Apelin and the gut microbiome: Potential interaction in human MASLD.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease with increasing numbers worldwide. Adipokines like apelin (APLN) can act as key players in the complex pathophysiology of MASLD. AIMS: Investigating the role of APLN in MASLD. METHODS: Fecal and blood samples were collected in a MASLD cohort and healthy controls (HC). MASLD patients with liver fibrosis and MASLD-associated hepatocellular carcinoma (HCC) were included into the study. Systemic concentration of Apelin, Apelin receptor (APLNR) and circulating cytokines were measured in serum samples. RESULTS: Apelin concentration correlated with the Fib-4 score and was elevated in MASLD patients (mild fibrosis, mF (Fib-4 <3.25) and severe fibrosis, sF (Fib-4 >3.25)) as well as in MASLD-associated HCC patients compared to HC. In accordance APLNR and circulating cytokines were also elevated in mF and sF. In contrast apelin levels were negatively associated with liver survival at three and five years. Changes in taxa composition at phylum level showed an increase of Enterobactericae, Prevotellaceae and Lactobacillaceae in patients with sF compared to mF. We could also observe an association between apelin concentrations and bacterial lineages (phyla). CONCLUSIONS: Circulating apelin is associated with liver fibrosis and HCC. In addition, there might exist an interaction between systemic apelin and the gut microbiome.

A gut bacterial signature in blood and liver tissue characterizes cirrhosis and hepatocellular carcinoma.

BACKGROUND: HCC is the leading cause of cancer in chronic liver disease. A growing body of experimental mouse models supports the notion that gut-resident and liver-resident microbes control hepatic immune responses and, thereby, crucially contribute to liver tumorigenesis. However, a comprehensive characterization of the intestinal microbiome in fueling the transition from chronic liver disease to HCC in humans is currently missing. METHODS: Here, we profiled the fecal, blood, and liver tissue microbiome of patients with HCC by 16S rRNA sequencing and compared profiles to nonmalignant cirrhotic and noncirrhotic NAFLD patients. RESULTS: We report a distinct bacterial profile, defined from 16S rRNA gene sequences, with reduced α-and ß-diversity in the feces of patients with HCC and cirrhosis compared to NAFLD. Patients with HCC and cirrhosis exhibited an increased proportion of fecal bacterial gene signatures in the blood and liver compared to NAFLD. Differential analysis of the relative abundance of bacterial genera identified an increased abundance of Ruminococcaceae and Bacteroidaceae in blood and liver tissue from both HCC and cirrhosis patients compared to NAFLD. Fecal samples from cirrhosis and HCC patients both showed a reduced abundance for several taxa, including short-chain fatty acid-producing genera, such as Blautia and Agathobacter. Using paired 16S rRNA and transcriptome sequencing, we identified a direct association between gut bacterial genus abundance and host transcriptome response within the liver tissue. CONCLUSIONS: Our study indicates perturbations of the intestinal and liver-resident microbiome as a critical determinant of patients with cirrhosis and HCC.

Transmission of oral microbiota to the biliary tract during endoscopic retrograde cholangiography.

BACKGROUND: Endoscopic retrograde cholangiography (ERC) possesses a translocation risk of microbes to the biliary system. We studied bile contamination during ERC and its impact on patients' outcome in a real-life-situation. METHODS: Ninety-nine ERCs were analyzed and microbial samples were taken from the throat before and from bile during ERC and from irrigation fluid of the duodenoscope before and after ERC. RESULTS: 91.2% of cholangitis patients had detectable microbes in the bile (sensitivity 91%), but the same was true for 86.2% in the non-cholangitis group. Bacteroides fragilis (p=0.015) was significantly associated with cholangitis. In 41.7% of ERCs with contaminated endoscopes these microbes were found in the bile after the procedure. Analysis of duodenoscopes' irrigation liquid after ERC matched the microbial bile analysis of these patients in 78.8%. Identical microbial species were in throat and in bile samples of the same ERC in 33% of all cases and in 45% in the non-cholangitis group. Transmission of microbes to the biliary tract did not result in more frequent cholangitis, longer hospital stays, or worse outcome. CONCLUSIONS: During ERC bile samples are regularly contaminated with microbes of the oral cavity but it did not affect clinical outcome.

Liver Transplantation after Successful Downstaging of a Locally Advanced Hepatocellular Carcinoma with Systemic Therapy.

INTRODUCTION: Liver transplantation (LT) is potentially curative for patients with cirrhosis and hepatocellular carcinoma (HCC). However, this procedure is usually reserved for patients with early tumor stages or after successful downstaging with local regional therapies. In patients with locally advanced HCC, current guidelines recommend locoregional and palliative systemic therapies for tumor stages Barcelona Clinic Liver Cancer (BCLC) B and C, respectively. CASE REPORT: In this article, we describe a 63-year-old male patient with locally advanced HCC (BCLC C) and hepatitis C-associated cirrhosis. Following systemic treatment with the immune checkpoint inhibitor atezolizumab and the anti-VEGF antibody bevacizumab, significant downstaging to a tumor stage within the Milan criteria was achieved after which LT was successfully performed. CONCLUSION: As more effective systemic therapies become available, LT and potential curative treatment could become feasible for selected patients with locally advanced HCC.

Interleukin-11 drives human and mouse alcohol-related liver disease.

OBJECTIVE: Alcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide. Interleukin-11 (IL-11) is a profibrotic, proinflammatory cytokine with increasingly recognised toxicities in parenchymal and epithelial cells. We explored IL-11 serum levels and their prognostic value in patients suffering from AH and cirrhosis of various aetiology and experimental ALD. DESIGN: IL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort (n=186). Primary human hepatocytes exposed to ethanol were studied in vitro. Ethanol-fed wildtype mice were treated with a neutralising murine IL-11 receptor-antibody (anti-IL11RA) and examined for severity signs and markers of ALD. RESULTS: IL-11 serum concentration and hepatic expression increased with severity of liver disease, mostly pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 pg/mL was a model of end-stage liver disease independent risk factor for transplant-free survival in patients with compensated and decompensated cirrhosis. In mice, severity of alcohol-induced liver inflammation correlated with enhanced hepatic IL-11 and IL11RA expression. In vitro and in vivo, anti-IL11RA reduced pathogenic signalling pathways (extracellular signal-regulated kinases, c-Jun N-terminal kinase, NADPH oxidase 4) and protected hepatocytes and murine livers from ethanol-induced inflammation and injury. CONCLUSION: Pathogenic IL-11 signalling in hepatocytes plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signalling might be a therapeutic option in human ALD, particularly AH.

Nonalcoholic Fatty Liver Disease and the Intestinal Microbiome: An Inseparable Link.

Nonalcoholic fatty liver disease (NAFLD) particularly affects patients with type 2 diabetes and obesity. The incidence of NAFLD has increased significantly over the last decades and is now pandemically across the globe. It is a complex systemic disease comprising hepatic lipid accumulation, inflammation, lipotoxicity, gut dysbiosis, and insulin resistance as main features and with the potential to progress to cirrhosis and hepatocellular carcinoma (HCC). In numerous animal and human studies the gut microbiota plays a key role in the pathogenesis of NAFLD, NAFLD-cirrhosis and NAFLD-associated HCC. Lipotoxicity is the driver of inflammation, insulin resistance, and liver injury. Likewise, western diet, obesity, and metabolic disorders may alter the gut microbiota, which activates innate and adaptive immune responses and fuels hereby hepatic and systemic inflammation. Indigestible carbohydrates are fermented by the gut microbiota to produce important metabolites, such as short-chain fatty acids and succinate. Numerous animal and human studies suggested a pivotal role of these metabolites in the progression of NAFLD and its comorbidities. Though, modification of the gut microbiota and/or the metabolites could even be beneficial in patients with NAFLD, NAFLD-cirrhosis, and NAFLD-associated HCC. In this review we collect the evidence that exogenous and endogenous hits drive liver injury in NAFLD and propel liver fibrosis and the progressing to advanced disease stages. NAFLD can be seen as the product of a complex interplay between gut microbiota, the immune response and metabolism. Thus, the challenge will be to understand its pathogenesis and to develop new therapeutic strategies.

MAFLD: what 2 years of the redefinition of fatty liver disease has taught us.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has appeared as the leading liver disease worldwide. Whereas the terminology nonalcoholic fatty liver disease (NAFLD) mainly reflected a negative selection and exclusion of alcohol-related liver disease (ALD), the new definition made its focus on the association of MAFLD with overweight/obesity, type 2 diabetes and metabolic risk factors especially also in normal weight/lean subjects. Several studies from the past 2 years have now used the new definition and have provided substantial information that this new definition might be accurate. Studies from the past 2 years have provided evidence that the new definition might be especially advantageous in the characterization and identification of patients with significant fibrosis. This has also been demonstrated in the well-known Rotterdam study in which the MAFLD-only group showed a higher rate of fibrosis and liver stiffness. MAFLD might also be able to predict all-cause mortality as demonstrated in the Third National Health and Nutrition Examination Survey. Furthermore, MAFLD might improve characterization of the cardiovascular risk of this patient population. As the term MAFLD has not yet been accepted universally, it remains important to coordinate efforts globally to adapt to this new definition and especially involve all specialities dealing with metabolic disorders such as diabetologists to further improve its definition and to prepare the medical community for its future use. The aim of this review is to summarize and critically address evidence emerging over the past 2 years that usage of the term MAFLD could be helpful in daily clinical practice.

A novel score predicts mortality after transjugular intrahepatic portosystemic shunt: MOTS - Modified TIPS Score.

BACKGROUND AND AIMS: The high risk for severe shunting-related post-interventional complications demands a stringent selection of candidates for transjugular intrahepatic portosystemic shunt (TIPS). We aimed to develop a simple and reliable tool to accurately predict early post-TIPS mortality. METHODS: 144 cases of TIPS implantation were retrospectively analysed. Using univariate and multivariate Cox regression analysis of factors predicting mortality within 90 days after TIPS, a score integrating urea, international normalized ratio (INR) and bilirubin was developed. The Modified TIPS-Score (MOTS) ranges from 0 to 3 points: INR >1.6, urea >71 mg/dl and bilirubin >2.2 mg/dl account for one point each. Additionally, MOTS was tested in an external validation cohort (n = 187) and its performance was compared to existing models. RESULTS: Modified TIPS-Score achieved a significant prognostic discrimination reflected by 90-day mortality of 8% in patients with MOTS 0-1 and 60% in patients with MOTS 2-3 (p < .001). Predictive performance (area under the curve) of MOTS was accurate (c = 0.845 [0.73-0.96], p < .001), also in patients with renal insufficiency (c = 0.830 [0.64-1.00], p = .02) and in patients with refractory ascites (c = 0.949 [0.88-1.00], p < .001), which are subgroups with particular room for improvement of post-TIPS mortality prediction. The results were reproducible in the validation cohort. CONCLUSIONS: Modified TIPS-Score is a novel, practicable tool to predict post-TIPS mortality, that can significantly simplify clinical decision making. Its practical applicability should be further investigated.

The global case fatality rate of coronavirus disease 2019 by continents and national income: A meta-analysis.

The aim of this study is to provide a more accurate representation of COVID-19's case fatality rate (CFR) by performing meta-analyses by continents and income, and by comparing the result with pooled estimates. We used multiple worldwide data sources on COVID-19 for every country reporting COVID-19 cases. On the basis of data, we performed random and fixed meta-analyses for CFR of COVID-19 by continents and income according to each individual calendar date. CFR was estimated based on the different geographical regions and levels of income using three models: pooled estimates, fixed- and random-model. In Asia, all three types of CFR initially remained approximately between 2.0% and 3.0%. In the case of pooled estimates and the fixed model results, CFR increased to 4.0%, by then gradually decreasing, while in the case of random-model, CFR remained under 2.0%. Similarly, in Europe, initially, the two types of CFR peaked at 9.0% and 10.0%, respectively. The random-model results showed an increase near 5.0%. In high-income countries, pooled estimates and fixed-model showed gradually increasing trends with a final pooled estimates and random-model reached about 8.0% and 4.0%, respectively. In middle-income, the pooled estimates and fixed-model have gradually increased reaching up to 4.5%. in low-income countries, CFRs remained similar between 1.5% and 3.0%. Our study emphasizes that COVID-19 CFR is not a fixed or static value. Rather, it is a dynamic estimate that changes with time, population, socioeconomic factors, and the mitigatory efforts of individual countries.

PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease.

BACKGROUND & AIMS: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. METHODS: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts. RESULTS: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. CONCLUSIONS: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.

Hepatic Meteorin-like and Krüppel-like Factor 3 are Associated with Weight Loss and Liver Injury.

OBJECTIVE: Laparoscopic adjustable gastric banding (LAGB) was found to be effective in reducing body weight and improving insulin resistance in patients with obesity and non-alcoholic fatty liver disease (NAFLD). The adipokine/myokine meteorin-like (METNRL) is an important regulator of whole-body energy expenditure. Krüppel-like factor 3 (KLF3), a regulator of METRNL expression in eosinophils, inhibits the beiging of adipose tissue in mice and therefore regulates adipose tissue development. METHODS: Thirty-three obese patients undergoing LAGB were included in the study. The hepatic and adipose tissue expression of METNRL and KLF3 was determined before (t0) and 6 months after (t6) LABG. The human liver cancer cell line (HepG2) was stimulated with cytokines and fatty acids and METNRL and KLF3 expressions were analyzed. RESULTS: LAGB-associated weight loss was correlated with decreased hepatic METNRL expression. The expression of METNRL and KLF3 in hepatic-and adipose tissues correlated before and after LAGB. Individuals with augmented LAGB-induced weight loss (>20 kg) showed lower hepatic METNRL and KLF3 expression before and after LAGB than patients with <20 kg weight loss. METNRL and KLF3 levels were higher in patients with higher NAFLD activity scores. HepG2 stimulation with interleukin-1ß, tumor necrosis factor-α, palmitic acid but not interleukin-6, oleic acid, or lipopolysaccharide, induced the expression of one or both investigated adipokines. CONCLUSIONS: The novel description of METRNL and KLF3 as hepatokines could pave the way to target their production and/or signaling in obesity, NAFLD, and related disorders. Both proteins may act as possible biomarkers to estimate weight loss after bariatric surgery.

Non-alcoholic Fatty Liver Disease and COVID-19 Susceptibility and Outcomes: a Korean Nationwide Cohort.

BACKGROUND: Evidence for the association between underlying non-alcoholic fatty liver disease (NAFLD), the risk of testing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive, and the clinical consequences of coronavirus disease 2019 (COVID-19) is controversial and scarce. We aimed to investigate the association between the presence of NAFLD and the risk of SARS-CoV-2 infectivity and COVID-19-related outcomes. METHODS: We used the population-based, nationwide cohort in South Korea linked with the general health examination records between January 1, 2018 and July 30, 2020. Data for 212,768 adults older than 20 years who underwent SARS-CoV-2 testing from January 1 to May 30, 2020, were obtained. The presence of NAFLDs was defined using three definitions, namely hepatic steatosis index (HSI), fatty liver index (FLI), and claims-based definition. The outcomes were SARS-CoV-2 test positive, COVID-19 severe illness, and related death. RESULTS: Among 74,244 adults who completed the general health examination, there were 2,251 (3.0%) who were SARS-CoV-2 positive, 438 (0.6%) with severe COVID-19 illness, and 45 (0.06%) COVID-19-related deaths. After exposure-driven propensity score matching, patients with pre-existing HSI-NAFLD, FLI-NAFLD, or claims-based NAFLD had an 11-23% increased risk of SARS-CoV-2 infection (HSI-NAFLD 95% confidence interval [CI], 1-28%; FLI-NAFLD 95% CI, 2-27%; and claims-based NAFLD 95% CI, 2-31%) and a 35-41% increased risk of severe COVID-19 illness (HSI-NAFLD 95% CI, 8-83%; FLI-NAFLD 95% CI, 5-71%; and claims-based NAFLD 95% CI, 1-92%). These associations are more evident as liver fibrosis advanced (based on the BARD scoring system). Similar patterns were observed in several sensitivity analyses including the full-unmatched cohort. CONCLUSION: Patients with pre-existing NAFLDs have a higher likelihood of testing SARS-CoV-2 positive and severe COVID-19 illness; this association was more evident in patients with NAFLD with advanced fibrosis. Our results suggest that extra attention should be given to the management of patients with NAFLD during the COVID-19 pandemic.

Using Infodemiology Metrics to Assess Public Interest in Liver Transplantation: Google Trends Analysis.

BACKGROUND: Liver transplantation (LT) is the only curative treatment for end-stage liver disease. Less than 10% of global transplantation needs are met worldwide, and the need for LT is still increasing. The death rates on the waiting list remain too high. OBJECTIVE: It is, therefore, critical to raise awareness among the public and health care providers and in turn increasingly acquire donors. METHODS: We performed a Google Trends search using the search terms liver transplantation and liver transplant on October 15, 2020. On the basis of the resulting monthly data, the annual average Google Trends indices were calculated for the years 2004 to 2018. We not only investigated the trend worldwide but also used data from the United Network for Organ Sharing (UNOS), Spain, and Eurotransplant. Using pairwise Spearman correlations, Google Trends indices were examined over time and compared with the total number of liver transplants retrieved from the respective official websites of UNOS, the Organización Nacional de Trasplantes, and Eurotransplant. RESULTS: From 2004 to 2018, there was a significant decrease in the worldwide Google Trends index from 78.2 in 2004 to 20.5 in 2018 (-71.2%). This trend was more evident in UNOS than in the Eurotransplant group. In the same period, the number of transplanted livers increased worldwide. The waiting list mortality rate was 31% for Eurotransplant and 29% for UNOS. However, in Spain, where there are excellent awareness programs, the Google Trends index remained stable over the years with comparable, increasing LT numbers but a significantly lower waiting list mortality (15%). CONCLUSIONS: Public awareness in LT has decreased significantly over the past two decades. Therefore, novel awareness programs should be initialized.

Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development.

BACKGROUND: Dysbiosis of the intestinal flora has emerged as an oncogenic contributor in different malignancies. Recent findings suggest a crucial tumor-promoting role of micro- and mycobiome alterations also in the development of pancreatic ductal adenocarcinoma (PDAC). METHODS: To summarize the current knowledge about this topic, a systematic literature search of articles published until October 2020 was performed in MEDLINE (PubMed). RESULTS: An increasing number of publications describe associations between bacterial and fungal species and PDAC development. Despite the high inter-individual variability of the commensal flora, some studies identify specific microbial signatures in PDAC patients, including oral commensals like Porphyromonas gingivalis and Fusobacterium nucleatum or Gram-negative bacteria like Proteobacteria. The role of Helicobacter spp. remains unclear. Recent isolation of Malassezia globosa from PDAC tissue suggest also the mycobiota as a crucial player of tumorigenesis. Based on described molecular mechanisms and interactions between the pancreatic tissue and the immune system this review proposes a model of how the micro- and the mycobial dysbiosis could contribute to tumorigenesis in PDAC. CONCLUSIONS: The presence of micro- and mycobial dysbiosis in pancreatic tumor tissue opens a fascinating perspective on PDAC oncogenesis. Further studies will pave the way for novel tumor markers and treatment strategies.

Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Modulation of Liver Inflammation and Fibrosis by Interleukin-37.

Background and Aims: Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-ß. TGF-ß promotes liver fibrosis via the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-ß signaling cascade to modulate liver fibrogenesis. Methods: The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity. Results: Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl4-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-ß-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1ß stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis. Conclusions: Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis.

Increased Fecal Neopterin Parallels Gastrointestinal Symptoms in COVID-19.

INTRODUCTION: Coronavirus disease (COVID-19) has spread from Wuhan, China, and become a worldwide pandemic. Most patients display respiratory symptoms but up to 50% report gastrointestinal symptoms. Neopterin is a surrogate marker for viral inflammation, and its production by macrophages is driven by interferon-γ. METHODS: We measured fecal neopterin in 37 hospitalized COVID-19 patients not requiring intensive care measures and 22 healthy controls. RESULTS: Fecal neopterin was elevated in stool samples from COVID-19 patients compared with that in samples from healthy controls. Especially, patients reporting gastrointestinal symptoms exhibited increased fecal neopterin values. DISCUSSION: COVID-19 is associated with an inflammatory immune response in the gastrointestinal tract.

Immunopathogenesis and treatment of cytokine storm in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.

Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19): a systematic review of in vitro, in vivo, and clinical trials.

Rationale: Coronavirus disease 2019 (COVID-19) has spread worldwide and poses a threat to humanity. However, no specific therapy has been established for this disease yet. We conducted a systematic review to highlight therapeutic agents that might be effective in treating COVID-19. Methods: We searched Medline, Medrxiv.org, and reference lists of relevant publications to identify articles of in vitro, in vivo, and clinical studies on treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 published in English until the last update on October 11, 2020. Results: We included 36 studies on SARS, 30 studies on MERS, and 10 meta-analyses on SARS and MERS in this study. Through 12,200 title and 830 full-text screenings for COVID-19, eight in vitro studies, 46 randomized controlled trials (RCTs) on 6,886 patients, and 29 meta-analyses were obtained and investigated. There was no therapeutic agent that consistently resulted in positive outcomes across SARS, MERS, and COVID-19. Remdesivir showed a therapeutic effect for COVID-19 in two RCTs involving the largest number of total participants (n = 1,461). Other therapies that showed an effect in at least two RCTs for COVID-19 were sofosbuvir/daclatasvir (n = 114), colchicine (n = 140), IFN-ß1b (n = 193), and convalescent plasma therapy (n = 126). Conclusions: This review provides information to help establish treatment and research directions for COVID-19 based on currently available evidence. Further RCTs are required.