Anti-tumor necrosis factor(TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases(IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from n...Anti-tumor necrosis factor(TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases(IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn's disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each antiTNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membranebound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with antiTNF antibodies in chronic intestinal inflammation, by predicting response to therapy.展开更多
The intestinal tract is inhabited by a tremendous number of microorganisms,termed the gut microbiota.These microorganisms live in a mutualistic relationship with their host and assist in the degradation of complex car...The intestinal tract is inhabited by a tremendous number of microorganisms,termed the gut microbiota.These microorganisms live in a mutualistic relationship with their host and assist in the degradation of complex carbohydrates.Although the gut microbiota is generally considered beneficial,the vast number of microbial cells also form a permanent threat to the host.Thus,the intestinal epithelium is covered with a dense layer of mucus to prevent translocation of the gut microbiota into underlying tissues.Intestinal mucus is an organized glycoprotein network with a host-specific glycan structure.While the mucus layer has long been considered a passive,host-designed barrier,recent studies showed that maturation and function of the mucus layer are strongly influenced by the gut microbiota.In return,the glycan repertoire of mucins can select for distinct mucosa-associated bacteria that are able to bind or degrade specific mucin glycans as a nutrient source.Because the intestinal mucus layer is at the crucial interface between host and microbes,its breakdown leads to gut bacterial encroachment that can eventually cause inflammation and infection.Accordingly,a dysfunctional mucus layer has been observed in colitis in mice and humans.Moreover,the increased consumption of a low-fiber Western-style diet in our modern society has recently been demonstrated to cause bacteria-mediated defects of the intestinal mucus layer.Here,I will review current knowledge on the interaction between gut bacteria and the intestinal mucus layer in health and disease.Understanding the molecular details of this host–microbe interaction may contribute to the development of novel treatment options for diseases involving a dysfunctional mucus layer,such as ulcerative colitis.展开更多
To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODSSerum IL9 as well as other cytokines (IL1β, IL6, IL13, IFN...To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODSSerum IL9 as well as other cytokines (IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn’s disease (CD) and 74 with ulcerative colitis (UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn’s Disease Activity Index (CDAI) and the Mayo Scoring System (MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex xMAP<sup>®</sup> technology. High-sensitive C-reactive protein concentrations (hsCRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTSSystemic IL9 was significantly lower in healthy individuals [9 pg/mL (95%CI: 8.2-10)] than in patients with inflammatory bowel disease (IBD): both inactive [14.3 pg/mL (11.9-19.9)] and active [27.6 pg/mL (24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/mL (23.4-32.2)] and in active UC [32.7 pg/mL (27-38.9)] compared to inactive diseases [15.9 pg/mL (10.8-23.4) in CD and 19.4 pg/mL (13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI (ρ = 0.32, P = 0.003) and MDAI (ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC (ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing (MH), IL9 had an accuracy superior to hsCRP and IL6 [97% (P < 0.0001), 67% (P = 0.071), and 55% (P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/mL (24.4-37.5) vs 21.88 pg/mL (18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations (ρ = -0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, 展开更多
Background:Endoscopic resection is increasingly used in the treatment for early gastric cancer(EGC);however,about 15%of endoscopic submucosal dissection(ESD)cases report non-curative resection.The efficacy of differen...Background:Endoscopic resection is increasingly used in the treatment for early gastric cancer(EGC);however,about 15%of endoscopic submucosal dissection(ESD)cases report non-curative resection.The efficacy of different remedial interventions after non-curative ESD for EGC remains controversial.This meta-analysis aimed to compare the long-term outcomes of additional surgery and non-gastrectomy treatment for EGC patients who underwent non-curative ESD.Methods:All relevant studies published up to October 2021 were systematically searched in the PubMed,Web of Science,and Embase databases.The medical subject headings terms"early gastric cancer,""gastrectomy,""endoscopic submucosal dissection,"and their related free keywords were used to search relevant articles without restrictions on regions,publication types,or languages.The Newcastle–Ottawa Quality Assessment Scale was used to evaluate the quality of the included studies.Odds ratios(ORs)with 95%confidence intervals(CIs)of 5-year overall survival(OS),disease-specific survival(DSS),disease-free survival(DFS)and hazard ratios(HRs)with 95%CIs of OS were calculated using a random-or fixed-effects model.Results:This meta-analysis included 17 retrospective cohort studies with 5880 patients,of whom 3167 underwent additional surgery and 2713 underwent non-gastrectomy.We found that patients receiving additional gastrectomy had better 5-year OS(OR=3.63,95%CI=3.05–4.31),DSS(OR=3.22,95%CI=2.22–4.66),and DFS(OR=4.39,95%CI=1.78–10.82)outcomes than those receiving non-gastrectomy treatments.The pooled HR also showed that gastrectomy following non-curative ESD significantly improved OS(HR=0.40,95%CI=0.33–0.48).In addition,elderly patients benefited from additional surgery in consideration of the 5-year OS(HR=0.54,95%CI=0.41–0.72).Conclusions:Compared with non-gastrectomy treatments,additional surgery offered better long-term survival outcomes for patients with EGC who underwent non-curative ESD.展开更多
In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hosp...In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.展开更多
Numerous pathogens can infect the olfactory tract,yet the pandemic caused by SARS-CoV-2 has strongly emphasized the importance of the olfactory mucosa as an immune barrier.Situated in the nasal passages,the olfactory ...Numerous pathogens can infect the olfactory tract,yet the pandemic caused by SARS-CoV-2 has strongly emphasized the importance of the olfactory mucosa as an immune barrier.Situated in the nasal passages,the olfactory mucosa is directly exposed to the environment to sense airborne odorants;however,this also means it can serve as a direct route of entry from the outside world into the brain.As a result,olfactotropic infections can have serious consequences,including dysfunction of the olfactory system,CNS invasion,dissemination to the lower respiratory tract,and transmission between individuals.Recent research has shown that a distinctive immune response is needed to protect this neuronal and mucosal tissue.A better understanding of innate,adaptive,and structural immune barriers in the olfactory mucosa is needed to develop effective therapeutics and vaccines against olfactotropic microbes such as SARS-CoV-2.Here,we summarize the ramifications of SARS-CoV-2 infection of the olfactory mucosa,review the subsequent immune response,and discuss important areas of future research for olfactory immunity to infectious disease.展开更多
Advancements in murine modeling systems for ulcerative colitis have diversified our understanding of the pathophysiological factors involved in disease onset and progression.This has fueled the identification of molec...Advancements in murine modeling systems for ulcerative colitis have diversified our understanding of the pathophysiological factors involved in disease onset and progression.This has fueled the identification of molecular targets,resulting in a rapidly expanding therapeutic armamentarium.Subsequently,management strategies have evolved from symptomatic resolution to well-defined objective endpoints,including clinical remission,endoscopic remission and mucosal healing.While the incorporation of these assessment modalities has permitted targeted intervention in the context of a natural disease history and the prevention of complications,studies have consistently depicted discrepancies associated with ascertaining disease status through clinical and endoscopic measures.Current recommendations lack consideration of histological healing.The simultaneous achievement of clinical,endoscopic,and histologic remission has not been fully investigated.This has laid the groundwork for a novel therapeutic outcome termed disease clearance(DC).This article summarizes the concept of DC and its current evidence.展开更多
Gastrointestinal luminal endoscopy is of paramount importance for diagnosis, monitoring and dysplasia surveillance in patients with both, Crohn's disease and ulcerative colitis. Moreover, with the recent recogniti...Gastrointestinal luminal endoscopy is of paramount importance for diagnosis, monitoring and dysplasia surveillance in patients with both, Crohn's disease and ulcerative colitis. Moreover, with the recent recognition that mucosal healing is directly linked to the clinical outcome of patients with inflammatory bowel disorders, a growing demand exists for the precise, timely and detailed endoscopic assessment of superficial mucosal layer. Further, the novel field of molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapeutic responses. Within this review, we describe how novel endoscopic approaches and advanced endoscopic imaging methods such as high definition and high magnification endoscopy, dye-based and dye-less chromoendoscopy, confocal laser endomicroscopy, endocytoscopy and molecular imaging now allow for the precise and ultrastructural assessment of mucosal inflammation and describe the potential of these techniques for dysplasia detection.展开更多
The gut microbiota plays a key role in host health and disease,particularly through their interactions with the immune system.Intestinal homeostasis is dependent on the symbiotic relationships between the host and the...The gut microbiota plays a key role in host health and disease,particularly through their interactions with the immune system.Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota,which is influenced by the highly co-evolved immune-microbiota interactions.The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system.In this review,we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes.We further highlight the essential roles of pattern recognition receptors(PRRs),the G protein-coupled receptors(GPCRs),aryl hydrocarbon receptor(AHR)and the nuclear receptors expressed in the intestinal epithelial cells(IECs)and the intestine-resident immune cells.We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease(IBD).展开更多
AIM To evaluate the utility of fecal calprotectin(FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease(IBD) cohort.METHODS All FC measurements that were obtained during a...AIM To evaluate the utility of fecal calprotectin(FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease(IBD) cohort.METHODS All FC measurements that were obtained during a 3-year period from patients with inflammatory bowel disease in clinical remission were identified. Data regarding the short-term(6 mo) course of the disease were extracted from the medical files. Exclusion criteria were defined as:(1) An established flare of the disease at the time of FC measurement,(2) Loss to follow up within 6 mo from baseline FC measurement, and,(3) Insufficient data on file. Statistical analysis was performed to evaluate whether baseline FC measurement could predict the short term clinical relapse and/or the presence of mucosal healing.RESULTS We included 149 [Crohn's disease(CD) = 113, Ulcerative colitis(UC) = 36, male = 77] IBD patients in our study. Within the determined 6-month period post-FC measurement, 47(31.5%) had a disease flare. Among 76 patients who underwent endoscopy, 39(51.3%) had mucosal healing. Baseline FC concentrations were significantly higher in those who had clinical relapse compared to those who remained in remission during follow up(481.0 μg/g, 286.0-600.0 vs 89.0, 36.0-180.8, P < 0.001). The significant predictive value of baseline median with IQR FC for clinical relapse was confirmed by multivariate Cox analysis [HR for 100μg/g: 1.75(95%CI: 1.28-2.39), P = 0.001]. Furthermore, lower FC baseline values significantly correlated to the presence of mucosal healing in endoscopy(69.0 μg/g, 30.0-128.0 vs 481.0, 278.0-600.0, in those with mucosal inflammation, median with IQR, P < 0.001). We were able to extract cut-off values for FC concentration with a high sensitivity and specificity for predicting clinical relapse(261 μg/g with AUC = 0.901, sensitivity 87.2%, specificity 85.3%, P < 0.001) or mucosal healing(174 μg/g with AUC = 0.956, sensitivity 91.9%, specificity 87.2%, P < 0.001). FC was better than CRP in predicting either outcome; nevertheless, h展开更多
AIM: To review the published literature concerning the accuracy of faecal inflammatory markers for identifying mucosal healing. METHODS: Bibliographical searches were performed in MEDLINE electronic database up to Feb...AIM: To review the published literature concerning the accuracy of faecal inflammatory markers for identifying mucosal healing. METHODS: Bibliographical searches were performed in MEDLINE electronic database up to February 2015,using the following terms: "inflammatory bowel disease","Crohn′s disease","ulcerative colitis","faecal markers","calprotectin","lactoferrin","S100A12","endoscop*","mucosal healing","remission". In addition,relevant references from these studies were also included. Data were extracted from the published papers including odds ratios with 95%CI,P values and correlation coefficients. Data were grouped together according to each faecal marker,Crohn's disease or ulcerative colitis,and paediatric compared with adult study populations. Studies included in this review assessed mucosal inflammation by endoscopic and/or histological means and compared these findings to faecal marker concentrations in inflammatory bowel diseases(IBD) patient cohorts. Articles had to be published between 1990 and February 2015 and written in English. Papers excluded from the review were those where the faecal biomarker concentration was compared between patients with IBD and controls or other disease groups,those where serum biomarkers were used,those with a heterogeneous study population and those only assessing post-operative disease. RESULTS: The available studies show that faecal markers,such as calprotectin and lactoferrin,are promising non-invasive indicators of mucosal healing. However,due to wide variability in study design,especially with regard to the definition of mucosal healing and evaluation of marker cut offs,the available data do not yet indicate the optimal roles of these markers. Thirty-six studies published between 1990 and 2014 were included. Studies comprised variable numbers of study participants,considered CD(15-164 participants) or UC(12-152 participants) separately or as a combined group(11-252 participants). Eight reports included paediatric patients. Several indices were used to document mu展开更多
基金Supported by DFG-CRC1181-Project number(C02)a research operating grant from the International Organization for the Study of Inflammatory Bowel Diseases
文摘Anti-tumor necrosis factor(TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases(IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn's disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each antiTNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membranebound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with antiTNF antibodies in chronic intestinal inflammation, by predicting response to therapy.
基金B.O.S.is supported by a Long-Term Fellowship from the Human Frontier Science Program(LT000109/2014).
文摘The intestinal tract is inhabited by a tremendous number of microorganisms,termed the gut microbiota.These microorganisms live in a mutualistic relationship with their host and assist in the degradation of complex carbohydrates.Although the gut microbiota is generally considered beneficial,the vast number of microbial cells also form a permanent threat to the host.Thus,the intestinal epithelium is covered with a dense layer of mucus to prevent translocation of the gut microbiota into underlying tissues.Intestinal mucus is an organized glycoprotein network with a host-specific glycan structure.While the mucus layer has long been considered a passive,host-designed barrier,recent studies showed that maturation and function of the mucus layer are strongly influenced by the gut microbiota.In return,the glycan repertoire of mucins can select for distinct mucosa-associated bacteria that are able to bind or degrade specific mucin glycans as a nutrient source.Because the intestinal mucus layer is at the crucial interface between host and microbes,its breakdown leads to gut bacterial encroachment that can eventually cause inflammation and infection.Accordingly,a dysfunctional mucus layer has been observed in colitis in mice and humans.Moreover,the increased consumption of a low-fiber Western-style diet in our modern society has recently been demonstrated to cause bacteria-mediated defects of the intestinal mucus layer.Here,I will review current knowledge on the interaction between gut bacteria and the intestinal mucus layer in health and disease.Understanding the molecular details of this host–microbe interaction may contribute to the development of novel treatment options for diseases involving a dysfunctional mucus layer,such as ulcerative colitis.
基金Supported by National Science Center,No.DEC-2011/01/D/NZ5/02835
文摘To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODSSerum IL9 as well as other cytokines (IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn’s disease (CD) and 74 with ulcerative colitis (UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn’s Disease Activity Index (CDAI) and the Mayo Scoring System (MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex xMAP<sup>®</sup> technology. High-sensitive C-reactive protein concentrations (hsCRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTSSystemic IL9 was significantly lower in healthy individuals [9 pg/mL (95%CI: 8.2-10)] than in patients with inflammatory bowel disease (IBD): both inactive [14.3 pg/mL (11.9-19.9)] and active [27.6 pg/mL (24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/mL (23.4-32.2)] and in active UC [32.7 pg/mL (27-38.9)] compared to inactive diseases [15.9 pg/mL (10.8-23.4) in CD and 19.4 pg/mL (13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI (ρ = 0.32, P = 0.003) and MDAI (ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC (ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing (MH), IL9 had an accuracy superior to hsCRP and IL6 [97% (P < 0.0001), 67% (P = 0.071), and 55% (P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/mL (24.4-37.5) vs 21.88 pg/mL (18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations (ρ = -0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC,
基金National Natural Science Foundation of China(No.82070653)
文摘Background:Endoscopic resection is increasingly used in the treatment for early gastric cancer(EGC);however,about 15%of endoscopic submucosal dissection(ESD)cases report non-curative resection.The efficacy of different remedial interventions after non-curative ESD for EGC remains controversial.This meta-analysis aimed to compare the long-term outcomes of additional surgery and non-gastrectomy treatment for EGC patients who underwent non-curative ESD.Methods:All relevant studies published up to October 2021 were systematically searched in the PubMed,Web of Science,and Embase databases.The medical subject headings terms"early gastric cancer,""gastrectomy,""endoscopic submucosal dissection,"and their related free keywords were used to search relevant articles without restrictions on regions,publication types,or languages.The Newcastle–Ottawa Quality Assessment Scale was used to evaluate the quality of the included studies.Odds ratios(ORs)with 95%confidence intervals(CIs)of 5-year overall survival(OS),disease-specific survival(DSS),disease-free survival(DFS)and hazard ratios(HRs)with 95%CIs of OS were calculated using a random-or fixed-effects model.Results:This meta-analysis included 17 retrospective cohort studies with 5880 patients,of whom 3167 underwent additional surgery and 2713 underwent non-gastrectomy.We found that patients receiving additional gastrectomy had better 5-year OS(OR=3.63,95%CI=3.05–4.31),DSS(OR=3.22,95%CI=2.22–4.66),and DFS(OR=4.39,95%CI=1.78–10.82)outcomes than those receiving non-gastrectomy treatments.The pooled HR also showed that gastrectomy following non-curative ESD significantly improved OS(HR=0.40,95%CI=0.33–0.48).In addition,elderly patients benefited from additional surgery in consideration of the 5-year OS(HR=0.54,95%CI=0.41–0.72).Conclusions:Compared with non-gastrectomy treatments,additional surgery offered better long-term survival outcomes for patients with EGC who underwent non-curative ESD.
文摘In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.
基金supported by R01NS121067.E.A.M.is also supported by R21NS133561 and R21DC021260.
文摘Numerous pathogens can infect the olfactory tract,yet the pandemic caused by SARS-CoV-2 has strongly emphasized the importance of the olfactory mucosa as an immune barrier.Situated in the nasal passages,the olfactory mucosa is directly exposed to the environment to sense airborne odorants;however,this also means it can serve as a direct route of entry from the outside world into the brain.As a result,olfactotropic infections can have serious consequences,including dysfunction of the olfactory system,CNS invasion,dissemination to the lower respiratory tract,and transmission between individuals.Recent research has shown that a distinctive immune response is needed to protect this neuronal and mucosal tissue.A better understanding of innate,adaptive,and structural immune barriers in the olfactory mucosa is needed to develop effective therapeutics and vaccines against olfactotropic microbes such as SARS-CoV-2.Here,we summarize the ramifications of SARS-CoV-2 infection of the olfactory mucosa,review the subsequent immune response,and discuss important areas of future research for olfactory immunity to infectious disease.
文摘Advancements in murine modeling systems for ulcerative colitis have diversified our understanding of the pathophysiological factors involved in disease onset and progression.This has fueled the identification of molecular targets,resulting in a rapidly expanding therapeutic armamentarium.Subsequently,management strategies have evolved from symptomatic resolution to well-defined objective endpoints,including clinical remission,endoscopic remission and mucosal healing.While the incorporation of these assessment modalities has permitted targeted intervention in the context of a natural disease history and the prevention of complications,studies have consistently depicted discrepancies associated with ascertaining disease status through clinical and endoscopic measures.Current recommendations lack consideration of histological healing.The simultaneous achievement of clinical,endoscopic,and histologic remission has not been fully investigated.This has laid the groundwork for a novel therapeutic outcome termed disease clearance(DC).This article summarizes the concept of DC and its current evidence.
文摘Gastrointestinal luminal endoscopy is of paramount importance for diagnosis, monitoring and dysplasia surveillance in patients with both, Crohn's disease and ulcerative colitis. Moreover, with the recent recognition that mucosal healing is directly linked to the clinical outcome of patients with inflammatory bowel disorders, a growing demand exists for the precise, timely and detailed endoscopic assessment of superficial mucosal layer. Further, the novel field of molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapeutic responses. Within this review, we describe how novel endoscopic approaches and advanced endoscopic imaging methods such as high definition and high magnification endoscopy, dye-based and dye-less chromoendoscopy, confocal laser endomicroscopy, endocytoscopy and molecular imaging now allow for the precise and ultrastructural assessment of mucosal inflammation and describe the potential of these techniques for dysplasia detection.
基金We would like to thank W.Tao,H.Ma,and other members of Zhu laboratory and Z.Wei in Richard Flavell’s lab for helpful discussions.This work was supported by grants from the National Key R&D Program of China(Grant No.2018YFA0508000,S.Z.)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB29030101,S.Z.)+1 种基金the CAS Project for Young Scientists in Basic Research(Grant No.YSBR-074,S.Z.)the National Natural Science Foundation of China(Grant No.82061148013,S.Z.).
文摘The gut microbiota plays a key role in host health and disease,particularly through their interactions with the immune system.Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota,which is influenced by the highly co-evolved immune-microbiota interactions.The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system.In this review,we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes.We further highlight the essential roles of pattern recognition receptors(PRRs),the G protein-coupled receptors(GPCRs),aryl hydrocarbon receptor(AHR)and the nuclear receptors expressed in the intestinal epithelial cells(IECs)and the intestine-resident immune cells.We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease(IBD).
文摘AIM To evaluate the utility of fecal calprotectin(FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease(IBD) cohort.METHODS All FC measurements that were obtained during a 3-year period from patients with inflammatory bowel disease in clinical remission were identified. Data regarding the short-term(6 mo) course of the disease were extracted from the medical files. Exclusion criteria were defined as:(1) An established flare of the disease at the time of FC measurement,(2) Loss to follow up within 6 mo from baseline FC measurement, and,(3) Insufficient data on file. Statistical analysis was performed to evaluate whether baseline FC measurement could predict the short term clinical relapse and/or the presence of mucosal healing.RESULTS We included 149 [Crohn's disease(CD) = 113, Ulcerative colitis(UC) = 36, male = 77] IBD patients in our study. Within the determined 6-month period post-FC measurement, 47(31.5%) had a disease flare. Among 76 patients who underwent endoscopy, 39(51.3%) had mucosal healing. Baseline FC concentrations were significantly higher in those who had clinical relapse compared to those who remained in remission during follow up(481.0 μg/g, 286.0-600.0 vs 89.0, 36.0-180.8, P < 0.001). The significant predictive value of baseline median with IQR FC for clinical relapse was confirmed by multivariate Cox analysis [HR for 100μg/g: 1.75(95%CI: 1.28-2.39), P = 0.001]. Furthermore, lower FC baseline values significantly correlated to the presence of mucosal healing in endoscopy(69.0 μg/g, 30.0-128.0 vs 481.0, 278.0-600.0, in those with mucosal inflammation, median with IQR, P < 0.001). We were able to extract cut-off values for FC concentration with a high sensitivity and specificity for predicting clinical relapse(261 μg/g with AUC = 0.901, sensitivity 87.2%, specificity 85.3%, P < 0.001) or mucosal healing(174 μg/g with AUC = 0.956, sensitivity 91.9%, specificity 87.2%, P < 0.001). FC was better than CRP in predicting either outcome; nevertheless, h
文摘AIM: To review the published literature concerning the accuracy of faecal inflammatory markers for identifying mucosal healing. METHODS: Bibliographical searches were performed in MEDLINE electronic database up to February 2015,using the following terms: "inflammatory bowel disease","Crohn′s disease","ulcerative colitis","faecal markers","calprotectin","lactoferrin","S100A12","endoscop*","mucosal healing","remission". In addition,relevant references from these studies were also included. Data were extracted from the published papers including odds ratios with 95%CI,P values and correlation coefficients. Data were grouped together according to each faecal marker,Crohn's disease or ulcerative colitis,and paediatric compared with adult study populations. Studies included in this review assessed mucosal inflammation by endoscopic and/or histological means and compared these findings to faecal marker concentrations in inflammatory bowel diseases(IBD) patient cohorts. Articles had to be published between 1990 and February 2015 and written in English. Papers excluded from the review were those where the faecal biomarker concentration was compared between patients with IBD and controls or other disease groups,those where serum biomarkers were used,those with a heterogeneous study population and those only assessing post-operative disease. RESULTS: The available studies show that faecal markers,such as calprotectin and lactoferrin,are promising non-invasive indicators of mucosal healing. However,due to wide variability in study design,especially with regard to the definition of mucosal healing and evaluation of marker cut offs,the available data do not yet indicate the optimal roles of these markers. Thirty-six studies published between 1990 and 2014 were included. Studies comprised variable numbers of study participants,considered CD(15-164 participants) or UC(12-152 participants) separately or as a combined group(11-252 participants). Eight reports included paediatric patients. Several indices were used to document mu
