Impact of gut–brain interaction in emerging neurological disorders

The central nervous system(CNS)is a reservoir of immune privilege.Specialized immune glial cells are responsible for maintenance and defense against foreign invaders.The blood–brain barrier(BBB)prevents detrimental pathogens and potentially overreactive immune cells from entering the periphery.When the double-edged neuroinflammatory response is overloaded,it no longer has the protective function of promoting neuroregeneration.Notably,microbiota and its derivatives may emerge as pathogen-associated molecular patterns of brain pathology,causing microbiome–gut–brain axis dysregulation from the bottom-up.When dysbiosis of the gastrointestinal flora leads to subsequent alterations in BBB permeability,peripheral immune cells are recruited to the brain.This results in amplification of neuroinflammatory circuits in the brain,which eventually leads to specific neurological disorders.Aggressive treatment strategies for gastrointestinal disorders may protect against specific immune responses to gastrointestinal disorders,which can lead to potential protective effects in the CNS.Accordingly,this study investigated the mutual effects of microbiota and the gut–brain axis,which may provide targeting strategies for future disease treatment.

Novel methylation gene panel in adjacent normal tissues predicts poor prognosis of colorectal cancer in Taiwan

BACKGROUND It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis.Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer(CRC).AIM To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis.METHODS We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways.Patients were divided into two groups based on the methylation status of the six evaluated genes,namely,the<3 aberrancy group and≥3 aberrancy group.Various tumor stages were divided into two subgroups(local and advanced stages)on the basis of the pathological type of the following tissues:Tumor and adjacent normal tissues(matched normal).We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression(TTP)and overall survival.RESULTS We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue.The 5-year TTP survival curves showed a significant difference between the≥3 aberrancy group and the<3 aberrancy group.Compared with the<3 aberrancy group,a significantly shorter TTP was observed in the≥3 aberrancy group.We further analyzed the interaction between CRC prognosis and different cancer stages(local and advanced)according to the methylation status of the selected genes in both types of tissues.There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages.We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues.CONCLUSION Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC.We recommend using these novel markers to assist in clinical decision-making.

MTNR1B polymorphisms with CDKN2A and MGMT methylation status are associated with poor prognosis of colorectal cancer in Taiwan

BACKGROUND Identifying novel colorectal cancer(CRC)prognostic biomarkers is crucial to helping clinicians make appropriate therapy decisions.Melatonin plays a major role in managing the circadian rhythm and exerts oncostatic effects on different kinds of tumours.AIM To explore the relationship between MTNR1B single-nucleotide polymorphism(SNPs)combined with gene hypermethylation and CRC prognosis.METHODS A total of 94 CRC tumour tissues were investigated.Genotyping for the four MTNR1B SNPs(rs1387153,rs2166706,rs10830963,and rs1447352)was performed using multiplex polymerase chain reaction.The relationships between the MTNR1B SNPs and CRC 5-year overall survival(OS)was assessed by calculating hazard ratios with 95%CIs.RESULTS All SNPs(rs1387153,rs2166706,rs10830963,and rs1447352)were correlated with decreased 5-year OS.In stratified analysis,rs1387153,rs10830963,and rs1447352 risk genotype combined with CDKN2A and MGMT methylation status were associated with 5-year OS.A strong cumulative effect of the four polymorphisms on CRC prognosis was observed.Four haplotypes of MTNR1B SNPs were also associated with the 5-year OS.MTNR1B SNPs combined with CDKN2A and MGMT gene methylation status could be used to predict shorter CRC survival.CONCLUSION The novel genetic biomarkers combined with epigenetic biomarkers may be predictive tool for CRC prognosis and thus could be used to individualise treatment for patients with CRC.

Differential DNA methylation analysis of SUMF2,ADAMTS5,and PXDN provides novel insights into colorectal cancer prognosis prediction in Taiwan

BACKGROUND Patients with colorectal cancer(CRC)undergo surgery,as well as perioperative chemoradiation or adjuvant chemotherapy primarily based on the tumor–node–metastasis(TNM)cancer staging system.However,treatment responses and prognostic outcomes of patients within the same stage vary markedly.The potential use of novel biomarkers can improve prognostication and shared decision making before implementation into certain therapies.AIM To investigate whether SUMF2,ADAMTS5,and PXDN methylation status could be associated with CRC prognosis.METHODS We conducted a Taiwan region cohort study involving 208 patients with CRC recruited from TriService General Hospital and applied the candidate gene approach to identify three genes involved in oncogenesis pathways.A methylation-specific polymerase chain reaction(MS-PCR)and Epi TYPER DNA methylation analysis were employed to detect methylation status and to quantify the methylation level of candidate genes in tumor tissue and adjacent normal tissue from participants.We evaluated SUMF2,ADAMTS5,and PXDN methylation as predictors of prognosis,including recurrence-free survival(RFS),progression-free survival(PFS),and overall survival(OS),using a Cox regression model and Kaplan–Meier analysis.RESULTS We revealed various outcomes related to methylation and prognosis.Significantly shorter PFS and OS were associated with the CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue compared with CpG_3+CpG_7 hypomethylation[hazard ratio(HR)=2.24,95%confidence interval(CI)=1.03-4.85 for PFS,HR=2.56 and 95%CI=1.08-6.04 for OS].By contrast,a significantly longer RFS was associated with CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue compared with CpG_2 and CpG_13 hypomethylation[HR(95%CI)=0.15(0.03-0.71)for CpG_2 and 0.20(0.04-0.97)for CpG_13].The relationship between the methylation status of PXDN and the prognosis of CRC did not reach statistical significance.CONCLUSION Our study found that CpG_3+CpG_7 hypermethylation of SUMF2 from tumor tissue was associated with significantly shorter PFS and OS compared with CpG_3+CpG_7 hypomethylation.CpG_2 and CpG_13 hypermethylation of ADAMTS5 from normal tissue was associated with a significantly longer RFS compared with CpG_2 and CpG_13 hypomethylation.These methylationrelated biomarkers which have implications for CRC prognosis prediction may aid physicians in clinical decision-making.

Ten- year follow- up investigation of stroke risk in systemic lupus erythematosus

Background and purpose To analyse the long-term risk of ischaemic stroke and the clinical effects of antithrombotics on the risk of haemorrhagic stroke in patients with systemic lupus erythematosus(SLE).Methods A retrospective cohort study was conducted using a population-based database taken from Taiwan National Health Insurance Research Database.Patients with SLE between 2000 and 2008 were registered and matched with two controls by the index date,age,gender and Charlson Comorbidity Index(CCI).These subjects were followed until either stroke event or 31 December 2013.Adjusted HRs(aHRs)for strokes were estimated with Cox regression models,and the cumulative incidence of ischaemic stroke was analysed by log-rank test and Kaplan-Meier survival analysis.Results In total,8310 patients with SLE and 16620 patients without SLE were included.In general,patients with SLE had higher rates of ischaemic stroke(5.4%vs 3.3%)and haemorrhagic stroke(1.5%vs 0.6%)than in controls.In multivariate analysis adjusted to age,gender,CCI,urbanisation level and antithrombotics uses,aHRs of all strokes,ischaemic stroke and haemorrhagic stroke were 1.73(95%CI:1.54 to 1.94),1.65(95%CI:1.45 to 1.87)and 2.24(95%CI:1.71 to 2.95),respectively,in patients with SLE.Patients with SLE were significantly more likely to suffer ischaemic stroke than patients without SLE,even 10 years after SLE diagnosis(6.12%vs 3.50%,p<0.001).Antiplatelet use increased the risk of haemorrhagic stroke in SLE group(aHR=1.74,95%CI:1.18 to 2.57).Conclusions Patients with SLE are at greater risk of developing ischaemic stroke that lasts for 10 years.Antiplatelets should be carefully administered to prevent cardiovascular events in patients with SLE due to the risk of haemorrhagic stroke.

Metabolic syndrome in non-obese Taiwan Residents： new definition of metabolically obese, normal-weight individual

Background Not only the obese, but also the non-obese adults have the high prevalence of metabolic syndrome in the upper normal weight. The aim of this study was to assess the prevalence rates of metabolic syndrome and its individual components in non-obese adult Taiwan Residents （body mass index （BMI） ≤ 26.9 kg/m^2）. Methods A cross-sectional study was conducted from January 2006 to December 2007. One thousand six hundred and fifty-nine subjects （aged 47.5±12.4 years）, 60.8% of which were men, were enrolled. The prevalence and odds ratios of metabolic syndrome, defined by the American Heart Association/National Heart, Lung and Blood Institute （2005）, were analyzed in the BMI category according to 2.0 unit increments, in individuals seeking a health examination. Results The higher the BMI categories, the more prevalent the metabolic syndrome was in women and in men （P 〈0.001）. Compared with those women with a BMI ≤20.9 kg/m^2, the odds ratios for metabolic syndrome in women were 1.3 （95% CI： 0.5-3.2） with BMI 21.0-22.9 kg/m^2, 3.0 （1.3-7.1） with BMI 23.0-24.9 kg/m^2, and 8.6 （3.6-20.8） for women with BMI 25.0-26.9 kg/m^2, after controlling for age, smoking status, alcohol consumption, betel nut chewing, blood routine, biochemical data, hepatitis B virus surface antigen and anti-hepatitis C virus. The corresponding odds ratios in men were 1.6 （0.6-4.2）, 3.7 （1.6-8.8）, and 9.9 （4.2-23.2）. Conclusions Individuals in the upper normal weight and slightly overweight BMI range have relatively high prevalence and increased risk of having metabolic syndrome. Therefore, physicians should screen metabolic syndrome in not only obese but also non-obese individuals for the prevention of cardiovascular disease.