to its increasing prevalence and relationship with other diseases,such as cancer and cardiovascular diseases.Probiotics are active microorganisms and have been proven to all...Obesity is a major focus of researchers due to its increasing prevalence and relationship with other diseases,such as cancer and cardiovascular diseases.Probiotics are active microorganisms and have been proven to alleviate obesity by modulating the microbiota.In this study,we found that oral administration of Bifidobacterium adolescentis CCFM8630 to obese mice inhibited high-fat diet(HFD)-induced changes in body weight and adipose tissue and alleviated hepatic oxidative stress.Furthermore,B.adolescentis CCFM8630 treatment primarily affected the relative abundances of the phyla Proteobacteria and Actinobacteria,and thereby decreased the production of lipopolysaccharide(LPS)and the occurrence of LPS related diseases.A high fiber intake increased the abundance of Lactobacillus and the concentrations of short chain fatty acids in obese mice,but these changes were reversed by B.adolescentis CCFM8630 treatment.In addition,targeted metabolomic analysis and microbiota relationship analysis revealed that B.adolescentis CCFM8630 treatment modified the microbiota of obese mice by promoting the conversion of tryptophan(Trp)to xanthurenic acid,kynurenic acid,tryptamine,indole-3-acetic acid,and indole-3-carboxaldehyde;facilitated the expression of interleukin-17A and the aryl hydrocarbon receptor to generate interleukin-22 in the colon;and upregulated the expression of tight junction proteins,thereby strengthening intestinal barriers.In summary,our findings suggest that the intake of B.adolescentis CCFM8630 may alleviate obesity by modulating the gut microbiota and related Trp metabolism.展开更多
Limosilac to bacillus reuteri QS01 is potential probiotic isolated from the intestinal microbiota of healthy women in early pregnancy.In the current study,we examined whether QS01 can prevent gestational diabetes mell...Limosilac to bacillus reuteri QS01 is potential probiotic isolated from the intestinal microbiota of healthy women in early pregnancy.In the current study,we examined whether QS01 can prevent gestational diabetes mellitus(GDM) in an enhanced mouse model of the condition.Female C57BL/6J mouse offspring(F1 generation) born to dams fed a control(CON) or low-protein diet(GDM group) during gestation and lactation were used.Pregnant F1 mice fed a standard diet were randomly assigned to 5 groups:CON,GDM,and GDM mice treated with metformin,QS01 or Lacticaseibacillus rhamnosus HN001.An oral glucose tolerance test was performed before sacrifice at gestational day 17.Glucose tolerance was significantly ameliorated by all 3 treatments.QS01 supplementation fortified the intestinal mucosal barrier and inhibited the escalation of plasma inflammatory cytokines.QS01 treatment altered the cecal microbiota composition and function.Plasma and cecal metabolite profiles were modulated by QS01,prominently demonstrating significant upregulation of indole lactate and L-tryptophan in plasma and 5-hydroxy-tryptophan in the cecum,positively correlated with gut Lactobacillus abundance.In summary,QS01 plays a role in preventing GDM by remodeling the intestinal microbiota,reinforcing the intestinal mucosal barrier and alleviating chronic inflammation.展开更多
Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-indu...Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-induced Sprague-Dawley rats fed by 35%fructose diets were used to evaluate colon barrier functions.Microbiome and metabolome were applied to screen potential biomarker bacteria and metabolites induced by fructose.HT-29 cells were applied to validate metabolite biomarker indoleacrylic acid(IAA)and indole-3-carboxaldehyde(I3A)function in colon barrier which impaired by fructose.Results:Fructose induced colon barrier dysfunction,aggravated colon impairment in DSS-induced rats.With fructose intake,the colon length shortened,goblet numbers declined,inflammation infiltration induced,inflammatory cytokines increased,and apoptosis signals upregulated in colon tissue.Moreover,fructose induced dysbiosis of microbiota and their metabolites.Adlercreutzia and Holdemania were screened out as potential bacteria biomarkers,IAA and I3A as tryptophan metabolites were selected as metabolite biomarkers inhibited by fructose.IAA and I3A treatment alleviated the impairment induced by fructose by increasing trans epithelial electric resistance value,tight junction proteins,and Aryl hydrocarbon receptor(Ah R)activity in HT-29 cell.Conclusion:Fructose stimulated inflammation,apoptosis,gut bacteria alteration,and induced the reduction of IAA and I3A.Since fructose inhibited production of IAA and I3A,Ah R remained inactivated and consequently induced colon barrier dysfunction.展开更多
Impaired healing of diabetic wounds is one of the most important complications of diabetes,often leading to lower limb amputations and incurring significant economic and psychosocial costs.Unfortunately,there are curr...Impaired healing of diabetic wounds is one of the most important complications of diabetes,often leading to lower limb amputations and incurring significant economic and psychosocial costs.Unfortunately,there are currently no effective prevention or treatment strategies available.Recent research has reported that an imbalance in the gut microbiota,known as dysbiosis,was linked to the onset of type 2 diabetes,as well as the development and progression of diabetic complications.Indeed,the gut microbiota has emerged as a promising therapeutic approach for treating type 2 diabetes and related diseases.However,there is few of literatures specifically discussing the relationship between gut microbiota and diabetic wounds.This review aims to explore the potential role of the gut microbiota,especially probiotics,and its associated byproducts such as short chain fatty acids,bile acids,hydrogen sulfide,and tryptophan metabolites on wound healing to provide fresh insights and novel perspectives for the treatment of chronic wounds in diabetes.展开更多
Obesity is a common noncommunicable disease characterized by persistent low-grade chronic inflammation and is associated with various metabolic disturbances,including insulin resistance and diabetes.The search for eff...Obesity is a common noncommunicable disease characterized by persistent low-grade chronic inflammation and is associated with various metabolic disturbances,including insulin resistance and diabetes.The search for effective obesity treatments has led to growing interest in the role of amino acids in metabolic regulation.Tryptophan(TRP),an essential amino acid,participates in several biological pathways,including the kynurenine,5-hydroxytryptamine(5-HT,also known as serotonin),and indole pathways.Recent evidence underscores the significance of TRP metabolism in obesity,showing that various metabolites and enzymes in its metabolic pathways are altered in individuals with obesity.These changes influence physiological processes,mood regulation,and overall metabolic health.This review provides a comprehensive overview of TRP metabolism.It highlights the potential of targeting TRP metabolism as a therapeutic strategy for managing obesity and its related metabolic and psychological comorbidities.展开更多
The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty ...The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty acids,tryptophan metabolites,and polyamines as key mediators linking dysbiosis to impaired erythropoiesis and iron homeostasis.We also propose a research framework that integrates multi-omics analysis and gnotobiotic models.Finally,we discuss the clinical potential of metabolite-based diagnostics and microbiome-targeted therapies in managing CAA.展开更多
Objectives:Triple-negative breast cancer(TNBC)is the breast cancer subtype with the poorest prognosis.This study aimed to elucidate the molecular pathways through which isoliquiritigenin(ISL),a natural chalcone compou...Objectives:Triple-negative breast cancer(TNBC)is the breast cancer subtype with the poorest prognosis.This study aimed to elucidate the molecular pathways through which isoliquiritigenin(ISL),a natural chalcone compound derived fromlicorice and other plant roots,targets interferon regulatory factor 5(IRF5)in TNBC.Methods:TNBC cell lines were cultured and subjected to IRF5 knockdown using short hairpin RNA.Cell proliferation was assessed by cell counting kit-8(CCK-8)assay and colony formation assays.Western blotting and quantitative reverse transcription polymerase chain reaction(RT-PCR)were employed to measure expression levels of IRF5,solute carrier family 7 member 5(SLC7A5),and indoleamine 2,3-dioxygenase 1(IDO1).Intracellular tryptophan and its metabolites were quantified using commercially available assay kits and high-performance liquid chromatography(HPLC).TNBC cells were treated with various concentrations of ISL to evaluate its effects on proliferation and tryptophanmetabolism.Results:IRF5 was highly expressed in TNBC cell lines.Silencing IRF5 significantly inhibited cellular proliferation and growth.Knockdown of IRF5 reduced the expression of SLC7A5 and IDO1,leading to decreased intracellular levels of tryptophan and its metabolites.ISL markedly suppressed TNBC cell proliferation and disrupted tryptophan metabolism in tumor cells.Conclusion:ISL may inhibit TNBC progression by downregulating IRF5 and interfering with SLC7A5/IDO1-mediated tryptophan metabolic reprogramming,suggesting a potential therapeutic mechanism for TNBC treatment.展开更多
The gene encoded for tryptophan decarboxylase (TDC), which is the key enzyme in terpenoil indole alkaloids pathway, was targeted to different subcellular compartments and stably expressed in transgenic tobacco (Nicoti...The gene encoded for tryptophan decarboxylase (TDC), which is the key enzyme in terpenoil indole alkaloids pathway, was targeted to different subcellular compartments and stably expressed in transgenic tobacco (Nicotiana tabacum L.) plants at the levels detected by Western blot and tryptamine accumulation analysis. It was shown that the TDC was located in subcellular compartments, the chloroplasts and cytosol. The recombinant TDC targeted to chloroplasts and cytosol in tobacco plants was effectively expressed as soluble protein by Western blot analysis and enzymatic assay. The level of tryptamine accumulation in chloroplast was higher than that in cytosol and very low in vacuole and endoplasmic reticulum (ER) to be hardly detected by Western blot analysis. It was indicated that the highest amount of tryptamine was in chloroplasts, lower in endoplasmic reticula and the lowest in vacuoles as compared to those in wild type plants. The TDC targeted to different subcellular compartments of tobacco plants and its expression level were studied by different nucleotide sequences coding signal peptides at 5'-end of tdc gene in order to know the effects of the TDC in compartmentation on its functionality.展开更多
基金provided by the National Natural Sciences Foundation of China (82270979)High-Level Hospital Construction Project (0224C001,0224C050)Cultivation Program for Reserve Talents for Academic Leaders (2023A208) of Nanjing Stomatological Hospital,Affiliated Hospital of Medical School,Institute of Stomatology,Nanjing University。
文摘Epidemiological studies have highlighted an association between periodontitis and osteoporosis.However,the mechanism underlining this association remains unclear.Here,we revealed significant differences in the salivary microbiota between periodontally healthy individuals and periodontitis patients,with periodontitis patients exhibiting increased salivary microbiota diversity and an elevated abundance of pathogenic bacteria.Using an ovariectomized(OVX) mouse model,we demonstrated that the salivary microbiota from periodontitis patients exacerbated bone destruction by modulating the gut microbiota.Metabolomic analysis revealed that the periodontitis-associated salivary microbiota suppressed tryptophan metabolism.The tryptophan metabolite indole-3-lactic acid(ILA) directly inhibited osteoclast formation and differentiation.In OVX mice treated with periodontitis salivary microbiota,supplementation with ILA effectively suppressed osteoclastogenesis and alleviated the detrimental effects of periodontitis-associated salivary microbiota on systemic bones.In summary,our data demonstrate that periodontitis can affect systemic bone metabolism via the oral-gut axis and that ILA supplementation serves as a potential therapeutic option to mitigate these adverse effects.
基金supported by Shanghai Shenkang Center Demonstration Research Ward Construction,No.SHDC2022CRW010(to MF)Shanghai Shenkang Center Medical Enterprise Integration and Innovation Collaborative Special Project,No.SHDC2022CRT018(to MF)+4 种基金Shanghai Health System Key Supported Discipline-Rehabilitation Medicine,No.2023ZDFC0301(to JT)Science and Technology Development Project of Shanghai University of Traditional Chinese Medicine,No.23KFL009(to JT)Shanghai Postdoctoral Excellence Program,No.2022515(to CY)Yangfan Special Project of Shanghai Science and Technology Innovation Action Plan,No.23YF1447600(to CY)China Postdoctoral Science Foundation,No.2023M732338(to CY).
文摘Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.
基金supported by grants from the Beijing Xisike Clinical Oncology Research Foundation(No.Y-Young2024-0138)China Postdoctoral Science Foundation(No.2024M750538)Qingdao Chengyang People’s Hospital Fund Project(No.202510300).
文摘Background:Tertiary lymphoid structures(TLSs)promote antitumor immunity and predict favorable immunotherapy outcomes in breast cancer.The study aimed to investigate how Tryptophan 2,3-dioxygenase(TDO2)-associated tryptophan metabolism influences TLS maturation and B cell class switching in breast cancer.Methods:Bulk transcriptomic data from The Cancer Genome Atlas-Breast Invasive Carcinoma(TCGA-BRCA,n=1055)were analyzed using Gene Set Variation Analysis(GSVA)-based metabolic scoring,immune deconvolution,and TLS quantification.Single-cell RNA sequencing(scRNA-seq,n=26)and spatial transcriptomics(n=1)were applied to map TDO2 expression and TLS spatial organization.Validation was performed by immunohistochemistry(n=38)and multiplex immunofluorescence(n=12).Results:We identified that elevated tryptophan metabolism was predominantly enriched in the Luminal A subtype and delineates an immune-cold phenotype with less immunogenicity,associated with a distinct immune-dominant cellular microenvironment,particularly enriched in T and plasma cells.High expression of the tryptophan-metabolizing enzyme TDO2 was significantly enriched in TLS-low tumors and negatively correlated with TLS maturation signatures.Functional enrichment revealed suppressed B cell class switching and attenuated C-X-C motif chemokine ligand 9(CXCL9)expression in TLS-deficient tumors.Spatial transcriptomics and hotspot analysis demonstrated an inverse spatial correlation between TDO2 expression and TLS core components.Tumors with high tryptophan metabolism showed decreased cluster of differentiation 20(CD20)^(+)and CXCL9^(+)cell infiltration within TLS zones.Tumors with strong TDO2-kynurenine activity displayed impaired TLS organization and attenuated humoral immunity.Conditional spatial co-occurrence modeling confirmed reduced proximity between tryptophan metabolism hotspots and TLS-related immune features.Conclusion:In conclusion,our findings suggest that TDO2-associated tryptophan metabolism is linked to impaired TLS maturation and suppressed B cell class switching in breast cancer.Targeting the TDO2-kynurenine axis may represent a promising strategy to restore TLS formation and enhance immunotherapy responsiveness in breast cancer.
基金supported by the STI 2030—Major Projects 2021ZD0204000,No.2021ZD0204003 (to XZ)the National Natural Science Foundation of China,Nos.32170973 (to XZ),32071018 (to ZH)。
文摘Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.
基金supported by the National Natural Science Foundation of China(81903334 and 82473647).
文摘Objective:Prenatal depression is one of the most common psychological disorders during pregnancy,with an incidence of approximately 19.7%in China,and the incidence is showing a significant upward trend.Prenatal depression seriously endangers maternal and infant health,may lead to self-injury and suicide,and has lasting effects on the health of offspring.Studies have shown that gut microbiota imbalance and disruption of the gutbrain axis can affect brain function and behavior and play an important role in the occurrence and development of depression.Significant changes occur in the gut microbiota of pregnant women during pregnancy,which may influence inflammation and metabolism.Gut microbiota play a key role in tryptophan metabolism;however,the mechanisms by which maternal gut microbiota regulate tryptophan metabolism to affect brain function and mood remain unclear.This study aims to clarify the role of plasma tryptophan in the relationship between gut microbiota and prenatal depression in pregnant women based on the gut-brain axis mechanism.Methods:A total of 73 pregnant women were included in the study.The Edinburgh Postnatal Depression Scale(EPDS)was used for assessment.According to the cutoff score(10 points),participants were divided into a prenatal depression group(pregnant women with prenatal depression)and a control group(pregnant women without prenatal depression).Demographic information,fecal samples,and plasma samples were collected.Gut microbiota sequencing was performed using 16S ribosomal RNA(rRNA)sequencing.Amino acid detection in plasma and feces was conducted using ultrahigh performance liquid chromatography-electrospray ionization tandem mass spectrometry(UHPLC-ESIMS/MS).Data were analyzed using SPSS 26.0 and R software,and mediation model analysis was performed using SPSS PROCESS.Results:There were no statistically significant differences inα-diversity orβ-diversity of gut microbiota between the 2 groups(all P>0.05).Compared with the control group,plasma tryptophan levels were significantly higher in the prenatal depression group(t=−2.964,P<0.05).The abundances of Candidatus_Soleaferrea(β=−19.945,OR<0.001,95%CI<0.001 to 0.002,P=0.004)and Enterococcus(β=−9.074,OR<0.001,95%CI<0.001 to 0.183,P=0.016)were negatively correlated with prenatal depression,whereas the abundance of Lachnospiraceae_NC2004_group was positively correlated with prenatal depression(β=5.870,OR=354.354,95%CI 1.248 to 100619.527,P=0.042).Plasma tryptophan levels played a mediating role between Enterococcus abundance and prenatal depression.Conclusion:Depressive symptoms during pregnancy are associated with the composition of gut microbiota during pregnancy.Tryptophan,as a precursor of serotonin,may play a mediating role in this process,providing new insights for improving prenatal depression through interventions targeting gut microbiota or tryptophan metabolism.
基金Supported by National Natural Science Foundation of China:Study on Acupuncture Alleviate Rheumatoid Arthritis Effect and Mechanism via miR-155 Reduce Monocyte Chemokine and Chemokine Receptor Expression (No. 82004473)Natural Science Foundation of Jiangsu Province:Study on the Role and Mechanism of Aryl Hydrocarbon Receptor-mediated Acupuncture in Regulating Immune Homeostasis of the Gut-joint Axis in Rheumatoid Arthritis (No. BK20230453)
文摘OBJECTIVE:To investigate the effect of central amino acid metabolic profiles on acupuncture analgesia.METHODS:BALB/c mice were injected with Complete Freund's Adjuvant(CFA)and acupuncture was applied at Zusanli(ST36)for 7 d after modeling.Paw withdrawal thermal latency(PWTL)and paw withdrawal mechanical threshold(PWMT)were tested during the experiment.The level of prostaglandin E2(PGE2)was measured by enzyme-linked immunosorbent assay(ELISA).Using liquid chromatography-mass spectrometry(LC-MS/MS)based on the multiple reaction monitoring(MRM)-targeted metabolomic approach,neurotransmitter in the brain and spinal cord as well as were detected,further tryptophan metabolites in spinal cord were detected,and the data was analyzed using multiquant software.RESULTS:Acupuncture significantly improved the PWTL and PWMT on the modeling side of CFA mice,and simultaneously,decreased the PGE2 level.Based on targeted neurotransmitter analysis,acupuncture increased the expression of phenylethylamine and decreased N-acetyl serotonin in the brain,while significantly up-regulated serotonin,and down-regulated the levels of homovanillic acid,5-hydroxy-L-tryptophan and 3,4-Dihydroxyphenylethylene Glyco in the spinal cord.Further investigation targeted tryptophan metabolism found that acupuncture considerably decreased the content of tryptophan and L-kynurenine,but increased serotonin.CONCLUSIONS:This study aims to assess changes in central neurotransmitters of CFA mice treated with acupuncture,revealing that abnormalities in central neurotransmitter metabolism may be a potential biochemical basis for pain.More importantly,our preliminary study suggests the potential role of tryptophan and its metabolites in acupuncture analgesia,which may provide new insight and direction for the pain management interface of neurometabolism.
基金Supported by Grants from Beijing Municipal Science and Technology Commission,No.Z191100006619020Beijing Municipal Administration of Hospitals Incubating Program,2023,No.PX2023070Beijing Municipal Administration of Hospitals Incubating Program,2024,No.PX2024072.
文摘BACKGROUND The tryptophan-kynurenine(TRP-KYN)pathway may be implicated in the pathophysiology of cognitive impairment and pain severity in major depressive disorder(MDD);however,few studies have explored the intricacies of their interaction.AIM To investigate the relationship between the TRP-KYN pathway and cognitive function in MDD patients with and without painful physical symptoms(PPS).METHODS Seventy patients with MDD were recruited,including 33 and 37 with and without PSS,respectively.The Hamilton Depression Scale,the Hamilton Anxiety Scale,and the Short-form of McGill pain questionnaire(SFMPQ)were used to assess clinical symptoms.Cognitive function was assessed by the MATRICS Consensus Cognitive Battery(MCCB)score.TRP-KYN pathway metabolites’serum levels were measured using high-performance liquid chromatography-tandem mass spectrometry.RESULTS The with PPS group exhibited significantly higher TRP-KYN ratios than did the without PPS group;in the former,the SFMPQ scores positively and negatively correlated with the TRP-KYN ratio and total MCCB score,respectively.Regression analysis indicated that body mass index and SFMPQ scores were significantly associated with the TRP-KYN ratio,predicting 30%of the variance.CONCLUSION The TRP-KYN ratio is a potential biomarker for identifying patients with depression accompanied by pain symptoms,and targeting it may represent a novel therapeutic strategy for managing pain in these individuals.Further elucidation of the biological mechanisms underlying cognitive impairment in MDD patients with PPS is warranted.
基金supported by the National Key R&D Program of China(No.2021YFF0600700)the National Natural Science Foundation of China(No.22034005)+1 种基金Research Projects of Putian University(No.2024172)the Startup Fund for Advanced Talents of Putian University(No.2024046)。
文摘Inflammation is often accompanied by glioblastoma cells(GBMs)and is considered a key factor for GBM growth.This feature is believed to be connected with the tryptophan pathway mainly affected by intestinal microbes since the concept of gut-brain axis(GBA)has been proposed.Here we present a microchip model co-culturing intestinal cells(Caco2),microbes(E.coli),and GBM cells(U87)to study inflammatory responses of GBM by investigating the tryptophan metabolism.E.coli after encapsulating with alginate hydrogel microparticles(AHMPs)was seeded in the microchip where Caco2 was located,forming the simulated system of intestinal physiology and avoiding excessive reproduction of microbes.Continuous flow was applied to maintain the cell viability,induce the morphogenesis,and simulate the tryptophan transportation in GBA.The morphological alterations of Caco2 and U87 were characterized by fluorescence imaging and the tryptophan metabolism,especially the tryptophan-kynurenine pathway,was analyzed by LC-MS.Above these results of molecular analysis and cell behavior,we can conclude that GBM inflammation is induced by tryptophan accumulation.This microchip-based model generally provides an alternative method for in vitro research of interactions in GBA.
基金supported by the National Natural Science Foundation of China(32201988)Natural Science Foundation of Jiangsu Province(BK20210456)+3 种基金Special Fund for Science and Technology Program of Jiangsu Province(BM2022019)the National Key R&D Program of China(2023YFC2506004)the Fundamental Research Funds for the Central Universities(JUSRP123047)the Program of Collaborative Innovation Centre of Food Safety and Quality Control in Jiangsu Province.
文摘The neurotransmitter 5-hydroxytryptamine(5-HT),primarily produced by intestinal enterochromaffin(EC)cells,relies on tryptophan hydroxylase 1(TPH1)for synthesis.Research suggested Bifidobacterium breve CCFM1025’s potential in regulating Tph1 gene expression,maintaining 5-HT levels in stressed mice,but its precise mechanisms were unclear.This study used metabolomic techniques to assess probiotic fermentation products,revealing acetate as the crucial element in Bb-CCFM1025’s regulation of gut 5-HT synthesis.Further exploration correlated acetate with Tph1 transcription in intestinal organoids.Transcriptomic methods and quantitative reverse transcription polymerase chain reaction validation demonstrated how acetate facilitated 5-HT synthesis and secretion.It unveiled that acetate orchestrates signaling pathways(phosphoinositide 3-kinase-protein kinase B(PI3K-AKT),phospholipase C-phosphorylated extracellular signal-regulated kinase(PLC-pERK),and PLC-1,4,5-trisphosphate(IP3)-Ca^(2+))within EC,enabling 5-HT production.These findings elucidate the biochemical mechanisms behind specific probiotics’effects,aiding in the targeted selection of similar beneficial strains.This study offers theoretical support for choosing probiotics with analogous functionalities based on their physiological impacts.
基金funded by National Key R&D Program of China(2023YFD1301200)the science and technology innovation Program of Hunan Province(2021RC3091).
文摘Background Tryptophan is essential for nutrition,immunity and neural activity,but cannot be synthesized endogenously.Certain natural products influence host health by modulating the gut microbiota to promote the production of tryptophan metabolites.Sanguinarine(SAN)enhances broiler immunity,however,its low bioavailability and underlying mechanisms remain unclear.This study aimed to decode the mechanisms by which sanguinarine enhances intestinal immune function in broilers.Methods Liquid chromatography-tandem mass spectrometry(LC-MS/MS)was employed to identify the main metabolites of sanguinarine in the intestine.Subsequently,equal concentrations of sanguinarine and its metabolites were separately added to the diets.The effects of sanguinarine and its metabolites on the intestinal immune function of broiler chickens were evaluated using 16S rRNA gene amplicon sequencing and tryptophan metabolomics approaches.Results We determined that dihydrosanguinarine(DHSA)is the main metabolite of sanguinarine in the intestine.Both compounds increased average daily gain and reduced feed efficiency,thereby improving growth performance.They also enhanced ileal villus height and the villus-to-crypt(V/C)ratio while decreasing crypt depth and upregulating the mRNA expression of tight junction proteins ZO-1,occludin and claudin-1.Furthermore,both compounds promoted the proliferation of intestinal Lactobacillus species,a tryptophan-metabolizing bacterium,stimulated short-chain fatty acid production,and lowered intestinal pH.They regulated tryptophan metabolism by increasing the diversity and content of indole tryptophan metabolites,activating the aryl hydrocarbon receptor(AhR)pathway,and elevating the mRNA levels of CYP1A1,CYP1B1,SLC3A1,IDO2 and TPH1.Inflammatory cytokines IL-1β and IL-6 were inhibited,while anti-inflammatory cytokines IL-10 and IL-22,serum SIgA concentration,and intestinal MUC2 expression were increased.Notably,DHSA exhibited a more pronounced effect on enhancing immune function compared to SAN.Conclusions SAN is converted to DHSA in vivo,which increases its bioavailability.DHSA regulates tryptophan metabolism by activating the AhR pathway and modulating immune-related factors through changes in the gut microbiota.Notably,DHSA significantly increases the abundance of Lactobacillus,a key tryptophan-metabolizing bacterium,thereby enhancing intestinal immune function and improving broiler growth performance.
基金Financial support for this research from Minnesota Corn Growers Association(Burnsville,MN,USA)Green Plains Energy(Omaha,NE,USA)is greatly appreciated.
文摘Background Diets with high inclusion of corn co-products such as corn fermented protein(CFP)may contain excess Leu,which has a negative impact on feed intake and growth performance of pigs due to increased catabolism of Val and Ile and reduced availability of Trp in the brain for serotonin synthesis.However,we hypothesized that the negative effect of using CFP in diets for weanling pigs may be overcome if diets are fortified with crystalline sources of Val,Trp,and(or)Ile.Methods Three hundred and twenty weanling pigs were randomly allotted to one of 10 dietary treatments in a com-pletely randomized design,with 4 pigs per pen and 8 replicate pens per treatment.A corn-soybean meal diet and 2 basal diets based on corn and 10%CFP or corn and 20%CFP were formulated.Seven additional diets were formu-lated by fortifying the basal diet with 20%CFP with Ile,Trp,Val,Ile and Val,Ile and Trp,Trp and Val,or Ile,Trp and Val.A two-phase feeding program was used,with d 1 to 14 being phase 1 and d 15 to 28 being phase 2.Fecal scores were recorded every other day.Blood samples were collected on d 14 and 28 from one pig per pen.On d 14,fecal samples were collected from one pig per pen in 3 of the 10 treatments to determine volatile fatty acids,ammonium concen-tration,and microbial protein.These pigs were also euthanized and ileal tissue was collected.Results There were no effects of dietary treatments on any of the parameters evaluated in phase 1.Inclusion of 10%or 20%CFP in diets reduced(P<0.05)final body weight on d 28,and average daily gain(ADG)and average daily feed intake(ADFI)in phase 2 and for the entire experimental period.However,pigs fed the CFP diet supplemented with Val,Ile,and Trp had final body weight,ADFI,ADG and gain to feed ratio in phase 2 and for the entire experiment that was not different from pigs fed the control diet.Fecal scores in phase 2 were reduced(P<0.05)if CFP was used.Conclusions Corn fermented protein may be included by up to 20%in diets for weanling pigs without affecting growth performance,gut health,or hindgut fermentation,if diets are fortified with extra Val,Trp,and Ile.Inclusion of CFP also improved fecal consistency of pigs.
基金Supported by the Open Bidding for Selecting the Best Candidates for Xin’an Medicine and the Modernization of Traditional Chinese Medicine of IHM,No.2023CXMMTCM024 and No.2023CXMMTCM003the Anhui University Collaborative Innovation Project,No.GXXT-2020-025+2 种基金the Scientific Research Project of Health and Wellness in Anhui Province,No.AHWJ2023BAc10002the Anhui Province New Era Education Quality Project,No.2023gjxslt014and the Clinical and Translational Research Project of Anhui Province,No.202427b10020046.
文摘BACKGROUND Prediabetes mellitus(PDM)is receiving increasing attention as a precursor to type 2 diabetes mellitus.Lifestyle and traditional Chinese medicine(TCM)inter-ventions are effective for PDM prevention and treatment.Therefore,we con-ducted a preliminary investigation and an exploratory randomised controlled trial to assess the effects of a combined lifestyle and TCM intervention on PDM indicators.AIM To study the effectiveness of Xiaokeqing granules(XQG)and lifestyle inter-ventions in PDM participants while using metabolomics to identify potential markers.METHODS Forty PDM participants with yin deficiency syndrome with excessive heat were recruited and randomly allocated to the control(Con)group or the XQG group(20 per group).The Con group underwent lifestyle interventions,whereas the XQG group underwent lifestyle and XQG interventions.The follow-up duration was 2 months.Fasting blood glucose,2-hour postprandial glucose(2hPG),gly-cated haemoglobin A1c,fasting insulin,homeostasis model assessment-insulin resistance levels,and serum metabolomics characteristics were compared via liquid chromatography-tandem mass spectrometry analysis.RESULTS There were significant differences in 2hPG between the two groups(P<0.05)in the intention-to-treat analysis and per-protocol analysis.The intervention method used in this study was safe(P>0.05).Groenlandicine,kaempferol,isomangiferin,etc.,are the XQG constituents absorbed in the blood.N-Nervonoyl methionine and 5-hydroxy-L-tryptophan are core potential metabolomic biomarkers for the effectiveness of XQG and lifestyle interventions.HTR1A,HTR2C,SLC6A4,etc.,are the core targets of XQG and lifestyle interventions,as well as the reason for their clinical efficacy.Possible mechanistic pathways include tryptophan metabolism,pantothenate and certificate of analysis biosynthesis,lysine degradation and biosynthesis of cofactors.CONCLUSION This pilot study provides evidence that a combined XQG and lifestyle intervention can improve 2hPG in par-ticipants with PDM.The mechanism of action is related to multiple constituents,targets and pathways.
基金supported by the National Natural Science Foundation of China(32272332,32021005,31820103010)the Fundamental Research Funds for the Central Universities(JUSRP622020,JUSRP22006,JUSRP51501)the Program of Collaborative Innovation Centre of Food Safety and Quality Control in Jiangsu Province.
文摘Obesity is a major focus of researchers due to its increasing prevalence and relationship with other diseases,such as cancer and cardiovascular diseases.Probiotics are active microorganisms and have been proven to alleviate obesity by modulating the microbiota.In this study,we found that oral administration of Bifidobacterium adolescentis CCFM8630 to obese mice inhibited high-fat diet(HFD)-induced changes in body weight and adipose tissue and alleviated hepatic oxidative stress.Furthermore,B.adolescentis CCFM8630 treatment primarily affected the relative abundances of the phyla Proteobacteria and Actinobacteria,and thereby decreased the production of lipopolysaccharide(LPS)and the occurrence of LPS related diseases.A high fiber intake increased the abundance of Lactobacillus and the concentrations of short chain fatty acids in obese mice,but these changes were reversed by B.adolescentis CCFM8630 treatment.In addition,targeted metabolomic analysis and microbiota relationship analysis revealed that B.adolescentis CCFM8630 treatment modified the microbiota of obese mice by promoting the conversion of tryptophan(Trp)to xanthurenic acid,kynurenic acid,tryptamine,indole-3-acetic acid,and indole-3-carboxaldehyde;facilitated the expression of interleukin-17A and the aryl hydrocarbon receptor to generate interleukin-22 in the colon;and upregulated the expression of tight junction proteins,thereby strengthening intestinal barriers.In summary,our findings suggest that the intake of B.adolescentis CCFM8630 may alleviate obesity by modulating the gut microbiota and related Trp metabolism.
基金supported by the grants from the Nutrition and care of Maternal and Child Research Funding program (2020BINCMCF056)。
文摘Limosilac to bacillus reuteri QS01 is potential probiotic isolated from the intestinal microbiota of healthy women in early pregnancy.In the current study,we examined whether QS01 can prevent gestational diabetes mellitus(GDM) in an enhanced mouse model of the condition.Female C57BL/6J mouse offspring(F1 generation) born to dams fed a control(CON) or low-protein diet(GDM group) during gestation and lactation were used.Pregnant F1 mice fed a standard diet were randomly assigned to 5 groups:CON,GDM,and GDM mice treated with metformin,QS01 or Lacticaseibacillus rhamnosus HN001.An oral glucose tolerance test was performed before sacrifice at gestational day 17.Glucose tolerance was significantly ameliorated by all 3 treatments.QS01 supplementation fortified the intestinal mucosal barrier and inhibited the escalation of plasma inflammatory cytokines.QS01 treatment altered the cecal microbiota composition and function.Plasma and cecal metabolite profiles were modulated by QS01,prominently demonstrating significant upregulation of indole lactate and L-tryptophan in plasma and 5-hydroxy-tryptophan in the cecum,positively correlated with gut Lactobacillus abundance.In summary,QS01 plays a role in preventing GDM by remodeling the intestinal microbiota,reinforcing the intestinal mucosal barrier and alleviating chronic inflammation.
基金supported by the Special Funds of Basic Research of Central Public Welfare Institute(JY2010 and ZX2410)。
文摘Background:Fructose may induce non-alcoholic fatty acids(NAFLD)due to the gut-liver axis interactions.The mechanism of fructose impairing colon barrier is unrevealed.Methods:Normal and dextran sulfate sodium(DSS)-induced Sprague-Dawley rats fed by 35%fructose diets were used to evaluate colon barrier functions.Microbiome and metabolome were applied to screen potential biomarker bacteria and metabolites induced by fructose.HT-29 cells were applied to validate metabolite biomarker indoleacrylic acid(IAA)and indole-3-carboxaldehyde(I3A)function in colon barrier which impaired by fructose.Results:Fructose induced colon barrier dysfunction,aggravated colon impairment in DSS-induced rats.With fructose intake,the colon length shortened,goblet numbers declined,inflammation infiltration induced,inflammatory cytokines increased,and apoptosis signals upregulated in colon tissue.Moreover,fructose induced dysbiosis of microbiota and their metabolites.Adlercreutzia and Holdemania were screened out as potential bacteria biomarkers,IAA and I3A as tryptophan metabolites were selected as metabolite biomarkers inhibited by fructose.IAA and I3A treatment alleviated the impairment induced by fructose by increasing trans epithelial electric resistance value,tight junction proteins,and Aryl hydrocarbon receptor(Ah R)activity in HT-29 cell.Conclusion:Fructose stimulated inflammation,apoptosis,gut bacteria alteration,and induced the reduction of IAA and I3A.Since fructose inhibited production of IAA and I3A,Ah R remained inactivated and consequently induced colon barrier dysfunction.
基金Supported by Sichuan Provincial Department of Science and Technology Youth Fund Project,No.2024NSFSC1609Sichuan Province Postdoctoral Special Funding Project,No.TB2023046。
文摘Impaired healing of diabetic wounds is one of the most important complications of diabetes,often leading to lower limb amputations and incurring significant economic and psychosocial costs.Unfortunately,there are currently no effective prevention or treatment strategies available.Recent research has reported that an imbalance in the gut microbiota,known as dysbiosis,was linked to the onset of type 2 diabetes,as well as the development and progression of diabetic complications.Indeed,the gut microbiota has emerged as a promising therapeutic approach for treating type 2 diabetes and related diseases.However,there is few of literatures specifically discussing the relationship between gut microbiota and diabetic wounds.This review aims to explore the potential role of the gut microbiota,especially probiotics,and its associated byproducts such as short chain fatty acids,bile acids,hydrogen sulfide,and tryptophan metabolites on wound healing to provide fresh insights and novel perspectives for the treatment of chronic wounds in diabetes.
文摘Obesity is a common noncommunicable disease characterized by persistent low-grade chronic inflammation and is associated with various metabolic disturbances,including insulin resistance and diabetes.The search for effective obesity treatments has led to growing interest in the role of amino acids in metabolic regulation.Tryptophan(TRP),an essential amino acid,participates in several biological pathways,including the kynurenine,5-hydroxytryptamine(5-HT,also known as serotonin),and indole pathways.Recent evidence underscores the significance of TRP metabolism in obesity,showing that various metabolites and enzymes in its metabolic pathways are altered in individuals with obesity.These changes influence physiological processes,mood regulation,and overall metabolic health.This review provides a comprehensive overview of TRP metabolism.It highlights the potential of targeting TRP metabolism as a therapeutic strategy for managing obesity and its related metabolic and psychological comorbidities.
文摘The review by Bangolo et al highlights the role of the gut microbiome in cancerassociated anemia(CAA).However,the impact of microbiome-derived metabolites is underexplored.In this letter,we focus on short-chain fatty acids,tryptophan metabolites,and polyamines as key mediators linking dysbiosis to impaired erythropoiesis and iron homeostasis.We also propose a research framework that integrates multi-omics analysis and gnotobiotic models.Finally,we discuss the clinical potential of metabolite-based diagnostics and microbiome-targeted therapies in managing CAA.
基金supported by the Science and Technology Program of Guangzhou(No.202103000020).
文摘Objectives:Triple-negative breast cancer(TNBC)is the breast cancer subtype with the poorest prognosis.This study aimed to elucidate the molecular pathways through which isoliquiritigenin(ISL),a natural chalcone compound derived fromlicorice and other plant roots,targets interferon regulatory factor 5(IRF5)in TNBC.Methods:TNBC cell lines were cultured and subjected to IRF5 knockdown using short hairpin RNA.Cell proliferation was assessed by cell counting kit-8(CCK-8)assay and colony formation assays.Western blotting and quantitative reverse transcription polymerase chain reaction(RT-PCR)were employed to measure expression levels of IRF5,solute carrier family 7 member 5(SLC7A5),and indoleamine 2,3-dioxygenase 1(IDO1).Intracellular tryptophan and its metabolites were quantified using commercially available assay kits and high-performance liquid chromatography(HPLC).TNBC cells were treated with various concentrations of ISL to evaluate its effects on proliferation and tryptophanmetabolism.Results:IRF5 was highly expressed in TNBC cell lines.Silencing IRF5 significantly inhibited cellular proliferation and growth.Knockdown of IRF5 reduced the expression of SLC7A5 and IDO1,leading to decreased intracellular levels of tryptophan and its metabolites.ISL markedly suppressed TNBC cell proliferation and disrupted tryptophan metabolism in tumor cells.Conclusion:ISL may inhibit TNBC progression by downregulating IRF5 and interfering with SLC7A5/IDO1-mediated tryptophan metabolic reprogramming,suggesting a potential therapeutic mechanism for TNBC treatment.
文摘The gene encoded for tryptophan decarboxylase (TDC), which is the key enzyme in terpenoil indole alkaloids pathway, was targeted to different subcellular compartments and stably expressed in transgenic tobacco (Nicotiana tabacum L.) plants at the levels detected by Western blot and tryptamine accumulation analysis. It was shown that the TDC was located in subcellular compartments, the chloroplasts and cytosol. The recombinant TDC targeted to chloroplasts and cytosol in tobacco plants was effectively expressed as soluble protein by Western blot analysis and enzymatic assay. The level of tryptamine accumulation in chloroplast was higher than that in cytosol and very low in vacuole and endoplasmic reticulum (ER) to be hardly detected by Western blot analysis. It was indicated that the highest amount of tryptamine was in chloroplasts, lower in endoplasmic reticula and the lowest in vacuoles as compared to those in wild type plants. The TDC targeted to different subcellular compartments of tobacco plants and its expression level were studied by different nucleotide sequences coding signal peptides at 5'-end of tdc gene in order to know the effects of the TDC in compartmentation on its functionality.
