Freya Wellhöner

Medizinische Hochschule Hannover

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Benjamin Heidrich

Medizinische Hochschule Hannover

Heiner Wedemeyer

Medizinische Hochschule Hannover

Michael P. Manns

Medizinische Hochschule Hannover

Dietmar H. Pieper

Helmholtz Centre for Infection Research

Marius Vital

Medizinische Hochschule Hannover

Silke Kahl

Helmholtz Centre for Infection Research

Iris Plumeier

Helmholtz Centre for Infection Research

Philipp Solbach

University Hospital Schleswig-Holstein

Henrike Lenzen

Medizinische Hochschule Hannover

Friederike Klein

Medizinische Hochschule Hannover

Cooperative Institutions

Medizinische Hochschule Hannover

German Center for Infection Research

Helmholtz Centre for Infection Research

Centre for Individualised Infection Medicine

ERN RARE-LIVER

German Liver Foundation

Center for Experimental and Clinical Infection Research

ERN GUARD-Heart

Endocrinology Research Center

University of Duisburg-Essen

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The impact of proton pump inhibitors on the intestinal microbiota in chronic hepatitis C patients

Scandinavian Journal of Gastroenterology (2019)

Freya Wellhöner Nico Döscher Tammo Lambert Tergast Marius Vital Iris Plumeier

Objectives: Proton pump inhibitors (PPI), a class of drugs commonly used, are known to be associated with changes in the intestinal microbiota. Published studies were done in heterogeneous cohorts which could hamper conclusions drawn as effects of diseases were not taken into consideration. We aimed to elucidate differences in the intestinal microbiota being associated to the use of PPI in a cohort study of patients with chronic hepatitis C.Material and Methods: The 16S rDNA gene was analyzed in stool samples of patients with and without PPI use. Patients with concomitant medication influencing the microbiota were excluded. Results were compared with the clinical course of hepatitis C patients with decompensated liver cirrhosis.Results: No differences in alpha diversity could be observed, while the microbial community structure differed significantly, especially in patients with liver cirrhosis. The relative abundance of Streptococcus spp., Enterobacter spp. and Haemophilus spp. was significantly increased in patients with PPI use irrespectively of the stage of liver disease. Finally, in patients with decompensated liver cirrhosis due to chronic HCV infection only in these using PPI bacterial phylotypes were isolated.Conclusions: PPI use was associated with significant alterations in the microbial community in patients with chronic hepatitis C, which were even pronounced in patients with liver cirrhosis. In patients with decompensated liver cirrhosis due to chronic HCV infection, the use of PPI may promote infections either directly or indirectly through changes in the microbial community structure. Future studies should further investigate long-term impact on the microbiota and the clinical outcome.

Spontaneous bacterial peritonitis

Chronic liver disease

Liver disease

Veillonella

10.1080/00365521.2019.1647280

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Citations (17)

Next Generation Sequencing Outperforms Cultivation-Based Methods for Detection of Bacterial Genera in Bile After Liver Transplantation

Journal of Clinical and Experimental Hepatology (2023)

Björn Grobe Freya Wellhöner Friederike Klein Patrick Chhatwal Marius Vital

10.1016/j.jceh.2023.08.001

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Citations (1)

Dulaglutide Alone and in Combination with Empagliflozin Attenuate Inflammatory Pathways and Microbiome Dysbiosis in a Non-Diabetic Mouse Model of NASH

Biomedicines (2021)

Katharina Luise Hupa‐Breier Janine Dywicki Björn Hartleben Freya Wellhöner Benjamin Heidrich

Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6CHigh and CD4+Foxp3+ T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH.

Empagliflozin

Dulaglutide

Steatosis

10.3390/biomedicines9040353

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Novel translational mouse models of Metabolic Dysfunction-associated steatotic liver disease comparable to human MASLD with severe obesity

Molecular Metabolism (2025)

Katharina Luise Hupa‐Breier Heiko Schenk Alejandro Campos-Murguía Freya Wellhöner Benjamin Heidrich

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, especially in patients with severe obesity. However, current mouse models for MASLD do not reflect the polygenetic background nor the metabolic changes in this population. Therefore, we investigated two novel mouse models of MASLD with a polygenetic background for the metabolic syndrome. TALLYHO/JngJ mice and NONcNZO10/LtJ mice were fed a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet. A second group of TH mice was additional treated with empagliflozin. After sixteen weeks of feeding, both strains developed metabolic syndrome with severe obesity and histological manifestation of steatohepatitis, which was associated with significantly increased intrahepatic CD8+cells, CD4+cells and Tregs, contributing to a significant increase in pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. In comparison with the human transcriptomic signature, we could demonstrate a good metabolic similarity, especially for the TH mouse model. Furthermore, TH mice also developed signs of kidney injury as an extrahepatic comorbidity of MASLD. Additional treatment with empagliflozin in TH mice attenuates hepatic steatosis and improves histological manifestation of MASH. Overall, we have developed two promising new mouse models that are suitable for preclinical studies of MASLD as they recapitulate most of the key features of MASLD.

10.1016/j.molmet.2025.102104

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Eradication of Chronic HCV Infection: Improvement of Dysbiosis Only in Patients Without Liver Cirrhosis

Hepatology (2021)

Freya Wellhöner Nico Döscher Franziska Woelfl Marius Vital Iris Plumeier

Background and Aims It is well accepted that liver diseases and their outcomes are associated with intestinal microbiota, but causality is difficult to establish. The intestinal microbiota are altered in patients with hepatitis C. As chronic HCV infection can now be cured in almost all patients, it is an ideal model to study the influence of liver disease on the microbiota. Approach and Results We aimed to prospectively analyze the changes in the gut microbiome in patients who received direct‐acting antivirals (DAA) and achieved sustained virological response (SVR). Amplicon sequencing of the V1‐V2 region in the 16S ribosomal RNA gene was performed in stool samples of patients with chronic hepatitis C. Patients in the treatment group received DAA (n = 65), whereas in the control group, no DAA were given (n = 33). Only patients achieving SVR were included. The alpha diversity increased numerically but not significantly from baseline to SVR at week 24 or 48 (SVR24/48; 2.784 ± 0.248 vs. 2.846 ± 0.224; P = 0.057). When stratifying for the presence of liver cirrhosis, a significant increase in diversity was only seen in patients without cirrhosis. Differences in the microbial community structure induced by the achievement of SVR were only observed in patients without liver cirrhosis. In patients with liver cirrhosis and in the control group, no significant differences were observed. Conclusions In conclusion, the achievement of SVR24/48 in patients with chronic HCV was associated with changes in the intestinal microbiota. However, these changes were only seen in patients without liver cirrhosis. A major role of liver remodeling on the intestinal microbiota is indicated by the dynamics of the intestinal microbial community structure depending on the stage of fibrosis in patients resolving chronic hepatitis C.

Dysbiosis

10.1002/hep.31700

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Citations (25)

Automated low-flow ascites pump in a real-world setting: complications and outcomes

European Journal of Gastroenterology & Hepatology (2018)

Philipp Solbach Christoph Höner zu Siederdissen Freya Wellhöner Nicolas Richter Benjamin Heidrich

The aim of this study was to investigate the Alfapump, an automated low-flow pump system for the treatment of refractory ascites (RA) as an alternative for repeated large-volume paracentesis in patients with contraindication for placement of a transjugular intrahepatic portosystemic shunt (TIPS) or liver transplantation.In 21 consecutive patients with RA and contraindication for a placement of a TIPS, the Alfapump was implanted at Hannover Medical School between December 2012 and May 2016. Repeated laboratory, clinical, and microbiology data were collected and analyzed to assess the outcome of patients with an Alfapump. Half of the patients received a modified peritoneal catheter.Twenty-one patients with RA in end-stage liver disease and with a contraindication to TIPS placement received the Alfapump. Diuretic dosages were significantly reduced, and the number of paracentesis declined from 2.3±2.7 to 0 per week. Using the Alfapump, kidney function and serum sodium remained stable. Likewise, serum albumin remained stable in the absence of albumin infusions. Thirty-three complications (dislocation and/or blockade of the catheter, infection, pump dysfunction) related to the Alfapump were observed in 15 of 21 patients (71.4%), and 21 surgical interventions were needed in 15 patients (71.4%, 1-3 interventions per patient). A new peritoneal catheter system could significantly reduce blockage of the peritoneal catheter.The Alfapump is an effective treatment in patients with RA. However, a high rate of complications were observed, which could be reduced with a modified peritoneal catheter.

Contraindication

Paracentesis

10.1097/meg.0000000000001149

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Citations (29)

Accumulation of regulatory T cells correlate with severity of NASH in patients and mice

Zeitschrift für Gastroenterologie (2024)

Janine Dywicki Laura Elisa Buitrago Molina Anna Baumann Ana Clara Marques Davalos‐Misslitz Katharina Luise Hupa‐Breier

Non-alcoholic fatty liver disease (NAFLD) affects approximately 30% of the world's population. NAFLD is associated with common metabolic comorbidities such as obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidaemia, hypertension and metabolic syndrome and 10-20% of NAFLD patients develop non-alcoholic steatohepatitis (NASH), which can progress to hepatocellular carcinoma (HCC). Therefore, although the majority of NAFLD patients die from cardiovascular events rather than liver-related causes, NAFLD is an increasing cause of fatal disease worldwide.

10.1055/s-0043-1777569

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Citations (0)

FRI-372-Next generation sequenzing outperforms standard microbiological cultivation for detection of bacteria in the biliary tract in patients with ischemic type biliary lesions and/or anastomotic stricture

Journal of Hepatology (2019)

Björn Grobe Philipp Solbach Freya Wellhöner Friederike Klein Marius Vital

10.1016/s0618-8278(19)31111-9

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Citations (2)

Cholangiocyte glycocalyx degradation boosts primary sclerosing cholangitis

medRxiv (Cold Spring Harbor Laboratory) (2024)

Friederike Klein Freya Wellhöner Anika Freise Kristina M. Niculovic Howard Junca

Summary Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tract eventually leading to bile duct destruction, liver failure, cholangiocellular adenocarcinoma and/or death. No disease modifying treatments are available 1 . Especially cytotoxicity of bile acids, are discussed as potential driver of disease progression 2 . Cholangiocytes are protected by a bicarbonate umbrella formed by the glycocalyx, a dense layer of membrane bound polyglycans extending into the extracellular space 3,4 . Bile of PSC patients harbors a unique microbiome 5 . Here we identified a new factor in the pathogenesis of PSC. The bacterial degradation of sialic acid and galactose are associated with a poor event free survival of PSC patients and could identify bacterial liberation of sialic acid as crucial element in cholangiocyte damage using cell culture experiments, individualized organoid models and liver biopsies. With this study the view on bacteria-host interactions in bile duct associated diseases is widened. Functional patterns of the bacterial community are crucial for bile duct destruction in PSC patients. This opens a new field of diagnostic tools, disease modifying treatment options and identification of patients at risk.

Glycocalyx

Primary Sclerosing Cholangitis

Cholangiocyte

Primary (astronomy)

Degradation

10.1101/2024.06.27.24309484

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The Impact of proton pump inhibitors on the intestinal microbiota in chronic hepatitis C patients

Journal of Hepatology (2018)

Freya Wellhöner Nico Döscher Vanga K Marius Iris Plumeier Silke Kahl

10.1016/s0168-8278(18)31475-2

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Citations (1)