Compartmentalization of Immune Response and Microbial Translocation in Decompensated Cirrhosis

Background: Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis. Data is, however, contradictory. Here we investigated whether levels of IL-6 and IL-8 putatively produced by myeloid cells in ascites are associated with systemic inflammation and whether inflammation depends on the presence of specific bacterial DNA. Methods and Materials: We enrolled 33 patients with decompensated liver cirrhosis from whom we collected paired samples of blood and ascites. IL-6 and IL-8 were measured in serum samples of all patients using ELISA. In a subset of 10 representative patients, bacterial DNA was extracted from ascites and whole blood, followed by 16S rRNA gene amplicon sequencing. Results: There were significantly higher levels of IL-6 in ascites fluid compared to blood samples in all patients. Interestingly, IL-6 levels in blood correlated tightly with disease severity and surrogates of systemic inflammation, while IL-6 levels in ascites did not. Moreover, patients with higher blood CRP levels showed greater SBP prevalence compared to patients with lower levels, despite similar positive culture results. Bacterial richness was also significantly higher in ascites compared to the corresponding patient blood. We identified differences in microbial composition and diversity between ascites and blood, but no tight relationship with surrogates of systemic inflammation could be observed. Discussion: In decompensated cirrhosis, markers of systemic inflammation and microbiota composition seem to be dysregulated in ascites and blood. While a relationship between systemic inflammation and microbiota composition seems to exist in blood, this is not the case for ascites in our hands. These data may suggest compartmentalization of the immune response and interaction of the latter with the microbiota especially in the blood compartment

Machine learning based prediction of COVID-19 mortality suggests repositioning of anticancer drug for treating severe cases

Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center ‘Lean European Open Survey on SARS-CoV-2-infected patients’ (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer's Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19

Combined analysis of gut microbiota, diet and PNPLA3 polymorphism in biopsy‐proven non‐alcoholic fatty liver disease

Background and aims: Non-alcoholic fatty liver disease (NAFLD) is a global health burden. Risk factors for disease severity include older age, increased body mass index (BMI), diabetes, genetic variants, dietary factors and gut microbiota alterations. However, the interdependence of these factors and their individual impact on disease severity remain unknown. Methods: In this cross-sectional study, we performed 16S gene sequencing using fecal samples, collected dietary intake, PNPLA3 gene variants and clinical and liver histology parameters in a well-described cohort of 180 NAFLD patients. Principal component analyses were used for dimensionality reduction of dietary and microbiota data. Simple and multiple stepwise ordinal regression analyses were performed. Results: Complete data were available for 57 NAFLD patients. In the simple regression analysis, features associated with the metabolic syndrome had the highest importance regarding liver disease severity. In the multiple regression analysis, BMI was the most important factor associated with the fibrosis stage (OR per kg/m2 : 1.23, 95% CI 1.10-1.37, P < .001). The PNPLA3 risk allele had the strongest association with the histological grade of steatosis (OR 5.32, 95% CI 1.56-18.11, P = .007), followed by specific dietary patterns. Low abundances of Faecalibacterium, Bacteroides and Prevotella and high abundances of Gemmiger were associated with the degree of inflammation, ballooning and stages of fibrosis, even after taking other cofactors into account. Conclusions: BMI had the strongest association with histological fibrosis, but PNPLA3 gene variants, gut bacterial features and dietary factors were all associated with different histology features, which underscore the multifactorial pathogenesis of NAFLD

Incidence and predictive biomarkers of Clostridioides difficile infection in hospitalized patients receiving broad-spectrum antibiotics

Trial enrichment using gut microbiota derived biomarkers by high-risk individuals can improve the feasibility of randomized controlled trials for prevention of Clostridioides difficile infection (CDI). Here, we report in a prospective observational cohort study the incidence of CDI and assess potential clinical characteristics and biomarkers to predict CDI in 1,007 patients ≥ 50 years receiving newly initiated antibiotic treatment with penicillins plus a beta- lactamase inhibitor, 3rd/4th generation cephalosporins, carbapenems, fluoroquinolones or clindamycin from 34 European hospitals. The estimated 90-day cumulative incidences of a first CDI episode is 1.9% (95% CI 1.1-3.0). Carbapenem treatment (Hazard Ratio (95% CI): 5.3 (1.7-16.6)), toxigenic C. difficile rectal carriage (10.3 (3.2-33.1)), high intestinal abundance of Enterococcus spp. relative to Ruminococcus spp. (5.4 (2.1-18.7)), and low Shannon alpha diversity index as determined by 16 S rRNA gene profiling (9.7 (3.2-29.7)), but not nor- malized urinary 3-indoxyl sulfate levels, predicts an increased CDI risk

Clinically defined chemotherapy-associated bowel syndrome predicts severe complications and death in cancer patients

Background Neutropenic patients are at risk of abdominal complications and yet the incidence and impact of these complications on patients' morbidity and mortality have not been sufficiently evaluated. We aimed to assess a clinical rule for early detection of abdominal complications leading to death or transfer to intensive care in patients with chemotherapy-associated neutropenia. Design and Methods This observational multicenter study was carried out in seven German hematology-oncology departments. For inclusion, neutropenia of at least 5 consecutive days was required. Risk factors for transfer to intensive care and death were assessed by backward-stepwise binary logistic regression analyses. Chemotherapy-associated bowel syndrome was defined as a combination of fever (T >= 37.8 degrees C) and abdominal pain and/or lack of bowel movement for 72 hours or more. Five hundred and twenty-one neutropenic episodes were documented in 359 patients. Results The incidence of chemotherapy-associated bowel syndrome was 126/359 (35%) in first episodes of neutropenia. Transfer to intensive care occurred in 41/359 (11%) and death occurred in 17/359 (5%) first episodes. Chemotherapy-associated bowel syndrome and duration of neutropenia were identified as risk factors for transfer to intensive care (P<0.001; OR 4.753; 95% CI 2.297-9.833, and P=0.003; OR 1.061/d; 95% CI 1.021-1.103). Chemotherapy-associated bowel syndrome and mitoxantrone administration were identified as risk factors for death (P=0.005; OR 4.611; 95% CI 1.573-13.515 and P=0.026; OR 3.628; 95% CI 1.169-11.256). Conclusions The occurrence of chemotherapy-associated bowel syndrome has a significant impact on patients' outcome. In future interventional clinical trials, this definition might be used as a selection criterion for early treatment of patients at risk of severe complications

Longitudinal Analysis of Coronavirus-Neutralizing Activity in COVID-19 Patients

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has now been continuing for more than two years. The infection causes COVID-19, a disease of the respiratory and cardiovascular system of variable severity. Here, the humoral immune response of 80 COVID-19 patients from the University Hospital Frankfurt/Main, Germany, was characterized longitudinally. The SARS-CoV-2 neutralization activity of serum waned over time. The neutralizing potential of serum directed towards the human alpha-coronavirus NL-63 (NL63) also waned, indicating that no cross-priming against alpha-coronaviruses occurred. A subset of the recovered patients (n = 13) was additionally vaccinated with the mRNA vaccine Comirnaty. Vaccination increased neutralization activity against SARS-CoV-2 wild-type (WT), Delta, and Omicron, although Omicron-specific neutralization was not detectable prior to vaccination. In addition, the vaccination induced neutralizing antibodies against the more distantly related SARS-CoV-1 but not against NL63. The results indicate that although SARS-CoV-2 humoral immune responses induced by infection wane, vaccination induces a broad neutralizing activity against multiple SARS-CoVs, but not to the common cold alpha-coronavirus NL63