MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage patients.Human placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease.Here,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC patients.The results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in vitro.Furthermore,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids.Thus,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

Gut microbiota alteration and modulation in hepatitis B virus-related fibrosis and complications:Molecular mechanisms and therapeutic inventions

Hepatitis B virus(HBV)has posed a threat to public health,mainly resulting in liver damage.With long-term accumulation of extracellular matrix,patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma.The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality.With deeper understanding of the bidirectional interaction between the liver and the gut(gut-liver axis),there is a growing consensus that the human health closely relates to the gut microbiota.Supported by animal and human studies,the gut microbiota alters as the HBV-related liver fibrosis initials and progresses,characterized as the decrease of the ratio between“good”and“potentially pathogenic”microbes.When the primary disease is controlled via antiviral treatment,the gut microbiota dysfunction tends to be improved.Conversely,the recovery of gut microbiota can promote the regression of liver fibrosis.Therapeutic strategies targeted on gut microbiota(rifaximin,probiotics,engineered probiotics and fecal microbiota transplantation)have been applied to animal models and patients,obtaining satisfactory results.

The “No-touch” technique improves the survival of patients with advanced hepatocellular carcinomas treated by liver transplantation: A single-center prospective randomized controlled trial

Background:Liver transplantation(LT)is the best treatment for patients with hepatocellular carcinoma(HCC).However,the surgical technique needs to be improved.The present study aimed to evaluate the“no-touch”technique in LT.Methods:From January 2018 to December 2019,we performed a prospective randomized controlled trial on HCC patients who underwent LT.The patients were randomized into two groups:a no-touch technique LT group(NT group,n=38)and a conventional LT technique group(CT group,n=46).Operative outcomes and survival in the two groups were analyzed.Results:The perioperative parameters were comparable between the two groups(P>0.05).There was no significant difference between the two groups in disease-free survival(DFS)(P=0.732)or overall survival(OS)(P=0.891).Of 36 patients who were beyond the Hangzhou criteria for LT,the DFS of the patients in the NT group was significantly longer than that in the CT group(median 402 vs.126 days,P=0.025).In 31 patients who had portal vein tumor thrombosis(PVTT),DFS and OS in the NT group were significantly better than those in the CT group(median DFS 420 vs.167 days,P=0.022;2-year OS rate 93.8%vs.66.7%,P=0.043).In 14 patients who had diffuse-type HCCs,DFS and OS were significantly better in the NT group than those in the CT group(median DFS 141 vs.56 days,P=0.008;2-year OS rate 75.0%vs.33.3%,P=0.034).Multivariate analysis showed that for patients with PVTT and diffusetype HCCs,the no-touch technique was an independent favorable factor for OS(PVTT:HR=0.018,95%CI:0.001-0.408,P=0.012;diffuse-type HCCs:HR=0.034,95%CI:0.002-0.634,P=0.024).Conclusions:The no-touch technique improved the survival of patients with advanced HCC compared with the conventional technique.The no-touch technique may provide a new and effective LT technique for advanced HCCs.

Surgical treatment for recurrent hepatocellular carcinoma:Current status and challenges

Primary liver cancer is the sixth most commonly diagnosed cancer and was the third leading cause of cancer deaths worldwide in 2020.It includes hepatocellular carcinoma(HCC)(representing 75%-85%of cases),intrahepatic cholangiocarcinoma(representing 10%-15%of cases),and other rare types.The survival rate of patients with HCC has risen with improved surgical technology and perioperative management in recent years;however,high tumor recurrence rates continue to limit long-term survival,even after radical surgical resection(exceeding 50%recurrence).For resectable recurrent liver cancer,surgical removal[either salvage liver transplantation(SLT)or repeat hepatic resection]remains the most effective therapy that is potentially curative for recurrent HCC.Thus,here,we introduce surgical treatment for recurrent HCC.Areas Covered:A literature search was performed for recurrent HCC using Medline and PubMed up to August 2022.Expert commentary:In general,long-term survival after the reresection of recurrent liver cancer is usually beneficial.SLT has equivalent outcomes to primary liver transplantation for unresectable recurrent illness in a selected group of patients;however,SLT is constrained by the supply of liver grafts.SLT seems to be inferior to repeat liver resection when considering operative and postoperative results but has the major advantage of disease-free survival.When considering the similar overall survival rate and the current situation of donor shortages,repeat liver resection remains an important option for recurrent HCC.

Alterations in the human oral microbiome in cholangiocarcinoma

Dear Editor,Alterations in the human microbiome are closely related to various hepatobiliary diseases.Gut microbial dysbiosis has been found in patients with cholangiocarcinoma(CCA)[1].However,the characteristics of oral microbiome in patients with CCA have not been studied.

An Evaluation Method of Human Gut Microbial Homeostasis by Testing Specific Fecal Microbiota

Research on microecology has been carried out with broad perspectives in recent decades,which has enabled a better understanding of the gut microbiota and its roles in human health and disease.It is of great significance to routinely acquire the status of the human gut microbiota;however,there is no method to evaluate the gut microbiome through small amounts of fecal microbes.In this study,we found ten predominant groups of gut bacteria that characterized the whole microbiome in the human gut from a large-sample Chinese cohort,constructed a real-time quantitative polymerase chain reaction(qPCR)method and developed a set of analytical approaches to detect these ten groups of predominant gut bacterial species with great maneuverability,efficiency,and quantitative features.Reference ranges for the ten predominant gut bacterial groups were established,and we found that the concentration and pairwise ratios of the ten predominant gut bacterial groups varied with age,indicating gut microbial dysbiosis.By comparing the detection results of liver cirrhosis(LC)patients with those of healthy control subjects,differences were then analyzed,and a classification model for the two groups was built by machine learning.Among the six established classification models,the model established by using the random forest algorithm achieved the highest area under the curve(AUC)value and sensitivity for predicting LC.This research enables easy,rapid,stable,and reliable testing and evaluation of the balance of the gut microbiota in the human body,which may contribute to clinical work.

Long non-coding RNA SNHG16 promotes human placenta-derived mesenchymal stem cell proliferation capacity through the PI3K/AKT pathway under hypoxia

BACKGROUND The effect of hypoxia on mesenchymal stem cells(MSCs)is an emerging topic in MSC biology.Although long non-coding RNAs(lncRNAs)and messenger RNAs(mRNAs)are reported to play a critical role in regulating the biological characteristics of MSCs,their specific expression and co-expression profiles in human placenta-derived MSCs(hP-MSCs)under hypoxia and the underlying mechanisms of lncRNAs in hP-MSC biology are unknown.AIM To reveal the specific expression profiles of lncRNAs in hP-MSCs under hypoxia and initially explored the possible mechanism of lncRNAs on hP-MSC biology.METHODS Here,we used a multigas incubator(92.5%N_(2),5%CO_(2),and 2.5%O_(2))to mimic the potential of hP-MSCs.RNA sequencing technology was applied to identify the exact expression profiles of lncRNAs and mRNAs under hypoxia.RESULTS We identified 289 differentially expressed lncRNAs and 240 differentially expressed mRNAs between the hypoxia and normoxia groups.Among them,the lncRNA SNHG16 was upregulated under hypoxia,which was also validated by reverse transcription-polymerase chain reaction.SNHG16 was confirmed to affect hP-MSC proliferation rates using a SNHG16 knockdown model.SNHG16 overexpression could significantly enhance the proliferation capacity of hP-MSCs,activate the PI3K/AKT pathway,and upregulate the expression of cell cycle-related proteins.CONCLUSION Our results revealed the specific expression characteristics of lncRNAs and mRNAs in hypoxiacultured hP-MSCs and that lncRNA SNHG16 can promote hP-MSC proliferation through the PI3K/AKT pathway.

肝脏移植术后糖尿病患者肠道微生物组的变化

Post-transplant diabetes mellitus(PTDM)increases the risk of graft failure and death in liver transplant(LT)recipients.Experimental studies have indicated that enteric dysbiosis mediated by immunosuppressive tacrolimus(TAC)could contribute to glucose disorders,but no data on human recipients with PTDM have been reported.Here,by combining high-throughput shotgun metagenomics sequencing and metabolomics profiling,we characterized the intestinal microbiome(IM)in LT recipient cohort with or without PTDM and deciphered the potential relationship among IM,TAC dosage,and diabetes.By comparing with both non-PTDM and classical type 2 diabetes mellitus(T2DM),we identified microbial signatures of PTDM,which was characterized by the enriched Proteobacteria and decreased Bacteroidetes.Additionally,the altered microbes,as well as the microbial metabolomics,correlated with the dosage of TAC.Specifically,the levels of beneficial microbes associated with PTDM were lowered in recipients with the high TAC trough concentrations(>5 ng·mL^(-1))than those with low ones(<5 ng·mL^(-1)),which was accompanied by reduced faecal metabolites involved in the biosynthesis of a-linolenic acid and arachidonic acid-lowering factors of developing T2DM.Moreover,these microbial signatures linked with the extent of glucose disorders in LT recipients.In summary,the faecal microbiome and metabolome differed between PTDM and non-PTDM patients,which were linked with TAC dosage.This study was the first to explore taxonomic alterations and bacterial gene functions to better understand the contribution of the IM to PTDM.

The correlation between gut microbiome and atrial fibrillation: pathophysiology and therapeutic perspectives

Regulation of gut microbiota and its impact on human health is the theme of intensive research.The incidence and prevalence of atrial fibrillation(AF)are continuously escalating as the global population ages and chronic disease survival rates increase;however,the mechanisms are not entirely clarified.It is gaining awareness that alterations in the assembly,structure,and dynamics of gut microbiota are intimately engaged in the AF progression.Owing to advancements in next-generation sequencing technologies and computational strategies,researchers can explore novel linkages with the genomes,transcriptomes,proteomes,and metabolomes through parallel meta-omics approaches,rendering a panoramic view of the culture-independent microbial investigation.In this review,we summarized the evidence for a bidirectional correlation between AF and the gut microbiome.Furthermore,we proposed the concept of“gut-immune-heart”axis and addressed the direct and indirect causal roots between the gut microbiome and AF.The intricate relationship was unveiled to generate innovative microbiota-based preventive and therapeutic interventions,which shed light on a definite direction for future experiments.

“Find Me”and“Eat Me”signals:tools to drive phagocytic processes for modulating antitumor immunity

Phagocytosis,a vital defense mechanism,involves the recognition and elimination of foreign substances by cells.Phagocytes,such as neutrophils and macrophages,rapidly respond to invaders;macrophages are especially important in later stages of the immune response.They detect“find me”signals to locate apoptotic cells and migrate toward them.Apoptotic cells then send“eat me”signals that are recognized by phagocytes via specific receptors.“Find me”and“eat me”signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy.These signals,such as calreticulin and phosphatidylserine,mediate potent pro-phagocytic effects,thereby promoting the engulfment of dying cells or their remnants by macrophages,neutrophils,and dendritic cells and inducing tumor cell death.This review summarizes the phagocytic“find me”and“eat me”signals,including their concepts,signaling mechanisms,involved ligands,and functions.Furthermore,we delineate the relationships between“find me”and“eat me”signaling molecules and tumors,especially the roles of these molecules in tumor initiation,progression,diagnosis,and patient prognosis.The interplay of these signals with tumor biology is elucidated,and specific approaches to modulate“find me”and“eat me”signals and enhance antitumor immunity are explored.Additionally,novel therapeutic strategies that combine“find me”and“eat me”signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.

Addressing chemoresistance with a lipid gemcitabine nanotherapeutic strategy for effective treatment of pancreatic cancer

Resistance to gemcitabine in pancreatic cancer poses a significant clinical challenge.Further investigation is warranted to assess whether nano-formulation strategy can be employed to enhance the sensitivity of resistant strains to gemcitabine therapy.In this study,using gemcitabine-resistant pancreatic cancer cell lines,we examined the therapeutic potential of a gemcitabine nanodelivery platform and assessed the ability to overcome drug resistance against resistant strains.Silencing of human equilibrative nucleoside transporter 1(hENT1)led to reduced cellular uptake of gemcitabine,resulting in chemoresistance in pancreatic cancer.Gemcitabine nanoparticles circumvented the entry blockade caused by hENT1 silencing through endocytosis.Nanoparticle entry via clathrin-mediated endocytosis increased intracellular gemcitabine accumulation in gemcitabine-resistant pancreatic cancer cells.Moreover,gemcitabine nanoparticles are preferential in vivo delivery to tumor tissues,likely due to the enhanced permeability and retention effect.In comparison to free gemcitabine,gemcitabine nanoparticles demonstrate a more pronounced cytotoxic effect on gemcitabine-resistant pancreatic cancer cells,with favorable biosafety.This study improved the efficacy of gemcitabine through nanotechnology,providing a novel strategy to address gemcitabine-resistant pancreatic cancer.

Long-term functional maintenance of primary hepatocytes in vitro using macroporous hydrogels engineered through liquid-liquid phase separation

Preserving the functionality of hepatocytes in vitro poses a significant challenge in liver tissue engineering and bioartificial liver,as these cells rapidly lose their metabolic and functional characteristics after isolation.Inspired by the macroporous structures found in native liver tissues,here we develop synthetic hydrogel scaffolds that closely mimic the liver’s structural organization through the phase separation between polyethylene glycol(PEG)and polysaccharides.Our hydrogels exhibit interconnected macroporous structures and appropriate mechanical properties,providing an optimal microenvironment conducive to hepatocyte adhesion and the formation of sizable aggregates.Compared to two-dimensional hepatocyte cultures,enhanced functionalities of hepatocytes cultured in our macroporous hydrogels were observed for 14 days,as evidenced by quantitative reverse-transcription–polymerase chain reactions(qRT-PCR),immunofluorescence,and enzyme linked immunosorbent assay(ELISA)analyses.Protein sequencing data further confirmed the establishment of cell–cell interactions among hepatocytes when cultured in our hydrogels.Notably,these hepatocytes maintained a protein expression lineage that closely resembled freshly isolated hepatocytes,particularly in the Notch and tumor necrosis factor(TNF)signaling pathways.These results suggest that the macroporous hydrogels are attractive scaffolds for liver tissue engineering.

Correlation of Oral Microbiota With Different Immune Responses to Antiretroviral Therapy in People Living With HIV

Both HIV infection and antiretroviral therapy(ART)affect the oral microbiome.Whether successful treatment with ART in people living with HIV(PLWH),which leads to a significant decline in viral loads and immune reconstitution,is associated with changes in or recovery of the oral microbiome remains unknown.Therefore,we performed a cross-sectional study of 118 PLWH receiving regular ART and 40 healthy controls(HCs).Among the 118 PLWH,18 immunological nonresponders(INRs;<200 CD4^(+)T cells/μL)and 30 immunological responders(IRs;≥500 CD4^(+)T cells/μL)were identified.The oral microbiota composition of all participants was analyzed using 16S rRNA gene sequencing of throat swab samples.Relative abundance of bacterial genera was compared between IRs and INRs,and Pearson correlations between bacterial abundance and peripheral blood immune cell counts were evaluated.The INR group showed lower alpha diversity than the IR and HC groups,which displayed similar alpha diversity.The genera Alloprevotella,Prevotella and Neisseria were more abundant in PLWH than in HCs,whereas the genera Rothia,Streptococcus and Fusobacterium were more abundant in HCs than in PLWH.The genus Rothia was more abundant in the INR group,whereas Prevotella,Alloprevotella,Porphyromonas and Haemophilus were more abundant in the IR group.The genera Rothia and Alloprevotella were negatively and positively associated with CD4^(+)T cell counts,respectively.Thus,an increased abundance of Rothia in the oral microbiome is associated with unfavorable outcomes regarding immune reconstitution in PLWH receiving regular ART,whereas Prevotella,Alloprevotella,Porphyromonas and Haemophilus are associated with favorable outcomes.

Bacterial persisters: molecular mechanisms and therapeutic development

Persisters refer to genetically drug susceptible quiescent(non-growing or slow growing)bacteria that survive in stress environments such as antibiotic exposure,acidic and starvation conditions.These cells can regrow after stress removal and remain susceptible to the same stress.Persisters are underlying the problems of treating chronic and persistent infections and relapse infections after treatment,drug resistance development,and biofilm infections,and pose significant challenges for effective treatments.Understanding the characteristics and the exact mechanisms of persister formation,especially the key molecules that affect the formation and survival of the persisters is critical to more effective treatment of chronic and persistent infections.Currently,genes related to persister formation and survival are being discovered and confirmed,but the mechanisms by which bacteria form persisters are very complex,and there are still many unanswered questions.This article comprehensively summarizes the historical background of bacterial persisters,details their complex characteristics and their relationship with antibiotic tolerant and resistant bacteria,systematically elucidates the interplay between various bacterial biological processes and the formation of persister cells,as well as consolidates the diverse anti-persister compounds and treatments.We hope to provide theoretical background for in-depth research on mechanisms of persisters and suggest new ideas for choosing strategies for more effective treatmentofpersistent infections.

Detection of Klebsiella pneumoniae Co-Producing KPC-2 and MCR-8 in the Feces of an ICU Patient From China

It is critical to acknowledge that the coexistence of genes related to carbapenem and polymyxin resistance can exacerbate challenges in antimicrobial therapy.In this study,we identified Klebsiella pneumoniae isolate L2425 fromthe feces of an ICU patient in China.The isolate belongs to sequence type 11 and carries the antimicrobial resistance genes blaKPC-2,bla_(CTX-M-65) and mcr-8.Through S1-nuclease pulsed-field gel electrophoresis and Southern blotting analysis,we confirmed the presence of a~110 kb plasmid harboring the mcr-8 gene with a conserved structure(inhA-mcr-8-ompR-dgkA-IS903B).Furthermore,another~130 kb plasmid carrying bla_(KPC-2) was detected along with a composite transposon flanked by insertion sequence IS26.Conjugation experiments demonstrated that both pL2425-KPC-2 and pL2425-MCR-8 plasmids were transferable.Importantly,this is the first instance of clinical fecal samples from China containing a K.pneumoniae strain carrying both blaKPC-2 and mcr-8 genes.These findings underscore the significance of surveillance for carbapenemases and mobile colistin–resistance variants.

Engineering Reversible Hydrogels for 3D Cell Culture and Release Using Diselenide Catalyzed Fast Disulfide Formation

Hydrogels crosslinked by dynamic covalent bonds can effectively mimic the viscoelastic properties of native extracellular matrix and have been widely explored for 3D cell culture.Disulfide is one of the most common dynamic bonds in biological systems whose formation and cleavage are catalyzed by a set of dedicated enzymes.However,in vitro formation of disulfide bonds is a slow process and requires harsh catalysts.Therefore,it is difficult to use disulfide crosslinked hydrogels for cell culture.n this work,we show that disulfide bonds can be formed by thiol-diselenide(Dise)exchange under blue light llumination.This reaction is fast,reversible,and biocompatible.Moreover,residual diselenide in the hydrogel network can also accelerate thiol-disulfide exchange reactions leading to faster cell release from the hydrogels upon the addition of thiol-containing agents.We anticipate that disulfide crosslinked hydrogels catalyzed by diselenide can find broad biomedical applications,such as cell culture,celldelivery,and drug-controlled release.

Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases.Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment.However,only a limited number of nanotherapies have enter clinical trials or are clinically approved.Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system(MPS),resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors.Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy.Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages.Polymer conjugation revived the parent camptothecin agent(e.g.,7-ethyl-10-hydroxy-camptothecin),enabling lipid nanoparticle encapsulation.Furthermore,macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin,increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy.When tested in a preclinical murine model of breast cancer,macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles.Furthermore,intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity.Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity.This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.

Unusual global outbreak of monkeypox:what should we do?

Recently,monkeypox has become a global concern amid the ongoing COVID-19 pandemic.Monkeypox is an acute rash zoonosis caused by the monkeypox virus,which was previously concentrated in Africa.The re-emergence of this pathogen seems unusual on account of outbreaks in multiple nonendemic countries and the incline to spread from person to person.We need to revisit this virus to prevent the epidemic from getting worse.In this review,we comprehensively summarize studies on monkeypox,including its epidemiology,biological characteristics,pathogenesis,and clinical characteristics,as well as therapeutics and vaccines,highlighting its unusual outbreak attributed to the transformation of transmission.We also analyze the present situation and put forward countermeasures from both clinical and scientific research to address it.

Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives

Nonalcoholic fatty liver disease(NAFLD)is a hepatic manifestation of metabolic syndrome and a common cause of liver cirrhosis and cancer.Akkermansia muciniphila(A.muciniphila)is a next-generation probiotic that has been reported to improve metabolic disorders.Emerging evidence indicates the therapeutic potential of A.muciniphila for NAFLD,especially in the inflammatory stage,nonalcoholic steatohepatitis.Here,the current knowledge on the role of A.muciniphila in the progression of NAFLD was summarized.A.muciniphila abundancy is decreased in animals and humans with NAFLD.The recovery of A.muciniphila presented benefits in preventing hepatic fat accumulation and inflammation in NAFLD.The details of how microbes regulate hepatic immunity and lipid accumulation in NAFLD were further discussed.The modulation mechanisms by which A.muciniphila acts to improve hepatic inflammation are mainly attributed to the alleviation of inflammatory cytokines and LPS signals and the downregulation of microbiota-related innate immune cells(such as macrophages).This review provides insights into the roles of A.muciniphila in NAFLD,thereby providing a blueprint to facilitate clinical therapeutic applications.

The Role of Dihydroresveratrol in Enhancing the Synergistic Effect of Ligilactobacillus salivarius Liol and Resveratrol in Ameliorating Colitis in Mice

Currently approved therapeutical strategies for inflammatory bowel diseases(IBD)suffer from variable efficacy and association with risk of serious side effects.Therefore,efforts have been made in searching for alternative therapeutics strategies utilizing gut microbiota manipulation.In this study,we show that the probiotic strain Ligilactobacillus salivarius Li01(Li01)and the phytochemical prebiotic resveratrol(RSV)have synergistic effect in ameliorating colitis in mice.Oral coadministration of Li01(109 CFU/d)and RSV(1.5 g/kg/d)promoted restoration of various inflammatory injuries and gut microbiota composition,exhibiting a favorable anti-inflammatory effect in DSS-induced colitis mice.The combination treatment was associated with reductions in the levels of proinflammatory cytokines IL-1βand IL-6 and increases in the levels of the anti-inflammatory cytokine IL-17A in mouse serum.Moreover,the combination treatment was found to alter the composition and metabolism of the gut microbiota,especially influencing the production of short chain fatty acids and anti-inflammatory related molecules.The mechanism underlying the improved anti-inflammatory effect from the RSV and Li01 combination treatment was found to be associated with the environmental sensor mammalian aryl hydrocarbon receptor(AHR)and tryptophan metabolism pathway.Administration of RSV in combination with Li01 in different mouse model led to enhanced conversion of RSV into metabolites,including dihydroresveratrol(DHR),resveratrol-sulfate,and resveratrol-glucuronide.DHR was found to be the dominant metabolite of RSV in conventional and colitis mice.An increased DHR/RSV ratio was confirmed to activate AHR and contribute to an enhanced anti-inflammatory effect.DHR is considered as a potential AHR ligand.The DHR/RSV ratio also affected the serotonin pathway by controlling the expression of Tph1,SERT,and 5-HT7R leading to amelioration of colitis in mice.Our data suggest that treatment with a combination of Li01 and RSV has potential as a therapeutic strategy for IBD;further investigation of this combination in clinical settings is warranted.