Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

Metabolic disease and the liver: A review

Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most common liver disease worldwide,with an estimated prevalence of 31%in Latin America.The presence of metabolic comorbidities coexisting with liver disease varies substantially among populations.It is acknowledged that obesity is boosting the type 2 diabetes mellitus“epidemic,”and both conditions are significant contributors to the increasing number of patients with MASLD.Nonalcoholic steatohepatitis represents a condition of chronic liver inflammation and is considered the most severe form of MASLD.MASLD diagnosis is based on the presence of steatosis,noninvasive scores and altered liver tests.Noninvasive scores of liver fibrosis,such as serum biomarkers,which should be used in primary care to rule out advanced fibrosis,are simple,inexpensive,and widely available.Currently,guidelines from international hepatology societies recommend using noninvasive strategies to simplify case finding and management of high-risk patients with MASLD in clinical practice.Unfortunately,there is no definite pharmacological treatment for the condition.Creating public health policies to treat patients with risk factors for MASLD prevention is essential.

Metabolic dysfunction-associated steatotic liver disease:Navigating terminological evolution,diagnostic frontiers and therapeutic horizon-an editorial exploration

Metabolic dysfunction-associated steatotic liver disease(MASLD),once known as non-alcoholic fatty liver disease(NAFLD),represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes.The redefinition of NAFLD in 2023 marked a significant reposition in terminology,emphasizing a broader understanding of liver steatosis and its associated risks.MASLD is now recognized as a major risk factor for liver cirrhosis,hepatocellular carcinoma,and systemic complications such as cardiovascular diseases or systemic inflammation.Diagnostic challenges arise,particularly in identifying MASLD in lean individuals,necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools.Therapeutically,there is an urgent need for effective treatments targeting MASLD,with emerging pharmacological options focusing on,among others,carbohydrate and lipid metabolism.Additionally,understanding the roles of bile acid metabolism,the microbiome,and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches.There is a strong need to emphasize the importance of collaborative efforts in understanding,diagnosing,and managing MASLD to improve physicians’approaches and patient outcomes.

FibroScan-aspartate transaminase:A superior non-invasive model for diagnosing high-risk metabolic dysfunction-associated steatohepatitis

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)with hepatic histological NAFLD activity score≥4 and fibrosis stage F≥2 is regarded as“at risk”non-alcoholic steatohepatitis(NASH).Based on an international consensus,NAFLD and NASH were renamed as metabolic dysfunction-associated steatotic liver disease(MASLD)and metabolic dysfunction-associated steatohepatitis(MASH),respectively;hence,we introduced the term“high-risk MASH”.Diagnostic values of seven non-invasive models,including FibroScan-aspartate transaminase(FAST),fibrosis-4(FIB-4),aspartate transaminase to platelet ratio index(APRI),etc.for high-risk MASH have rarely been studied and compared in MASLD.AIM To assess the clinical value of seven non-invasive models as alternatives to liver biopsy for diagnosing high-risk MASH.METHODS A retrospective analysis was conducted on 309 patients diagnosed with NAFLD via liver biopsy at Beijing Ditan Hospital,between January 2012 and December 2020.After screening for MASLD and the exclusion criteria,279 patients wereincluded and categorized into high-risk and non-high-risk MASH groups.Utilizing threshold values of each model,sensitivity,specificity,positive predictive value(PPV),and negative predictive values(NPV),were calculated.Receiver operating characteristic curves were constructed to evaluate their diagnostic efficacy based on the area under the curve(AUROC).RESULTS MASLD diagnostic criteria were met by 99.4%patients with NAFLD.The MASLD population was analyzed in two cohorts:Overall population(279 patients)and the subgroup(117 patients)who underwent liver transient elastography(FibroScan).In the overall population,FIB-4 showed better diagnostic efficacy and higher PPV,with sensitivity,specificity,PPV,NPV,and AUROC of 26.9%,95.2%,73.5%,72.2%,and 0.75.APRI,Forns index,and aspartate transaminase to alanine transaminase ratio(ARR)showed moderate diagnostic efficacy,whereas S index and gamma-glutamyl transpeptidase to platelet ratio(GPR)were relatively weaker.In the subgroup,FAST had the highest diagnostic efficacy,its sensitivity,specificity,PPV,NPV,and AUROC were 44.2%,92.3%,82.1%,67.4%,and 0.82.The FIB-4 AUROC was 0.76.S index and GPR exhibited almost no diagnostic value for high-risk MASH.CONCLUSION FAST and FIB-4 could replace liver biopsy as more effectively diagnostic methods for high-risk MASH compared to APRI,Forns index,ARR,S index,and GPR;FAST is superior to FIB-4.

Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China

BACKGROUND Within the normal range,elevated alanine aminotransferase(ALT)levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease(MAFLD).AIM To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively.METHODS A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected.The incidence rate,cumulative times,and equally and unequally weighted cumulative effects of excess high-normal ALT levels(ehALT)were measured.Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD.RESULTS A total of 83.13%of participants with MAFLD had normal ALT levels.The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group.Compared with those in the low-normal ALT group,the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651[95%confidence interval(CI):1.199-2.273]and 1.535(95%CI:1.119-2.106)in the third quartile and 1.616(95%CI:1.162-2.246)and 1.580(95%CI:1.155-2.162)in the fourth quartile,respectively.CONCLUSION Most participants with MAFLD had normal ALT levels.Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

Omics-based biomarkers as useful tools in metabolic dysfunctionassociated steatotic liver disease clinical practice:How far are we?

Unmet needs exist in metabolic dysfunction-associated steatotic liver disease(MASLD)risk stratification.Our ability to identify patients with MASLD with advanced fibrosis and at higher risk for adverse outcomes is still limited.Incorporating novel biomarkers could represent a meaningful improvement to current risk predictors.With this aim,omics technologies have revolutionized the process of MASLD biomarker discovery over the past decades.While the research in this field is thriving,much of the publication has been haphazard,often using single-omics data and specimen sets of convenience,with many identified candidate biomarkers but lacking clinical validation and utility.If we incorporate these biomarkers to direct patients’management,it should be considered that the roadmap for translating a newly discovered omics-based signature to an actual,analytically valid test useful in MASLD clinical practice is rigorous and,therefore,not easily accomplished.This article presents an overview of this area’s current state,the conceivable opportunities and challenges of omics-based laboratory diagnostics,and a roadmap for improving MASLD biomarker research.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor prognosis.As the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies.Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully elucidated.Methods Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of TNBC.We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies.Key signaling pathway components were evaluated using multi-omics approaches.Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.Results We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming.Mechanistically,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.Conclusions Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM.RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Alanine aminotransferase predicts incident steatotic liver disease of metabolic etiology: Long life to the old biomarker!

Alanine aminotransferase(ALT)serum levels increase because of hepatocellular damage.Metabolic dysfunction-associated fatty liver disease(MAFLD),which identifies steatotic liver disease(SLD)associated with≥2 metabolic abnormalities,has prominent sexual differences.The Metabolic Syndrome defines a cluster comprising abdominal obesity,altered glucose metabolism,dyslipidemia,and hypertension.Male sex,body mass index,glucose,lipids,ferritin,hypertension,and age independently predict ALT levels among blood donors.Over the last few decades,the reference range of ALT levels has been animatedly debated owing to attempts to update sex-specific reference ranges.With this backset,Chen et al have recently published a study which has two main findings.First,>80%of indi-viduals with MAFLD had normal ALT levels.Second,there was a linear increa-sing trend in the association between cumulative excess high-normal ALT levels and the rate of incident MAFLD.This study has biologically credible findings.However,it inaccurately considered sex differences in the MAFLD arena.Therefore,future studies on SLD owing to metabolic dysfunction should adopt locally determined and prospectively validated reference ranges of ALT and carefully consider sex differences in liver enzymes and MAFLD pathobiology.

Immunoglobulin G-mediated food intolerance and metabolic syndrome influence the occurrence of reflux esophagitis in Helicobacter pylori-infected patients

BACKGROUND Reflux esophagitis has an increasing prevalence and complex and diverse symptoms.Identifying its risk factors is crucial to understanding the etiology,prevention,and management of the disease.The occurrence of reflux esophagitis may be associated with food reactions,Helicobacter pylori(H.pylori)infection,and metabolic syndromes.AIM To investigate the risk factors for reflux esophagitis and analyze the effects of immunoglobulin(Ig)G-mediated food intolerance,H.pylori infection,and metabolic syndrome on reflux esophagitis.METHODS Outpatients attending the Second Medical Center of the PLA General Hospital between 2017 and 2021 were retrospectively enrolled.The patients’basic information,test results,gastroscopy results,H.pylori test results,and IgG-mediated food intolerance results were collected.Multivariate logistic regression analysis was used to analyze risk factors for reflux esophagitis.Statistical mediation analysis was used to evaluate the effects of IgG-mediated food intolerance and metabolic syndrome on H.pylori infection affecting reflux esophagitis.RESULTS A total of 7954 outpatients were included;the prevalence of reflux esophagitis,IgG-mediated food intolerance,H.pylori infection,and metabolic syndrome were 20.84%,61.77%,35.91%,and 60.15%,respectively.Multivariate analysis showed that the independent risk factors for reflux esophagitis included IgG-mediated food intolerance(OR=1.688,95%CI:1.497-1.903,P<0.00001)and metabolic syndrome(OR=1.165,95%CI:1.030-1.317,P=0.01484),and the independent protective factor for reflux esophagitis was H.pylori infection(OR=0.400,95%CI:0.351-0.456,P<0.00001).IgG-mediated food intolerance had a partially positive mediating effect on H.pylori infection as it was associated with reduced occurrence of reflux esophagitis(P=0.0200).Metabolic syndrome had a partially negative mediating effect on H.pylori infection and reduced the occurrence of reflux esophagitis(P=0.0220).CONCLUSION Patients with IgG-mediated food intolerance and metabolic syndrome were at higher risk of developing reflux esophagitis,while patients with H.pylori infection were at lower risk.IgG-mediated food intolerance reduced the risk of reflux esophagitis pathogenesis in patients with H.pylori infection;however,metabolic syndrome increased the risk of patients with H.pylori infection developing reflux esophagitis.

Body composition and metabolic syndrome in patients with type 1 diabetes

BACKGROUND In recent years,the prevalence of obesity and metabolic syndrome in type 1 diabetes(T1DM)patients has gradually increased.Insulin resistance in T1DM deserves attention.It is necessary to clarify the relationship between body composition,metabolic syndrome and insulin resistance in T1DM to guide clinical treatment and intervention.AIM To assess body composition(BC)in T1DM patients and evaluate the relationship between BC,metabolic syndrome(MS),and insulin resistance in these indi-viduals.METHODS A total of 101 subjects with T1DM,aged 10 years or older,and with a disease duration of over 1 year were included.Bioelectrical impedance analysis using the Tsinghua-Tongfang BC Analyzer BCA-1B was employed to measure various BC parameters.Clinical and laboratory data were collected,and insulin resistance was calculated using the estimated glucose disposal rate(eGDR).RESULTS MS was diagnosed in 16/101 patients(15.84%),overweight in 16/101 patients(15.84%),obesity in 4/101(3.96%),hypertension in 34/101(33.66%%)and dyslip-idemia in 16/101 patients(15.84%).Visceral fat index(VFI)and trunk fat mass were significantly and negatively correlated with eGDR(both P<0.001).Female patients exhibited higher body fat percentage and visceral fat ratio compared to male patients.Binary logistic regression analysis revealed that significant factors for MS included eGDR[P=0.017,odds ratio(OR)=0.109],VFI(P=0.030,OR=3.529),and a family history of diabetes(P=0.004,OR=0.228).Significant factors for hypertension included eGDR(P<0.001,OR=0.488)and skeletal muscle mass(P=0.003,OR=1.111).Significant factors for dyslipidemia included trunk fat mass(P=0.033,OR=1.202)and eGDR(P=0.037,OR=0.708).CONCLUSION Visceral fat was found to be a superior predictor of MS compared to conventional measures such as body mass index and waist-to-hip ratio in Chinese individuals with T1DM.BC analysis,specifically identifying visceral fat(trunk fat),may play an important role in identifying the increased risk of MS in non-obese patients with T1DM.

Incidence and risk factors of depression in patients with metabolic syndrome

BACKGROUND Many studies have explored the relationship between depression and metabolic syndrome(MetS),especially in older people.China has entered an aging society.However,there are still few studies on the elderly in Chinese communities.AIM To investigate the incidence and risk factors of depression in MetS patients in China's Mainland and to construct a predictive model.METHODS Data from four waves of the China Health and Retirement Longitudinal Study were selected,and middle-aged and elderly patients with MetS(n=2533)were included based on the first wave.According to the center for epidemiological survey-depression scale(CESD),participants with MetS were divided into depression(n=938)and non-depression groups(n=1595),and factors related to depression were screened out.Subsequently,the 2-,4-,and 7-year follow-up data were analyzed,and a prediction model for depression in MetS patients was constructed.RESULTS The prevalence of depression in middle-aged and elderly patients with MetS was 37.02%.The prevalence of depression at the 2-,4-,and 7-year follow-up was 29.55%,34.53%,and 38.15%,respectively.The prediction model,constructed using baseline CESD and Physical Self-Maintenance Scale scores,average sleep duration,number of chronic diseases,age,and weight had a good predictive effect on the risk of depression in MetS patients at the 2-year follow-up(area under the curve=0.775,95%confidence interval:0.750-0.800,P<0.001),with a sensitivity of 68%and a specificity of 74%.CONCLUSION The prevalence of depression in middle-aged and elderly patients with MetS has increased over time.The early identification of and intervention for depressive symptoms requires greater attention in MetS patients.

Update in lean metabolic dysfunction-associated steatotic liver disease

BACKGROUND A new nomenclature consensus has emerged for liver diseases that were previously known as non-alcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated fatty liver disease(MAFLD).They are now defined as metabolic dysfunction-associated steatotic liver disease(MASLD),which includes cardiometabolic criteria in adults.This condition,extensively studied in obese or overweight patients,constitutes around 30%of the population,with a steady increase worldwide.Lean patients account for approximately 10%-15%of the MASLD population.However,the pathogenesis is complex and is not well understood.AIM To systematically review the literature on the diagnosis,pathogenesis,characteristics,and prognosis in lean MASLD patients and provide an interpretation of these new criteria.METHODS We conducted a comprehensive database search on PubMed and Google Scholar between January 2012 and September 2023,specifically focusing on lean NAFLD,MAFLD,or MASLD patients.We include original articles with patients aged 18 years or older,with a lean body mass index categorized according to the World Health Organization criteria,using a cutoff of 25 kg/m2 for the general population and 23 kg/m2 for the Asian population.RESULTS We include 85 studies in our analysis.Our findings revealed that,for lean NAFLD patients,the prevalence rate varied widely,ranging from 3.8%to 34.1%.The precise pathogenesis mechanism remained elusive,with associations found in genetic variants,epigenetic modifications,and adaptative metabolic response.Common risk factors included metabolic syndrome,hypertension,and type 2 diabetes mellitus,but their prevalence varied based on the comparison group involving lean patients.Regarding non-invasive tools,Fibrosis-4 index outperformed the NAFLD fibrosis score in lean patients.Lifestyle modifications aided in reducing hepatic steatosis and improving cardiometabolic profiles,with some medications showing efficacy to a lesser extent.However,lean NAFLD patients exhibited a worse prognosis compared to the obese or overweight counterpart.CONCLUSION MASLD is a complex disease comprising epigenetic,genetic,and metabolic factors in its pathogenesis.Results vary across populations,gender,and age.Limited data exists on clinical practice guidelines for lean patients.Future studies employing this new nomenclature can contribute to standardizing and generalizing results among lean patients with steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease:A silent pandemic

The worldwide epidemiology of non-alcoholic fatty liver disease(NAFLD)is showing an upward trend,parallel to the rising trend of metabolic syndrome,owing to lifestyle changes.The pathogenesis of NAFLD has not been fully understood yet.Therefore,NAFLD has emerged as a public health concern in the field of hepatology and metabolisms worldwide.Recent changes in the nomenclature from NAFLD to metabolic dysfunction-associated steatotic liver disease have brought a positive outlook changes in the understanding of the disease process and doctor-patient communication.Lifestyle changes are the main treatment modality.Recently,clinical trial using drugs that target‘insulin resistance’which is the driving force behind NAFLD,have shown promising results.Further translational research is needed to better understand the underlying pathophysiological mechanism of NAFLD which may open newer avenues of therapeutic targets.The role of gut dysbiosis in etiopathogenesis and use of fecal microbiota modification in the treatment should be studied extensively.Prevention of this silent epidemic by spreading awareness and early intervention should be our priority.

Effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease:Clinical implications

In this editorial,we comment on the article by Chen et al recently published in 2024.We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase(ALT)would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease(MAFLD).This is important given the increasing prevalence of MAFLD and obesity globally.Currently,a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT.The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered,particularly as their study found that 83.12%of their study population with a diagnosis of MAFLD had a normal ALT.The main advantages of screening would be to identify patients and provide intervention early,the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis.However,there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered.Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity,although studies have not yet shown a significant improvement in fibrosis regression.It would also require a huge amount of resource if a reduced ALT level alone was used as criteria;it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk.Currently,there is not a good argument to recommend wide-spread screening with a reduced ALT level as this is unlikely to be cost-effective.This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories.Although studies previously have suggested a more pragmatic approach in screening those over the age of 60,this is likely to change with the increasing incidence of obesity within the younger age groups.The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.

Rethinking neurodegenerative diseases:neurometabolic concept linking lipid oxidation to diseases in the central nervous system

Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

Metagenomic analysis revealing the metabolic role of microbial communities in the free amino acid biosynthesis of Monascus rice vinegar during fermentation

Free amino acid(FAA)is the important component of vinegar that infl uences quality perception and consumer acceptance.FAA is one of the major metabolites produced by microorganisms;however,the microbial metabolic network on FAA biosynthesis remains unclear.Through metagenomic analysis,this work aimed to elucidate the roles of microbes in FAA biosynthesis during Monascus rice vinegar fermentation.Taxonomic profiles from functional analyses showed 14 dominant genera with high contributions to the metabolism pathways.The metabolic network for FAA biosynthesis was then constructed,and the microbial distribution in different metabolic pathways was illuminated.The results revealed that 5 functional genera were closely involved in FAA biosynthesis.This study illuminated the metabolic roles of microorganisms in FAA biosynthesis and provided crucial insights into the functional attributes of microbiota in vinegar fermentation.

Impact of metabolic syndrome components on clinical outcomes in hypertriglyceridemia-induced acute pancreatitis

BACKGROUND The incidence of hypertriglyceridemia(HTG)-induced acute pancreatitis(AP)is steadily increasing in China,becoming the second leading cause of AP.Clinical complications and outcomes associated with HTG-AP are generally more severe than those seen in AP caused by other etiologies.HTG-AP is closely linked to metabolic dysfunction and frequently coexists with metabolic syndrome or its components.However,the impact of metabolic syndrome components on HTGAP clinical outcomes remains unclear.AIM To investigate the impact of metabolic syndrome component burden on clinical outcomes in HTG-AP.METHODS In this retrospective study of 255 patients diagnosed with HTG-AP at the First Affiliated Hospital of Guangxi Medical University,we collected data on patient demographics,clinical scores,complications,and clinical outcomes.Subsequently,we analyzed the influence of the presence and number of individual metabolic syndrome components,including obesity,hyperglycemia,hypertension,and low high-density lipoprotein cholesterol(HDL-C),on the aforementioned parameters in HTG-AP patients.RESULTS This study found that metabolic syndrome components were associated with an increased risk of various complications in HTG-AP,with low HDL-C being the most significant risk factor for clinical outcomes.The risk of complications increased with the number of metabolic syndrome components.Adjusted for age and sex,patients with highcomponent metabolic syndrome had significantly higher risks of renal failure[odds ratio(OR)=3.02,95%CI:1.12-8.11)],SAP(OR=5.05,95%CI:2.04-12.49),and intensive care unit admission(OR=6.41,95%CI:2.42-16.97)compared to those without metabolic syndrome.CONCLUSION The coexistence of multiple metabolic syndrome components can synergistically worsen the clinical course of HTGAP,making it crucial to monitor these components for effective disease management.

Metabolic syndrome’s new therapy:Supplement the gut microbiome

This letter to the editor discusses the publication on gut microbiome supple-mentation as therapy for metabolic syndrome.Gut microbiome dysbiosis disrupts intestinal bacterial homeostasis and is related to chronic inflammation,insulin resistance,cardiovascular diseases,type 2 diabetes mellitus,and obesity.Previous research has found that increasing the abundance of beneficial microbiota in the gut modulates metabolic syndrome by reducing chronic inflammation and insulin resistance.Prebiotics,probiotics,synbiotics,and postbiotics are often used as supplements to increase the number of beneficial microbes and thus the produc-tion of short-chain fatty acids,which have positive effects on the gut microbiome and metabolic syndrome.In this review article,the author summarizes the available supplements to increase the abundance of beneficial gut microbiota and reduce the abundance of harmful microbiota in patients with metabolic disorders.Our group is also researching the role of the gut microbiota in chronic liver disease.This article will be of great help to our research.At the end of the letter,the mechanism of the gut microbiota in chronic liver disease is discussed.

Exploring non-invasive diagnostics for metabolic dysfunctionassociated fatty liver disease

The population with metabolic dysfunction-associated fatty liver disease(MAFLD)is increasingly common worldwide.Identification of people at risk of progression to advanced stages is necessary to timely offer interventions and appropriate care.Liver biopsy is currently considered the gold standard for the diagnosis and staging of MAFLD,but it has associated risks and limitations.This has spurred the exploration of non-invasive diagnostics for MAFLD,especially for steatohepatitis and fibrosis.These non-invasive approaches mostly include biomarkers and algorithms derived from anthropometric measurements,serum tests,imaging or stool metagenome profiling.However,they still need rigorous and widespread clinical validation for the diagnostic performance.

Hepatic angiotensin-converting enzyme 2 expression in metabolic dysfunction-associated steatotic liver disease and in patients with fatal COVID-19

BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD),characterised by hepatic lipid accumulation,causes inflammation and oxidative stress accompanied by cell damage and fibrosis.Liver injury(LI)is also frequently reported in patients hospitalised with coronavirus disease 2019(COVID-19),while preexisting MASLD increases the risk of LI and the development of COVID-19-associated cholangiopathy.Mechanisms of injury at the cellular level remain unclear,but it may be significant that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)which causes COVID-19,uses angiotensin-converting expression enzyme 2(ACE2),a key regulator of the‘anti-inflammatory’arm of the renin-angiotensin system,for viral attachment and host cell invasion.AIM To determine if hepatic ACE2 levels are altered during progression of MASLD and in patients who died with severe COVID-19.METHODS ACE2 protein levels and localisation,and histological fibrosis and lipid droplet accumulation as markers of MASLD were determined in formalin-fixed liver tissue sections across the MASLD pathological spectrum(isolated hepatocellular steatosis,metabolic dysfunction-associated steatohepatitis(MASH)+/-fibrosis,end-stage cirrhosis)and in post-mortem tissues from patients who had died with severe COVID-19,using ACE2 immunohistochemistry and haematoxylin and eosin and picrosirius red staining of total collagen and lipid droplet areas,followed by quantification using machine learning-based image pixel classifiers.RESULTS ACE2 staining is primarily intracellular and concentrated in the cytoplasm of centrilobular hepatocytes and apical membranes of bile duct cholangiocytes.Strikingly,ACE2 protein levels are elevated in non-fibrotic MASH compared to healthy controls but not in the progression to MASH with fibrosis and in cirrhosis.ACE2 protein levels and histological fibrosis are not associated,but ACE2 and liver lipid droplet content are significantly correlated across the MASLD spectrum.Hepatic ACE2 levels are also increased in COVID-19 patients,especially those showing evidence of LI,but are not correlated with the presence of SARS-CoV-2 virus in the liver.However,there is a clear association between the hepatic lipid droplet content and the presence of the virus,suggesting a possible functional link.CONCLUSION Hepatic ACE2 levels were elevated in nonfibrotic MASH and COVID-19 patients with LI,while lipid accumulation may promote intra-hepatic SARS-CoV-2 replication,accelerating MASLD progression and COVID-19-mediated liver damage.