肠上皮细胞Axin1缺失可调节肠道微生态预防结肠炎

Intestinal homeostasis is maintained by specialized host cells and the gut microbiota.Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis,and its dysregulation has been implicated in inflammation and colorectal cancer.Axin1 negatively regulates activated Wnt/β-catenin signaling,but little is known regarding its role in regulating host–microbial interactions in health and disease.Here,we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation.Axin1 expression was analyzed in human inflammatory bowel disease datasets.To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis,we generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell(IEC;Axin1^(ΔIEC))and Paneth cell(PC;Axin1^(ΔPC))to compare with control(Axin1^(LoxP);LoxP:locus of X-over,P1)mice.We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease(IBD).Axin1^(ΔIEC) mice exhibited altered goblet cell spatial distribution,PC morphology,reduced lysozyme expression,and enriched Akkermansia muciniphila(A.muciniphila).The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium(DSS)-induced colitis in vivo.Axin1^(ΔIEC) and Axin1^(ΔPC)mice became more susceptible to DSS-colitis after cohousing with control mice.Treatment with A.muciniphila reduced DSS-colitis severity.Antibiotic treatment did not change the IEC proliferation in the Axin1Loxp mice.However,the intestinal proliferative cells in Axin1^(ΔIEC)mice with antibiotic treatment were reduced compared with those in Axin1^(ΔIEC) mice without treatment.These data suggest non-colitogenic effects driven by the gut microbiome.In conclusion,we found that the loss of intestinal Axin1 protects against colitis,likely driven by epithelial Axin1 and Axin1-associated A.muciniphila.Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota.Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.

精神医学中的生物统计学(16) 把握度分析在横断面研究和纵向研究设计中的应用(英文)

1.Introduction Power and sample size estimation constitutes an important component of designing and planning modern scientific studies.It provides information for assessing the feasibility of a study to detect treatment effects and for estimating the resources needed to conduct the project.This tutorial discusses the basic concepts of power analysis and the major differences between hypothesis testing and power analyses.We also

Pretreating and normalizing metabolomics data for statistical analysis

Metabolomics as a research field and a set of techniques is to study the entire small molecules in biological samples.Metabolomics is emerging as a powerful tool generally for pre-cision medicine.Particularly,integration of microbiome and metabolome has revealed the mechanism and functionality of microbiome in human health and disease.However,metabo-lomics data are very complicated.Preprocessing/pretreating and normalizing procedures on metabolomics data are usually required before statistical analysis.In this review article,we comprehensively review various methods that are used to preprocess and pretreat metabolo-mics data,including MS-based data and NMR-based data preprocessing,dealing with zero and/or missing values and detecting outliers,data normalization,data centering and scaling,data transformation.We discuss the advantages and limitations of each method.The choice for a suitable preprocessing method is determined by the biological hypothesis,the characteristics of the data set,and the selected statistical data analysis method.We then provide the perspective of their applications in the microbiome and metabolome research.

Microbiome and intestinal pathophysiology in post-acute sequelae of COVID-19

Long CoVID,also known for post-acute sequelae of CovID-19,describes the people who have the signs and symptoms that continue or develop after the acute coviD-19 phase.Long CovID patients suffer from an inflammation or host responses towards the virus approx-imately 4 weeks after initial infection with the SARS CoV-2 virus and continue for an unchar-acterized duration.Anyone infected with CovID-19 before could experience long-CcovID conditions,including the patients who were infected with SARS CoV-2 virus confirmed by tests and those who never knew they had an infection early.People with long CoviD may experience health problems from different types and combinations of symptoms over time,such as fa-tigue,dyspnea,cognitive impairments,and gastrointestinal(Gl)symptoms(e.g.,nausea,vom-iting,diarrhea,decreased or loss of appetite,abdominal pain,and dysgeusia).The critical role of the microbiome in these Gl symptoms and long CovID were reported in clinical patients and experimental models.Here,we provide an overall view of the critical role of the Gl tract and microbiome in the development of long COVID,including the clinical Gl symptoms in patients,dysbiosis,viral-microbiome interactions,barrier function,and inflammatory bowel disease patients with long CovID.We highlight the potential mechanisms and possible treatment based on Gl health and microbiome.Finally,we discuss challenges and future direction in the long CoVID clinic and research.

Transmission risk of asymptomatic SARS-CoV-2 infection:a systematic review and meta-analysis

Background:Global evidence on the transmission of asymptomatic SARS-CoV-2 infection needs to be synthesized.Methods:A search of 4 electronic databases(PubMed,EMBASE,Cochrane Library,and Web of Science databases)as of January 24,2021 was performed.Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines were followed.Studies which reported the transmission rate among close contacts with asymptomatic SARS-CoV-2 cases were included,and transmission activities occurred were considered.The trans-mission rates were pooled by zero-inflated beta distribution.The risk ratios(RRs)were calculated using random-effects models.Results:Of 4923 records retrieved and reviewed,15 studies including 3917 close contacts with asymptomatic indexes were eligible.The pooled transmission rates were 1.79 per 100 person-days(or 1.79%,95%confidence interval[CI]0.41%-3.16%)by asymptomatic index,which is significantly lower than by presymptomatic(5.02%,95%CI 2.37%-7.66%;p<0.001),and by symptomatic(5.27%,95%CI 2.40%-8.15%;p<0.001).Subgroup anal-yses showed that the household transmission rate of asymptomatic index was(4.22%,95%CI 0.91%-7.52%),four times significantly higher than non-household transmission(1.03%,95%CI 0.73%-1.33%;p=0.03),and the asymptomatic transmission rate in China(1.82%,95%CI 0.11%-3.53%)was lower than in other countries(2.22%,95%CI 0.67%-3.77%;p=0.01).Conclusions:People with asymptomatic SARS-CoV-2 infection are at risk of transmitting the virus to their close contacts,particularly in household settings.The transmission potential of asymptomatic infection is lower than symptomatic and presymptomatic infections.This meta-analysis provides evidence for predict-ing the epidemic trend and promulgating vaccination and other control measures.Registered with PROS-PERO International Prospective Register of Systematic Reviews,CRD42021269446;https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=269446.

Breast and gut microbiome in health and cancer

The microbiota plays essential roles in health and disease,in both the intestine and the extra-intestine.Dysbiosis of the gut microbiota causes dysfunction in the intestine,which leads to inflammatory,immune,and infectious diseases.Dysbiosis is also associated with dis-eases beyond the intestine via microbial translocation or metabolisms.The in situ breast mi-crobiome,which may be sourced from the gut through lactation and sexual contact,could be altered and cause breast diseases.In this review,we summarize the recent progress in under-standing the interactions among the gut microbiome,breast microbiome,and breast diseases.We discuss the intestinal microbiota,microbial metabolites,and roles of microbiota in immune system.We emphasize the novel roles and mechanisms of the microbiome(both in situ and gastrointestinal sourced)and bacterial products in the development and progression of breast cancer.The intestinal microbial translocation suggests that the gut microbiome is translocated to the skin and subsequently to the breast tissue.The gut bacterial translocation is also due to the increased intestinal permeability.The breast and intestinal microbiota are important fac-tors in maintaining healthy breasts.Micronutrition queuine(Q)is derived from a de novo syn-thesized metabolite in bacteria.All human cells use queuine and incorporate it into the wobble anticodon position of specific transfer RNAs.We have demonstrated that Q modifica-tion regulates genes critical in tight junctions and migration in human breast cancer cells and a breast tumor model.We further discuss the challenges and future perspectives that can move the field forward for prevention,diagnosis,and treatment of breast diseases.

Hypothesis testing and statistical analysis of microbiome

After the initiation of Human Microbiome Project in 2008,various biostatistic and bioinformatic tools for data analysis and computational methods have been developed and applied to microbiome studies.In this review and perspective,we discuss the research and statistical hypotheses in gut microbiome studies,focusing on mechanistic concepts that underlie the complex relationships among host,microbiome,and environment.We review the current available statistic tools and highlight recent progress of newly developed statistical methods and models.Given the current challenges and limitations in biostatistic approaches and tools,we discuss the future direction in developing statistical methods and models for the microbiome studies.

A simple and sensitive method to detect vitamin D receptor expression in various disease models using stool samples

Vitamin D receptor(VDR)executes the main biological functions of its ligand vitamin D.VDR/vitamin D plays critical roles in regulating host immunity,maintaining barrier functions,and shaping gut microbiome.Reduction of intestinal VDR has been reported in various diseases,including inflammatory diseases and colon cancer.However,it is always challenging to get biopsies to test the pathologic changes of VDR in intestine.In the current study,we reported a simple and sensitive quantitative PCR(qPCR)method to detect reduction of intestinal VDR using fecal samples.We validated this method in several experimental models,such as colitis,bacterial infection,and aging.We further correlated the qPCR data of VDR with the protein level of VDR in colon or serum 25(OH)D_(3) in mice with different VDR status(VDR^(+/+),VDR^(+/-),and VDR^(-/-)).Our data indicate that the qPCR method to test VDR using fecal samples could detect the expression level of intestinal VDR in various diseases.Our study highlights the feasibility,sensitivity,and simplicity of a molecular method to study the status of VDR as a biomarker.

Inflammation and intestinal leakiness in older HIVD individuals with fish oil treatment

Fish oil is a natural product that has shown efficacy for managing inflammatory conditions with few side effects.There is emerging evidence that crosstalks between gut epithelial cells and immune cells contribute to chronic infectious diseases.HIV-infected(HIVt)older adults show age-related co-morbidities at a younger age than their uninfected counterparts.Persistent inflammation related to the chronic viral infection and its sequelae is thought to contribute to this disparity.However,little is known about whether fish oil reduces intestinal inflammation in HIV t patients.We measure inflammation and gut barrier function in HIV t older adults(median age Z 52,N Z 33),following 12 weeks of fish oil supplementation(a total daily dose of 1.6 g of omega-3 fatty acids).We showed a reduction in inflammation and gut permeability as measured by CD14,inflammatory cytokines,lipopolysaccharide,and lipopolysaccharide binding protein.The results indicate that older HIV t adults may benefit from a diet supplemented with the omega-3 fatty acids found in fish oil.