STAT3-Dependent Effects of Polymeric Immunoglobulin Receptor in Regulating Interleukin-17 Signaling and Preventing Autoimmune Hepatitis

One-third of patients with autoimmune hepatitis(AIH)have cirrhosis at the time of diagnosis.The relevance of these variables,although unknown,is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic factors.Dysbiosis of the gut flora and elevated polymeric immunoglobulin receptor(pIgR)levels have been observed in both patients and mouse models.Moreover,there is a direct relationship between pIgR expression and transaminase levels in patients with AIH.In this study,we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta(Reg3b)and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of AIH.Reg3b expression was reduced in pIgR gene(Pigr)-knockout mice compared to that in wild-type mice,leading to increased microbiota disruption.Conversely,exogenous pIgR supplementation increased Reg3b expression and maintained microbiota homeostasis.RNA sequencing revealed the participation of the interleukin(IL)-17 signaling pathway in the regulation of Reg3b through pIgR.Furthermore,the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH,and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3(STAT3).In this study,pIgR facilitated the upregulation of Reg3b via the STAT3 pathway,which plays a crucial role in preserving the balance of the intestinal microbiota in AIH.Through this research,we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

Prognostic significance of regional lymphadenectomy in T1b gallbladder cancer:Results from 24 hospitals in China

BACKGROUND Whether regional lymphadenectomy(RL)should be routinely performed in patients with T1b gallbladder cancer(GBC)remains a subject of debate.AIM To investigate whether RL can improve the prognosis of patients with T1b GBC.METHODS We studied a multicenter cohort of patients with T1b GBC who underwent surgery between 2008 and 2016 at 24 hospitals in 13 provinces in China.The logrank test and Cox proportional hazards model were used to compare the overall survival(OS)of patients who underwent cholecystectomy(Ch)+RL and those who underwent Ch only.To investigate whether combined hepatectomy(Hep)improved OS in T1b patients,we studied patients who underwent Ch+RL to compare the OS of patients who underwent combined Hep and patients who did not.RESULTS Of the 121 patients(aged 61.9±10.1 years),77(63.6%)underwent Ch+RL,and 44(36.4%)underwent Ch only.Seven(9.1%)patients in the Ch+RL group had lymph node metastasis.The 5-year OS rate was significantly higher in the Ch+RL group than in the Ch group(76.3%vs 56.8%,P=0.036).Multivariate analysis showed that Ch+RL was significantly associated with improved OS(hazard ratio:0.51;95%confidence interval:0.26-0.99).Among the 77 patients who underwent Ch+RL,no survival improvement was found in patients who underwent combined Hep(5-year OS rate:79.5%for combined Hep and 76.1%for no Hep;P=0.50).CONCLUSION T1b GBC patients who underwent Ch+RL had a better prognosis than those who underwent Ch.Hep+Ch showed no improvement in prognosis in T1b GBC patients.Although recommended by both the National Comprehensive Cancer Network and Chinese Medical Association guidelines,RL was only performed in 63.6%of T1b GBC patients.Routine Ch+RL should be advised in T1b GBC.

Berberine might block colorectal carcinogenesis by inhibiting the regulation of B-cell function by Veillonella parvula

Background:Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment.Our previous clinical trial demonstrated that berberine(BBR)hydrochloride might reduce the recurrence and canceration of colorectal adenoma(CRA).The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer(CRC).Methods:We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial,and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction.We further performed Apc Min/+animal intervention tests,RNA sequencing,flow cytometry,immunohistochemistry,and enzyme-linked immunosorbent assays.Results:The abundance of fecal Veillonella parvula(V.parvula)decreased significantly after BBR administration(P=0.0016)and increased through the development from CRA to CRC.Patients with CRC with a higher V.parvula abundance had worse tumor staging and a higher lymph node metastasis rate.The intestinal immune pathway of Immunoglobulin A production was activated,and the expression of TNFSF13B(Tumor necrosis factor superfamily 13b,encoding B lymphocyte stimulator[BLyS]),the representative gene of this pathway,and the genes encoding its receptors(interleukin-10 and transforming growth factor beta)were significantly upregulated.Animal experiments revealed that V.parvula promoted colorectal carcinogenesis and increased BLyS levels,while BBR reversed this effect.Conclusion:BBR might inhibit V.parvula and further weaken the immunomodulatory effect of B cells induced by V.parvula,thereby blocking the development of colorectal tumors.Trial Registraion:ClinicalTrials.gov,No.NCT02226185.

Identification of two migratory colon ILC2 populations differentially expressing IL-17A and IL-5/IL-13

Group 2 innate lymphoid cells(ILC2s)play important tissue resident roles in anti-parasite immunity,allergic immune response,tissue homeostasis,and tumor immunity.ILC2s are considered tissue resident cells with little proliferation at steady state.Recent studies have shown that a subset of small intestinal ILC2s could leave their residing tissues,circulate and migrate to different organs,including lung,liver,mesenteric LN and spleen,upon activation.However,it remains unknown whether other ILC populations with migratory behavior exist.In this study,we find two major colon ILC2 populations with potential to migrate to the lung in response to IL-25 stimulation.One subset expresses IL-17A and resembles inflammatory ILC2s(iILC2s)but lacks CD27 expression,whereas the other expresses CD27 but not IL-17A.In addition,the IL-17A^(+)ILC2s express lower levels of CD127,CD25,and ST2 than CD27^(+)ILC2s,which express higher levels of IL-5 and IL-13.Surprisingly,we found that both colon ILC2 populations still maintained their colonic features of preferential expression of IL-17A and CD27,IL-5/IL-13,respectively.Together,our study identifies two migratory colon ILC2 subsets with unique surface markers and cytokine profiles which are critical in regulating lung and colon immunity and homeostasis.

Single cell transcriptome revealed SARS-CoV-2 entry genes enriched in colon tissues and associated with coronavirus infection and cytokine production

Dear Editor,The novel COVID-19 coronavirus(SARS-CoV-2)endangers thousands of lives.Recently,nearly 10%COVID-19 patients with symptoms of the digestive tract were subsequently diagnosed in newly discovered SARS-CoV-2 infected cases,1 which indicates that SARSCoV-2 may infect people via digestive systems.The expression profile of angiotensin-converting enzyme homolog 2(ACE2)has been analyzed in gastrointestinal tract using external datasets.Unfortunately,most data of these datasets are not from Asian adults and the expression of other SARS-CoV-2 entry genes have not been detected in human gastrointestinal tract.Therefore,to provide more implications of viral transmission in clinical diagnosis and treatment,it is urgent to explore the expression of SARS-CoV-2 entry genes in the gastrointestinal tract of Asian people.Here,we used single-cell RNA sequencing profiled~27,800 cells of intestinal tissues from six patients with basic intestinal disease of Renji hospital.

ASAP3 regulates microvilli structure in parietal cells and presents intervention target for gastric acidity

Gastric acidity-associated disorders such as peptic ulcer and reflux diseases are widespread,and the reported resistance and side effects of currently used medicines suggest an urgent requirement for alternative therapeutic approaches.Here we demonstrate a critical role of ASAP3 in regulating the microvilli structure of parietal cells in vivo,and reveal the feasibility of controlling gastric acidity by targeting ASAP3.Conditional knockout of ASAP3 in mice caused elongation and stacking of microvilli in parietal cells,and substantially decreased gastric acid secretion.These were associated with active assembly of F-actin caused by a higher level of GTP-bound Arf6 GTPase.Consistently,a small molecular compound QS11 inhibited ASAP3 function and significantly reduced gastric acidity in vivo.Of note,the expression of ASAP3 was positively correlated with gastric acid secretion in 90 human cases,and high expression of ASAP3 was associated with reflux disease and peptic ulcer.These results reveal for the first time that ASAP3 regulates the microvilli structures in parietal cells.Our data also suggest ASAP3 as a feasible and drugable therapeutic target for gastric acidity-associated diseases.

FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine;however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca^(2+)/calmodulin-dependent protein kinasekinase 2 (CaMKKβ) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

Author correction to‘FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis’[Acta Pharm Sin B 14(2024)1605–1623]

The authors regret that due to the mistake of copying and pasting in the process of assembling figures and negligence in the proofreading,there are picture pasting errors in Fig.8 and Supporting Information Fig.S2,respectively,but the above errors did not affect the conclusion.The author has now revised Fig.8 and Fig.S2 as follows.The authors apologize for any inconvenience caused to the journal and readers.

Gut microbiome,liver immunology,and liver diseases

The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology.The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota.The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens.Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases.Of immense importance is the step from high-throughput sequencing(correlation)to mechanistic studies(causality)and therapeutic intervention.Here,we review the gut microbiota,liver immunology,and the interaction between the gut and liver.In addition,the impairment in the gut-liver axis found in various liver diseases is reviewed here,with an emphasis on alcohol-associated liver disease(ALD),nonalcoholic fatty liver disease(NAFLD),and autoimmune liver disease(AILD).On the basis of growing evidence from these preclinical studies,we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.

Comprehensive review of targeted therapy for colorectal cancer

Colorectal cancer(CRC)is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018.Surgery and chemotherapy have long been the first choices for cancer patients.However,the prognosis of CRC has never been satisfying,especially for patients with metastatic lesions.Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients.Following successes with the anti-EGFR(epidermal growth factor receptor)agent cetuximab and the anti-angiogenesis agent bevacizumab,new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate.Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials.This review provides an overview of existing CRC-targeted agents and their underlying mechanisms,as well as a discussion of their limitations and future trends.

The microbiome and autoimmunity: a paradigm from the gut–liver axis

Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experimental data in germ-free and gnotobiotic studies.Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown,as observed in rheumatic fever triggered by Streptococci via molecular mimicry,epitope spread and bystander effects.The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases,including rheumatoid arthritis,type 1 diabetes,multiple sclerosis and autoimmune liver disease.It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena.In fact,there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity,and microbial therapeutics is being investigated to prevent or halt autoimmune diseases.As a putative mechanism,it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens,giving rise to the differentiation of autoreactive Th17 cells and other T helper cells.This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity,with an emphasis on how dysbiosis may influence systemic autoimmunity.In particular,a gut–liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm,considering its anatomic and physiological connections.

Disability-adjusted life years and the trends of the burden of colorectal cancer:a population-based study in Shanghai,China during 2002 to 2016

Background:Colorectal cancer(CRC)still ranks the top in morbidity and mortality of cancers worldwide,posing a huge threat and burden to the society.We aimed to determine the age-standardized incidence,mortality,and disability-adjusted life years(DALYs)of CRC and explore potential changes in the temporal trends of the CRC burden in Shanghai during 2002 to 2016.Methods:The cancer statistics and demographics were obtained from the Cancer Registry and the Statistics Bureau of Pudong New Area,respectively.Data from 2002 to 2016 were included and analyzed retrospectively.DALYs were calculated using DisMod and the age-standardized rates(ASRs)were obtained according to Segi world standard population.Joinpoint regression was used to measure the trends in CRC incidence and to estimate the annual percent change.Results:The increasing trend of CRC ASR incidence halted after 2014,coinciding with the introduction of the Shanghai CRC screening program.The ASRs of mortality and DALYs increased,at 0.42%(P<0.05)and 4.07%(P<0.001)per year,respectively,which were mainly driven by men and individuals aged above the CRC screening program target.Conclusions:The disease burden of CRC in Shanghai remains serious,especially among men,and individuals aged>74 years.The benefits of the screening program have been partially proven by the ASRs of CRC incidence,providing important insights into better and wider application of screening programs.

Microbe-based management for colorectal cancer

Colorectal cancer(CRC)is one of the most prevalent,most lethal cancers in the world.Increasing evidence suggests that the intestinal microbiota is closely related to the pathogenesis and prognosis of CRC.The normal microbiota plays an essential role in maintaining gut barrier function and the immune microenvironment.Recent studies have identified carcinogenic bacteria such as enterotoxigenic Bacteroides fragilis(ETBF)and Streptococcus gallolyticus(S.gallolyticus),as well as protective bacterial such as Akkermansia muciniphila(A.muciniphila),as potential targets of CRC treatment.Gut microbiota modulation aims to restore gut dysbiosis,regulate the intestinal immune system and prevent from pathogen invasion,all of which are beneficial for CRC prevention and prognosis.The utility of probiotics,prebiotics,postbiotics,fecal microbiota transplantation and dietary inventions to treat CRC makes them novel microbe-based management tools.In this review,we describe the mechanisms involved in bacteria-derived colorectal carcinogenesis and summarized novel bacteria-related therapies for CRC.In summary,we hope to facilitate clinical applications of intestinal bacteria for preventing and treating CRC.

Organoid models of gastrointestinal Neoplasms:Origin,current status and future applications in personalized medicine

The in vitro organoid model is a major technological breakthrough that has been established as an important tool in many basic biological and clinical applications.This near-physiological 3D culture system accurately models various biological processes,including tissue renewal,stem cell/niche functions and tissue responses to drugs,mutations or damage.Organoids have the potential value of being an accurate model for disease predictions or drug screening applications and to identify the ideal treatment for that patient.Carcinogenesis can be modeled by mutating specific cancer genes in wild-type organoids;and patient-derived organoids provide an important resource in the development of personalized cancer treatment.Organoids from cancer patients could be used to identify the ideal treatment for a specific patient by growing matched healthy and diseased organoids from human cancer patients which additionally enables clinical screens for drug combinations.Organoids could also provide autologous cells ordin the futuredtissue for transplantation.In this review,we discuss the current advances,challenges and potential applications of this technique in gastrointestinal neoplasms.

Epigenetics of autoimmune liver diseases: current progress and future directions

Autoimmune liver disease,including autoimmune hepatitis,primary biliary cholangitis,and primary sclerosing cholangitis,is a chronic autoimmune liver condition characterized by abnormal accumulation of proinflammatory immune cells.As more and more genetic studies are conducted,it is becoming increasingly clear that genetic risk cannot fully explain disease pathogenesis.Epigenetic modifications,including CpG island DNA methylation,histone modification,and microRNA-mediated gene silencing,are gradually being acknowledged to play a role in immune cellular identity and disease heterogeneity.Given the heterogeneity and environmental exposure bias observed in patients,it is essential to uncover the epigenetic mechanisms of autoimmune liver disease,which could integrate environmental skewing,cell lineage commitment,and genetics to provide a fuller mechanistic understanding of the disease.Epigenetic profiling holds promise for identifying diagnostic and prognostic biomarkers,and epigenetic manipulations could result in novel therapies.Cutting-edge breakthroughs are frequently being made in epigenetics,which might guide future explorations into autoimmune liver disease.

Autoimmune Hepatitis in the Asia-Pacific Area

Autoimmune hepatitis has been considered as a relatively rare immunological liver disease,especially in the Asia-Pacific area.Although the diagnosis criteria and immunosuppressive treatment regimens have been established,there are still some challenges.According to the different presentations,the personalized management of patients who suffer from this disease,including those with chronic or acute severe onset,the autoantibody-negative phenotype and cirrhosis are necessarily descriptive.Each subgroup of patients should receive an individualized therapy.Here,we review the recent studies of autoimmune hepatitis,mainly focusing on the epidemiology and genetics,personalized diagnostics,individualized treatment strategies,special subgroups and outcomes.Most of the research in the literature is based on Japanese and Chinese populations.

Intestinal homeostasis in autoimmune liver diseases

Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system.Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease(AILD).Autoimmune hepatitis,primary biliary cholangitis,primary sclerosing cholangitis,and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis.Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD.Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation.Additionally,the gut and liver are continuously exposed to microbial metabolic products,mediating variable effects on liver immune pathologies.Importantly,microbiota-specific or associated immune responses,either hepatic or systemic,are abnormal in AILD.Comprehensive knowledge about host-microbiota interactions,included but not limited to this review,facilitates novel clinical practice from a microbiome-based perspective.However,many challenges and controversies remain in the microbiota field of AILD,and there is an urgent need for future investigations.

Risk SNP-induced lncRNA-SLCCl drives colorectal cancer through activating glycolysis signaling

Long non-coding RNAs(lncRNAs)play key roles in colorectal carcinogenesis.Here,we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis.First,we identified rs6695584 as the causative SNP in 1 q41 locus.The A>G mutation of rs6695584 created a protein-binding motif of BATF,altered the enhancer activity,and subsequently activated IncSLCCl expression.Further validation in two independent CRC cohorts confirmed the upregulation of IncSLCCl in CRC tissues,and revealed that increased IncSLCCl expression was associated with poor survival in CRC patients.Mechanistically,lncRNA-SLCCl interacted with AHR and transcriptionally activated HK2 expression,the crucial enzyme in glucose metabolism,thereby driving the glycolysis pathway and accelerating CRC tumor growth.The functional assays revealed that IncSLCCl induced glycolysis activation and tumor growth in CRC mediated by HK2.In addition,HK2 was upregulated in colorectal cancer tissues and positively correlated with IncSLCCl expression and patient survival.Taken together,our findings reveal a risk SNP-mediated oncogene lncRNA-SLCCl promotes CRC through activating the glycolysis pathway.

Decoding early myelopoiesis from dynamics of core endogenous network

A decade ago mainstream molecular biologists regarded it impossible or biologically ill-motivated to understand the dynamics of complex biological phenomena, such as cancer genesis and progression, from a network perspective. Indeed, there are numerical difficulties even for those who were determined to explore along this direction. Undeterred, seven years ago a group of Chinese scientists started a program aiming to obtain quantitative connections between tumors and network dynamics. Many interesting results have been obtained. In this paper we wish to test such idea from a different angle: the connection between a normal biological process and the network dynamics. We have taken early myelopoiesis as our biological model. A standard roadmap for the cell-fate diversification during hematopoiesis has already been well established experimentally, yet little was known for its underpinning dynamical mechanisms. Compounding this difficulty there were additional experimental challenges, such as the seemingly conflicting hematopoietic roadmaps and the cell-fate inter-conversion events. With early myeloid cell-fate determination in mind, we constructed a core molecular endogenous network from well-documented gene regulation and signal transduction knowledge. Turning the network into a set of dynamical equations, we found computationally several structurally robust states. Those states nicely correspond to known cell phenotypes. We also found the states connecting those stable states.They reveal the developmental routes—how one stable state would most likely turn into another stable state. Such interconnected network among stable states enabled a natural organization of cell-fates into a multi-stable state landscape. Accordingly, both the myeloid cell phenotypes and the standard roadmap were explained mechanistically in a straightforward manner. Furthermore,recent challenging observations were also explained naturally. Moreover, the landscape visually enables a prediction of a pool of additional cell states and developmental routes, including the non-sequential and cross-branch transitions, which are testable by future experiments. In summary, the endogenous network dynamics provide an integrated quantitative framework to understand the heterogeneity and lineage commitment in myeloid progenitors.