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BACKGROUD: Trimethylamine oxide (TMAO) represents a gut metabolite and it's physiological concentration is proposed to be influenced by the abundance of precursor trimethylamine (TMA)-producing microbiota in the gut. OBJECTIVE: Lifestyle factors, such as diet and exercise, modify the microbiome, but their long-term impact on plasma TMAO and TMA production in the gut is poorly understood. METHODS: Fecal microbiome composition was analyzed and correlated with TMAO serum concentrations in female Sprague-Dawley rats that received either a healthy normal or a high-fat diet (HFD) for 10 months. Half of the animals performed regular running exercise, the other half served as sedentary controls. RESULTS: HFD consumption induced an alteration of the fecal microbiome with increased alpha diversity on ASV levels. More importantly, HFD reduced the abundance of genera containing potential TMA producers, such as certain members of Clostridia and Lachnospiraceae. In line with this observation, serum TMAO concentrations were found to be lower with HFD and to correlate with the abundance of these genera. Regular exercise also induced changes in microbiome beta diversity but had no effect on serum TMAO in female rats. CONCLUSION: A diet containing high amounts of dietary fat reduced serum TMAO, probably through a reduced intestinal abundance of TMA-producing bacteria. In contrast, regular exercise altered beta diversity of the microbiome composition, but without significant effects on serum TMAO concentrations. more...

The COVID-19 pandemic has occupied the time and resources of health care professionals for more than 1 year. The risk of missed diagnoses has been discussed in the medical literature, mainly for common diseases such as cancer and cardiovascular events. However, rare diseases also need appropriate attention in times of a pandemic.We report a 34-year-old woman with fever, pinprick sensation in her chest and thoracic spine, and dizziness after receiving the first dose of ChAdOx1 nCoV-19 vaccination. The patient's condition worsened with abdominal pain, red urine, and hyponatremia, needing intensive care admission. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) was diagnosed. Vaccine-induced thrombocytopenia and thrombosis were ruled out. Acute hepatic porphyria was finally diagnosed, and the patient recovered completely after treatment with hemin.Currently, the focus of physicians is on COVID-19 and associated medical problems, such as vaccine side effects. However, it is important to be vigilant for other uncommon medical emergencies in medically exceptional situations that may shift our perception.Die COVID-19-Pandemie beansprucht seit mehr als einem Jahr Zeit und Ressourcen von Angehörigen der Gesundheitsberufe. Kollateralschäden infolge verspäteter Diagnosen wurden in der medizinischen Literatur hauptsächlich für Volkskrankheiten wie Krebs und kardiovaskuläre Ereignisse diskutiert. Aber auch seltene Krankheiten bedürfen in Zeiten einer Pandemie der entsprechenden Aufmerksamkeit.Wir berichten über eine 34-jährige Frau mit Fieber, Parästhesien in Brust und Brustwirbelsäule und Schwindel nach der ersten Dosis der ChAdOx1-nCoV-19-Impfung. Der Zustand der Patientin verschlechterte sich mit Bauchschmerzen, rotem Urin und Hyponatriämie und sie musste intensivmedizinisch behandelt werden. Es wurde ein Syndrom der inadäquaten Sekretion des antidiuretischen Hormons (SIADH) diagnostiziert. Eine Vakzin-induzierte Thrombozytopenie und Thrombose wurde ausgeschlossen. Schließlich wurde eine akute hepatische Porphyrie diagnostiziert und die Patientin erholte sich nach Behandlung mit Hämin vollständig.Aktuell liegt der Fokus der Mediziner*innen auf COVID-19 und den damit verbundenen medizinischen Problemen, wie zum Beispiel Impfnebenwirkungen. Es ist jedoch wichtig, in medizinisch außergewöhnlichen Situationen auf andere seltene medizinische Notfälle zu achten, die unsere Wahrnehmung verändern können. more...

Background Health care professionals have to judge the appropriateness of treatment in critical care on a daily basis. There is general consensus that critical care interventions should not be performed when they are inappropriate. It is not yet clear which chances of survival are considered necessary or which risk for serious disabilities is acceptable in quantitative terms for different stakeholders to start intensive care treatment. Methods We performed an anonymous online survey in a random sample of 1,052 participants recruited via email invitation and social media. Age, sex, nationality, education, professional involvement in health care, critical care medicine and treatment decisions in critical care medicine as well as personal experience with critical illness were assessed as potential influencing variables. Participants provided their opinion on the necessary chances of survival and the acceptable risk for serious disabilities to start a high-risk or uncomfortable therapy for themselves, relatives or for their patients on a scale of 0–100%. Results Answers ranged from 0 to 100% for all questions. A three-peak pattern with different distributions of the peaks was observed. Sex, education, being a health care professional, being involved in treatment decisions and religiosity influence these opinions. Male respondents and those with a university education would agree that a risky and uncomfortable treatment should be started even with a low chance of survival for themselves, relatives and patients. More respondents would choose a lower necessary chance of survival (0–33% survival) when deciding for patients compared to themselves or relatives to start a risky and uncomfortable treatment. On the other hand, the majority of respondents would accept only a low risk of severe disability for both themselves and their patients. Conclusion No cut-off can be identified for the necessary chances of survival or the acceptable risk of disability to help quantify the “inappropriateness” of critical care treatment. Sex and education are the strongest influencing factors on this opinion. The large variation in personal opinions, depending on demographic and personality variables and education needs to be considered in the communication between health care professionals and patients or surrogates. more...

Background and Aim Fibroscan® is used to assess fibrosis and steatosis of the liver noninvasively. The company suggests to use the S+‐probe in people 75 cm and adults with a skin–liver capsule distance 75 cm in fasting state and after intake of a standardized light meal (300 kcal). Results We examined 50 volunteers (26 female, 24 ± 3 years). Twenty‐two participants were in the TC ≤75 cm group and 28 in TC >75 cm group. LS values with the S+‐probe were 15% higher than with the M+‐probe in both groups (median difference 0.6 kPa, P, Graphical extract was created using BioRender.com (TC, thoracic circumference; SCD, skin‐capsule distance). Lean adults with a thoracic circumference of more...

Colorectal cancer (CRC) ranks third in incidence and second in mortality of all cancers worldwide. At the time of primary diagnosis, around 20% of patients already have metastatic CRC and only around 20% are candidates for radical resection. Thus, most of the patients have to undergo chemotherapy (CTx). Due to chemoresistance and side effects, novel treatment additives are crucial for controlling the disease and prolonging patient survival. The aim of this study was to evaluate probiotic supplementation and its antitumorigenic effects in an experimental CRC liver metastasis model. Six-week-old male Wistar rats received either a multispecies probiotic (1.2 × 109 CFU/daily) or placebo mixture. On day 14 of the experiment, rat CRC cells (CC531) were implanted under the liver capsule later treated by FOLFOX CTx. Change in tumor volume was measured by performing micro computed tomography (micro-CT) scanning on experimental days 28 and 34. Additionally, immunohistochemical staining with anti-MPO, anti-Ki67, and anti-CD31 were performed. Tumor apoptosis was evaluated using TUNEL staining. Micro-CT image analysis indicates that probiotic supplementation significantly inhibits tumor growth. No synergistic effects between probiotic supplementation and FOLFOX CTx was observed. Reduced tumor volume was achieved by inhibiting angiogenesis, as tumor microvascular density was significantly lower in rats receiving probiotic supplementation. This study shows that a multispecies probiotic mixture significantly reduces angiogenesis and inhibits CRC liver metastasis growth in an experimental rat model. more...

ZusammenfassungProtonenpumpenhemmer werden seit etwa 30 Jahren erfolgreich gegen magensäureassoziierte Erkrankungen, wie peptische Ulzera oder Refluxerkrankungen, eingesetzt. Durch ihre kovalente Bindung an die Protonenpumpen in den Parietalzellen des Magens kann die Magensäureproduktion effektiv reduziert und die therapeutische Wirkung der Protonenpumpenhemmer entfaltet werden. Auf diese Weise wird aber auch ein wichtiger Bestandteil der unspezifischen Immunabwehr ausgeschaltet, der den Körper – und vor allem das Darmmikrobiom – vor mit der Nahrung aufgenommenen Pathogenen oder eingeschwemmten Mundkeimen schützt. Daraus ergeben sich Veränderungen des Darmmikrobioms, wie eine Reduktion der Diversität des Mikrobioms oder eine Fehlbesiedelung des Dünndarms, die mit verschiedenen Nebenwirkungen der Protonenpumpen-(Langzeit-)Therapie, wie einem erhöhten Risiko für Clostridium-difficile-Infektionen oder gastrointestinalen Beschwerden, assoziiert sind. Bei Menschen mit Leberzirrhose bspw. ist die Einwanderung von oralen Bakterien in den Darm mit intestinaler Inflammation und Permeabilität verbunden und kann als Biomarker für das 3-Jahres-Überleben herangezogen werden. Mikrobiomassoziierte Nebenwirkungen sollten daher in den Diskurs über die Risiken von Langzeittherapien mit Protonenpumpenhemmern und dem Abwägen von Alternativen miteinbezogen werden. more...

BackgroundSubtotal gastrectomy with Billroth II reconstruction (SGB2) results in increased gastric pH and diminished gastric barrier. Increased gastric pH following PPI therapy has an impact on the gut microbiome, intestinal inflammation, and possibly patient health. If similar changes are present after SGB2, these can be relevant for patient health and long-term outcomes after surgery. The aim of the study is to investigate whether SGB2 is associated with specific changes in gut microbiome composition and intestinal inflammation.Patients and MethodsThis cross-sectional proof-of-concept study includes patients after SGB2 (n = 14) for early gastric cancer and their nongastrectomized in-house relatives as controls (n = 8). Fecal microbiome composition, intestinal inflammation (fecal calprotectin), gut permeability (DAO, LBP, sCD14), systemic inflammation (CRP) markers, and gastrointestinal symptoms are investigated. This study is registered at ClinicalTrials.gov (NCT03418428).ResultsMicrobiome oralization following SGB2 was defined by an increase inEscherichia–Shigella,Enterococcus,Streptococcus, and other typical oral cavity bacteria (Veillonella,Oribacterium, andMogibacterium) abundance. The fecal calprotectin was increased in the SGB2 group [100.9 (52.1; 292) vs. 25.8 (17; 66.5);p = 0.014], and calprotectin levels positively correlated with the abundance ofStreptococcus(rs = 0.639;padj = 0.023). Gastrointestinal symptoms in SGB2 patients were associated with distinct taxonomic changes of the gut microbiome.ConclusionsSGB2 is associated with oralization of the gut microbiome; intestinal inflammation and microbiome changes were associated with gastrointestinal symptoms. These novel findings may open gut microbiome as a new target for therapy to improve quality of life and general patient health in long-term survivors after SGB2. more...

Background: We aimed to gain insights in a co-culture of 10 bacteria and their postbiotic supernatant. Methods: Abundances and gene expression were monitored by shotgun analysis. The supernatant was characterized by liquid chromatography mass spectroscopy (LC-MS) and gas chromatography mass spectroscopy (GC-MS). Supernatant was harvested after 48 h (S48) and 196 h (S196). Susceptibility testing included nine bacteria and C. albicans. Bagg albino (BALBc) mice were fed with supernatant or culture medium. Fecal samples were obtained for 16S analysis. Results: A time-dependent decrease of the relative abundances and gene expression of L. salivarius, L. paracasei, E. faecium and B. longum/lactis and an increase of L. plantarum were observed. Substances in LC-MS were predominantly allocated to groups amino acids/peptides/metabolites and nucleotides/metabolites, relating to gene expression. Fumaric, panthotenic, 9,3-methyl-2-oxovaleric, malic and aspartic acid, cytidine monophosphate, orotidine, phosphoserine, creatine, tryptophan correlated to culture time. Supernatant had no effect against anaerobic bacteria. S48 was reactive against S. epidermidis, L. monocytogenes, P. aeruginosae, E. faecium and C. albicans. S196 against S. epidermidis and Str. agalactiae. In vivo S48/S196 had no effect on alpha/beta diversity. Linear discriminant analysis effect size (LEfSe) and analysis of composition of microbiomes (ANCOM) revealed an increase of Anaeroplasma and Faecalibacterium prausnitzii. Conclusions: The postbiotic supernatant had positive antibacterial and antifungal effects in vitro and promoted the growth of distinct bacteria in vivo. more...

The use of chemotherapeutic agents is of paramount importance when treating colorectal cancer (CRC). Unfortunately, one of the most frequent chemotherapy (CTx) side effects is intestinal mucositis (IM), which may present with several clinical symptoms such as nausea, bloating, vomiting, pain, and diarrhea and even can result in life-threatening complications. There is a focused scientific effort towards developing new therapies to prevent and treat IM. The aim of this study was to assess the outcomes of probiotic supplementation on CTx-induced IM in a CRC liver metastasis rat model. Six-week-old male Wistar rats received either a multispecies probiotic or placebo mixture. On the 28th experiment day, rats received FOLFOX CTx, and afterwards, the severity of diarrhea was evaluated twice daily. Stool samples were collected for further microbiome analysis. Additionally, immunohistochemical stainings of ileum and colon samples with were performed with MPO, Ki67, and Caspase-3 antibodies. Probiotic supplementation alleviates the severity and length of CTx-induced diarrhea. Additionally, probiotics significantly reduced FOLFOX-induced weight and blood albumin loss. Furthermore, probiotic supplementation mitigated CTx-induced histological changes in the gut and promoted intestinal cell regeneration. This study shows that multispecies probiotic supplementation attenuates FOLFOX-induced IM symptoms by inhibiting apoptosis and promoting intestinal cell proliferation. more...

Background & aims Compositional changes of the faecal microbiome in cirrhosis are well described and have been associated with complications and prognosis. However, it is less well known, which disease or treatment-related factors affect microbiome composition most distinctively. Methods 16S rDNA sequencing data of 88 cirrhotic outpatients were investigated. Factors influencing microbiome composition were analysed by univariate and multivariate redundancy analysis. The association of the identified factors with changes in diversity and taxonomic composition was studied in depth using analysis of composition of microbiome, LDA-effect size and least absolute shrinkage and selection operator regularized regression. Results Disease severity and aetiology, proton pump inhibitor (PPI) use, nutritional status, age and C-reactive protein are significant explanatory variables for faecal microbiome composition in liver cirrhosis. Despite some taxonomic overlaps especially between disease severity and PPI use, we could show that the effects of disease severity, aetiology, PPI use and age are independent factors influencing microbiome composition also in subgroup analyses. Conclusion Our cross sectional system biology study identifies disease severity, aetiology, PPI use and age as independent factors that influence microbiome composition in liver cirrhosis. In chronic diseases with high morbidity, such as liver cirrhosis, precise patient metadata documentation is of utmost importance in microbiome analysis. Further studies with a higher sample size are necessary to validate this finding. Trial registration number NCT01607528. more...

Proton pump inhibitors (PPI) are an invaluable therapy option for acid related diseases; however, PPI therapy is also linked to a series of side effects in cirrhosis, such as microbiome alterations, spontaneous bacterial peritonitis and hepatic encephalopathy. Decision tools to balance benefits and risks of PPI therapy are largely missing. In this study, we tested gut-derived biomarkers to identify PPI-associated dysbiosis, its association with gut barrier function and liver-related mortality. In this observational study, faecal microbiome composition data obtained from 16S rDNA sequencing of 90 cirrhotic patients with and without long-term PPI use and additional potential biomarkers identified from the literature were evaluated for their predictive value regarding PPI-associated dysbiosis and liver-related three-year mortality. In addition, faecal calprotectin, faecal zonulin and serum lipopolysaccharides were assessed as markers for intestinal inflammation, gut permeability and bacterial translocation. Streptococcus salivarius, Veillonella parvula and the genus Streptococcus were significantly increased in patients with long-term PPI therapy and performed well as biomarkers for PPI-associated dysbiosis (accuracy: 74%, 72% and 74%, respectively). The abundance of Streptococcus salivarius was linked to intestinal inflammation and gut barrier dysfunction, whereas the abundance of Veillonella parvula showed associations with liver disease severity; both were independent predictors for liver-related three-year mortality. Gut-derived biomarkers of PPI-associated dysbiosis are linked to worse outcome and a potential option to evaluate the risks of adverse events during long-term PPI therapy. more...

Proton pump inhibitors are valuable treatment options for gastric acid associated diseases, such as peptic ulcer disease or reflux diseases. Due to their irreversible inhibition of the proton pumps in the parietal cells of the stomach, gastric acid secretion can be effectively reduced. With the reduction in gastric acid, however, proton pump inhibitors also block a highly conserved, crucial part of the unspecific immune system. The gastric barrier protects the body - and here mainly the intestinal microbiome - from food-borne pathogens and oral bacteria that can reach more distal parts of the gastrointestinal tract during proton pump inhibitor therapy. Resulting changes in the intestinal microbiome, such as the reduction in microbial diversity or small intestinal bacterial overgrowth, can be linked to side effects of (long-term) proton pump inhibitor therapy, such as the increased risk of Clostridium difficile infections or gastrointestinal discomfort. In liver cirrhosis patients, the increase in oral bacteria in the intestine is associated with intestinal inflammation and permeability, and can even be used as a biomarker for 3-year liver related mortality. Therefore, microbiome-mediated side effects should be included in the risk assessment of proton pump inhibitor therapy and the evaluation of potential alternatives.Protonenpumpenhemmer werden seit etwa 30 Jahren erfolgreich gegen magensäureassoziierte Erkrankungen, wie peptische Ulzera oder Refluxerkrankungen, eingesetzt. Durch ihre kovalente Bindung an die Protonenpumpen in den Parietalzellen des Magens kann die Magensäureproduktion effektiv reduziert und die therapeutische Wirkung der Protonenpumpenhemmer entfaltet werden. Auf diese Weise wird aber auch ein wichtiger Bestandteil der unspezifischen Immunabwehr ausgeschaltet, der den Körper – und vor allem das Darmmikrobiom – vor mit der Nahrung aufgenommenen Pathogenen oder eingeschwemmten Mundkeimen schützt. Daraus ergeben sich Veränderungen des Darmmikrobioms, wie eine Reduktion der Diversität des Mikrobioms oder eine Fehlbesiedelung des Dünndarms, die mit verschiedenen Nebenwirkungen der Protonenpumpen-(Langzeit-)Therapie, wie einem erhöhten Risiko für Clostridium-difficile-Infektionen oder gastrointestinalen Beschwerden, assoziiert sind. Bei Menschen mit Leberzirrhose bspw. ist die Einwanderung von oralen Bakterien in den Darm mit intestinaler Inflammation und Permeabilität verbunden und kann als Biomarker für das 3-Jahres-Überleben herangezogen werden. Mikrobiomassoziierte Nebenwirkungen sollten daher in den Diskurs über die Risiken von Langzeittherapien mit Protonenpumpenhemmern und dem Abwägen von Alternativen miteinbezogen werden. more...

Background: Health care professionals have to judge the appropriateness of treatment in critical care on a daily basis. While there is general consensus that critical care interventions should not be performed when they are futile, it is unclear in quantitative terms, which chances of survival are considered necessary and which risk for serious disabilities is acceptable for different stakeholder in the process of intensive care treatment. Methods: We performed an anonymous online survey in 1052 people. We considered age, gender, nationality, education, involvement in health care, critical care medicine and treatment decisions as well as personal experience with critical illness as potential influencing variables. On a scale from 0-100%, participants were asked to give their opinion on the necessary survival changes and the acceptable risk for serious disabilities in order to start a high-risk or unpleasant therapy for themselves, relatives and for their patients, if the respondents were health care professionals who are involved in treatment decisions. Results: For all questions, a maximum of individual variations was observed with answers ranging from 0-100% for necessary survival chances and acceptable risk of disability. A three-peak pattern with different distributions of the peaks was observed for all answers. More respondents would choose a lower necessary chance of survival (0-33% survival) when deciding for patients compared to themselves or relatives to start a risky and uncomfortable treatment. On the other hand, the majority of respondents would accept only a low risk of severe disability for both themselves and their patients. Gender, education, being a health care professional, being involved in treatment decisions and religiosity influence these opinions. Male respondents and those with university education accept a lower survival chance for themselves, relatives and patients.Conclusion: Our study shows that people have very diverging views on the necessary chances of survival as well as on the acceptable risks for starting a risky and uncomfortable treatment, close relatives and patients. No general cut-off can be identified for the necessary survival chances or acceptable risk to help to quantify “futility”. Individual communication between health care professionals, patients and relatives in each case seems necessary. more...

Fibroblast growth factor 21 (FGF21) is produced in the liver and binds to different complex receptor/coreceptor systems. Besides many other processes, FGF21 regulates the intake of simple sugars and alcohol. Increased levels of FGF21 decrease harmful alcohol intake in mice. To increase our understanding on the relationship between FGF21 and alcohol intake in humans, we aimed to measure FGF21 levels in patients with alcoholic liver cirrhosis (ALC) in comparison to patients with nonalcoholic liver cirrhosis (NALC) and healthy persons based on their present alcohol consumption.Alcohol intake was verified by urinary ethyl glucuronide (uETG) levels, eating and drinking behaviour by a Food Frequency Questionnaire and FGF 21 plasma levels were determined by ELISA in 96 persons (ALC n = 41; NALC n = 34; healthy n = 21).Both ALC and NALC patients with elevated ETG levels (≥0.5 μg/ml; indicating alcohol consumption in the last 12-72 h) showed significantly higher FGF21 plasma levels in comparison to patients with negative ETG levels. Eating behaviour did not have an impact on FGF21 plasma levels.Increased FGF21 levels in patients with recent alcohol consumption (verified by ETG) confirmed the first part of the liver-brain endocrine axis: alcohol consumption was associated with increased FGF21 levels. We could not confirm that elevated FGF21 levels were associated with reduced alcohol intake as a result. That points towards a pathology in this pathway, which might be caused by a malfunction of β‑Klotho or FGF receptors according to other studies and chronic alcohol dependency. Further research is required to clarify these pathologies, which may open new pharmacological treatment for patients with alcohol use disorder and alcohol dependence.GRUNDLAGEN: Fibroblast-Growth-Factor 21 (FGF21) wird in der Leber produziert und bindet an verschiedene komplexe Rezeptor/Corezeptor-Systeme. FGF21 reguliert neben vielen anderen Prozessen die Aufnahme von einfachem Zucker und Alkohol. Erhöhte FGF21-Spiegel verringern den schädlichen Alkoholkonsum bei Mäusen. Um die Beziehung zwischen FGF21 und Alkoholkonsum beim Menschen besser zu verstehen, wurden FGF21-Spiegel bei PatientInnen mit alkoholischer Leberzirrhose (ALC) im Vergleich zu PatientInnen mit nichtalkoholischer Leberzirrhose (NALC) und gesunden Personen gemessen und in Korrelation mit ihrem gegenwärtigen Alkoholkonsum analysiert.Der Alkoholkonsum wurde durch Ethylglukuronid(uETG)-Werte im Urin, das Ess- und Trinkverhalten durch einen Lebensmittelfrequenz-Fragebogen verifiziert, und die FGF21-Plasmaspiegel wurden mittels ELISA bei 96 Personen bestimmt (ALC n = 41; NALC n = 34; gesund n = 21).ALC- und NALC-PatientInnen mit erhöhten ETG-Spiegeln (≥0,5 μg/ml; entspricht Alkoholkonsum in den letzten 12–72 h) zeigten signifikant höhere FGF21-Plasmaspiegel im Vergleich zu Patienten mit negativen ETG-Spiegeln. Das Essverhalten hatte keinen Einfluss auf die FGF21-Plasmaspiegel.Erhöhte FGF21-Spiegel bei Patienten mit kürzlich aufgetretenem Alkoholkonsum (durch ETG verifiziert) bestätigten den ersten Teil der endokrinen Achse von Leber und Gehirn: Alkoholkonsum ist mit erhöhten FGF21-Spiegeln verbunden. Wir konnten nicht bestätigen, dass erhöhte FGF21-Spiegel mit einem in Folge reduzierten Alkoholkonsum einhergehen. Dies deutet auf eine Pathologie auf diesem Weg hin, die durch eine Fehlfunktion der β‑Klotho- oder FGF-Rezeptoren und die chronische Alkoholkrankheit verursacht werden könnte. Weitere Forschungen sind erforderlich, um diese Pathologien zu klären, die möglicherweise eine neue pharmakologische Behandlung für Patienten mit Alkoholkonsumstörung und Alkoholabhängigkeit eröffnen. more...

Chronic hepatitis C virus infection is characterized by multiple extra-hepatic manifestations. Innate immune dysfunction and hemolysis are symptoms which might be associated with each other. We investigated the impact of direct acting antivirals on neutrophil function and its connection to hemolysis. In this prospective study, 85 patients with or without cirrhosis and 21 healthy controls were included. Patients' blood samples were taken at baseline, at the end of therapy and at follow-up 12 weeks after end of therapy. Neutrophil phagocytosis, oxidative burst, and hemolysis parameters were studied. Multivariate analysis was performed to decipher the relationship between hemolysis and neutrophil function. Ex vivo cross-incubation experiments with neutrophils and serum fractions were done. Impaired neutrophil phagocytosis and mild hemolysis were observed in patients with and without cirrhosis. A proteome approach revealed different expression of hemolysis-related serum proteins in patients and controls. Direct acting antiviral therapy restored neutrophil function irrespective of severity of liver disease, achievement of sustained virologic response or type of drug and reduced hemolysis. Treatment with ribavirin delayed the improvement of neutrophil function. Statistical analysis revealed associations of haptoglobin with neutrophil phagocytic capacity. Neutrophil dysfunction could be transferred to healthy cells by incubation with patients' serum fractions (>30 kDa) ex vivo. Neutrophil dysfunction and hemolysis represent extrahepatic manifestations of chronic hepatitis C virus infection and simultaneously improve during direct acting antiviral therapy independently of therapy-related liver function recovery. Therefore, large-scale treatment would not only drive viral eradication but also improve patients' immune system and may reduce susceptibility to infections. more...

Malignant diseases can cause tumor-associated cachexia (TAC). Supplementation with prebiotic non-digestible carbohydrates exerts positive metabolic effects in experimental oncologic diseases. The aim of this project was to assess the effect of prebiotic supplementation with OMNi-LOGiC&reg, FIBRE on intestinal microbiome, bacterial metabolism, gut permeability, and inflammation in a murine model of neuroblastoma (NB)-associated TAC. For this study, 2,000,000 NB cells (MHH-NB11) were implanted into athymic mice followed by daily supplementation with water or 200 mg prebiotic oligosaccharide (POS) OMNi-LOGiC&reg, FIBRE (NB-Aqua, n = 12, NB-POS, n = 12). Three animals of each tumor group did not develop NB. The median time of tumor growth (first visibility to euthanasia) was 37 days (IQR 12.5 days) in the NB-Aqua group and 37 days (IQR 36.5 days) in the NB-POS group (p = 0.791). At euthanasia, fecal microbiome and volatile organic compounds (VOCs), gut permeability (fluorescein isothiocyanate-dextran (FITC-dextran), and gut barrier markers were measured. Values were compared to sham animals following injection of culture medium and gavage of either water or OMNi-LOGiC&reg, FIBRE (SH-Aqua, n = 10, SH-POS, n = 10). Alpha diversity did not differ significantly between the groups. Principal coordinate analysis (PCoA) revealed clustering differences between Aqua and POS animals. Both NB and POS supplementation led to taxonomic alterations of the fecal microbiome. Of 49 VOCs, 22 showed significant differences between the groups. NB animals had significantly higher gut permeability than Aqua animals, POS did not ameliorate these changes. The pore and leak pathways of tight junctions did not differ between groups. In conclusion, our results suggest that NB-induced TAC causes increased gut permeability coupled with compositional changes in the fecal microbiome and VOC profile. Prebiotic supplementation with OMNi-LOGiC&reg, FIBRE seemed to induce modifications of the fecal microbiome and VOC profile but did not improve gut permeability. more...

Probiotics have been used in trials to therapeutically modulate the gut microbiome and have shown beneficial effects in cirrhosis. However, their effect on the microbiome of cirrhosis patients is not fully understood yet. Here, we tested the effects of a multispecies probiotic on microbiome composition in compensated cirrhosis. The gut microbiome composition of 58 patients with compensated cirrhosis from a randomized controlled trial who received a daily dose of multispecies probiotics or placebo for six months was analysed by 16S rRNA gene sequencing. Microbiome composition of patients who received probiotics was enriched with probiotic strains and the abundance of Faecalibacterium prausnitzii, Syntrophococcus sucromutans, Bacteroides vulgatus, Alistipes shahii and a Prevotella species was increased in the probiotic group compared to the placebo group. Patients who had microbiome changes in response to probiotic treatment also showed a significant increase in neopterin and a significant decrease in faecal zonulin levels after intervention, which was not observed in placebo-treated patients or patients with unchanged microbiome compositions. In conclusion, multispecies probiotics may enrich the microbiome of compensated cirrhotic patients with probiotic bacteria during a six-month intervention and beneficially change the residential microbiome and gut barrier function. more...

Rationale: Chemotherapy (CTx) with FOLFOX is indicated prior to resection of liver metastases; however, its effect is limited due to chemoresistance and its toxicity prevents from aggressive surgery needed in some cases. Hepatoprotective glycine has been shown to have anti-tumorigenic properties in various cancers. Thus, this study was designed to evaluate the effects of glycine combined with FOLFOX on colorectal liver metastases (CRLM). Methods: The effect of glycine combined with 5-fluorouracil and oxaliplatin was investigated in vitro on colorectal cancer (CC531). Further, Wag/Rij rats with CRLM were treated with 5% dietary glycine ± FOLFOX. µCT liver scan, anti-Ki67, and anti-CD31 were compared. Results: Glycine alone and combined with CTx has no effect on both CC531 viability in vitro and tumor proliferation in vivo; however, glycine significantly decreased tumor volume to about 42-35% of controls in vivo (p more...

Increased intestinal or gastric permeability is one of the major hallmarks of liver cirrhosis. The current gold standard for diagnosis of aberrant gut permeability due to disease is the triple-sugar test, where carbohydrates are orally administered and urinary excretion is measured. Hereby, elevated lactulose levels indicate intestinal permeability, whereas increased sucrose levels reveal gastric permeability. However, reliable detection and quantification of these sugars in a complex biological fluid still remains challenging due to interfering substances. Here we used Nuclear Magnetic Resonance (NMR) spectroscopy with a simple and fast protocol, without any additional sample extraction steps, for straight-forward simultaneous quantification of sugars in urine in order to detect increased intestinal and gastric permeability. Collected urine samples were diluted in buffer and one- and two-dimensional proton spectra were recorded in order to reveal carbohydrate concentrations in individual urine samples containing mannitol, sucrose and/or lactulose. Overall, this article presents a fast and robust method for simultaneous quantification of different sugars down to low micro-molar concentrations for research studies and can be further extended for clinical studies with automation of the quantification process. more...

C-type regenerating islet derived-3 (Reg3) lectins defend against pathogens and keep commensal bacteria at a distance. Deficiency of Reg3g and Reg3b facilitates alcohol-induced bacterial translocation and alcoholic liver disease. Intestinal Reg3g is down-regulated in animal models of diet-induced obesity, but the functional consequences for nonalcoholic steatohepatitis (NASH) are unknown. The aim of this study was to investigate the role of Reg3 lectins in NASH. NASH was induced by a Western-style fast-food diet in mice deficient for Reg3g or Reg3b and in transgenic mice overexpressing Reg3g in intestinal epithelial cells (Reg3gTg). Glucose tolerance was assessed after 18 weeks and insulin resistance after 19 weeks of feeding. After 20 weeks, mice were assessed for features of the metabolic syndrome. Obesity was not different in genetically modified mice compared with their respective wild-type littermates. Glucose intolerance, liver injury, hepatic inflammation, steatosis, fibrosis, and bacterial translocation to mesenteric lymph nodes and to the liver were not different in Reg3g-deficient mice compared with wild-type littermates. Plasma endotoxin levels were higher in Reg3g-deficient mice. Reg3b deficiency protected against glucose intolerance, but liver disease, bacterial translocation, and plasma endotoxin levels were similar to wild-type littermates. Absence of either REG3G or REG3B protein in the ileum was not compensated for by up-regulation of the respective other REG3 protein. Transgenic Reg3g mice also developed liver injury, steatosis, and fibrosis similar to their wild-type littermates. Conclusion: In contrast to alcoholic liver disease, loss of intestinal Reg3 lectins is not sufficient to aggravate diet-induced obesity and NASH. This supports a multi-hit pathogenesis in NASH. Only glucose metabolism is affected by Reg3b deficiency. (Hepatology Communications 2018;2:393-406). more...

Complications of end-stage renal disease (ESRD) are critically related to inflammation. The gut microbiome is a key driver of inflammation. Since dialysis modalities may differently influence the gut microbiome, we aimed to compare the effects of haemodialysis (HD) and peritoneal dialysis (PD) on patients’ gut microbiome composition and function. We therefore studied faecal microbiome composition and function as well as inflammation and gut permeability in 30 patients with ESRD (15 HD, 15 PD) and compared to 21 healthy controls. We found an increase in potentially pathogenic species and a decrease in beneficial species in patients on HD and to a lesser extend in patients on PD when compared to controls. These changes in taxonomic composition also resulted in differences in predicted metagenome functions of the faecal microbiome. In HD but not in PD, changes in microbiome composition were associated with an increase in c-reactive protein (CRP) but not with intestinal inflammation or gut permeability. In conclusion microbiome composition in ESRD differs from healthy controls but also between modes of dialysis. These differences are associated with systemic inflammation and cannot completely be explained by dialysis vintage. The mode of renal replacement therapy seems to be an important driver of dysbiosis in ESRD. more...