Detlef Schuppan

Johannes Gutenberg University Mainz | JGU · Institut für Translationale Immunologie

Background Reliable, noninvasive tools to diagnose at-risk metabolic dysfunction–associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high-risk patients with MASH (NAFLD activity score >4 and fibrosis s...

LINKED CONTENT This article is linked to Armandi et al papers. To view these articles, visit https://doi.org/10.1111/apt.17941 and https://doi.org/10.1111/apt.17969.

Background The current management of metabolic dysfunction‐associated steatotic liver disease (MASLD) relies on lifestyle intervention. Prior studies have shown that nutritional wheat amylase trypsin inhibitors (ATI) activate toll‐like receptor 4 on intestinal myeloid cells to enhance intestinal and extra‐intestinal inflammation, including the prom...

Aims We examined the cardiovascular effects of celiac disease (CeD) in a humanized mouse model, with a focus on vascular inflammation, endothelial dysfunction, and oxidative stress. Methods and results NOD.DQ8 mice genetically predisposed to CeD were subjected to a diet regime and oral gavage to induce the disease (gluten group vs. control). We te...

During fibrosis, (myo)fibroblasts deposit large amounts of extracellular matrix proteins, thereby replacing healthy functional tissue. In liver fibrosis, this leads to the loss of hepatocyte function, portal hypertension, variceal bleeding, and increased susceptibility to infection. At an early stage, liver fibrosis is a dynamic and reversible proc...

Aim: The semisynthetic derivatives MePip-SF5 and isogarcinol, which are aligned with the natural products curcumin and garcinol, were tested for their antitumor effects in a preclinical model of pulmonary melanoma metastasis. Methods and results: MePip-SF5 was almost five times more effective in inhibiting B16F10 melanoma cell proliferation than...

Introduction Scurfy mice have a complete deficiency of functional regulatory T cells (Treg) due to a frameshift mutation in the Foxp3 gene. The impaired immune homeostasis results in a lethal lymphoproliferative disorder affecting multiple organs, including the liver. The autoimmune pathology in scurfy mice is in part accompanied by autoantibodies...

The prevalence of hypersensitivities towards wheat has increased in the last decades. Apart from celiac disease these include allergic and other inflammatory reactions summarized under the term non-celiac wheat sensitivity. One suspected trigger is the family of amylase/trypsin-inhibitors (ATIs), non-gluten proteins that are prominent wheat allerge...

Objective: Wheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating intestinal myeloid cells via toll-like receptor 4, in experimental autoimmune encephalitis (EAE), a model of multiple sclerosis (MS). Design: EAE was induced in C57BL/6J mice o...

This review aims to evaluate the current preclinical state of liver bioengineering, the clinical context for liver cell therapies, the cell sources, the delivery routes, and the results of clinical trials for end-stage liver disease. Different clinical settings, such as inborn errors of metabolism, acute liver failure, chronic liver disease, liver...

Objective Stellate cells are responsible for liver and pancreas fibrosis and strictly correlate with tumourigenesis. Although their activation is reversible, an exacerbated signalling triggers chronic fibrosis. Toll-like receptors (TLRs) modulate stellate cells transition. TLR5 transduces the signal deriving by the binding to bacterial flagellin fr...

The enzyme transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis. Active TG2 is located mainly extracellularly in the lamina propria but also in the villous enterocytes of the duodenum. The TG2 inhibitor ZED1227 is a promising drug candidate for treating CeD and is designed to block the TG2-catalyzed deamidation and crossli...

Background Western lifestyle has been associated with an increase in relapsing–remitting multiple sclerosis (RRMS). In mice, dietary wheat amylase–trypsin inhibitors (ATIs) activate intestinal myeloid cells and augment T cell-mediated systemic inflammation. Objective The aim of this study was to assess whether a wheat- and thus ATI-reduced diet mi...

Background: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. Met...

Mycoplasma infection leads to false and non-reproducible scientific data and poses a risk to human health. Despite strict guidelines calling for regular mycoplasma screening, there is no universal and widely established standard procedure. Here, we describe a reliable and cost-effective PCR method that establishes a universal protocol for mycoplasm...

Background aims: Detecting non-alcoholic steatohepatitis (NASH) remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning (ML) techniques, with clinical data and biomarkers to stage and grade no...

Simple Summary Oral cancer is a life-threatening disease and among the ten most common cancer types. Specific protein biomarkers in the blood of these patients may allow early tumor detection, earlier intervention and help to individualize therapy resulting in improved patient survival. This exploratory study analyzed the serum proteome with a high...

Wheat is an important staple food and its processing quality is largely driven by proteins. However, there is a sizable number of people with inflammatory reactions to wheat proteins, namely celiac disease, wheat allergy and the syndrome of non-celiac wheat sensitivity. Thus, proteome profiles should be of high importance for stakeholders along the...

Background Patients with irritable bowel syndrome (IBS) often report gastrointestinal symptoms after consuming wheat and gluten-containing foods. It is, however, unclear whether gluten is the main driver of symptoms, as other immunogenic peptides, such as amylase trypsin inhibitors (ATI), poorly digestible fiber (inulin, part of FODMAP) or even the...

The chemical modification of aeroallergens by reactive oxygen and nitrogen species (ROS/RNS) may contribute to the growing prevalence of respiratory allergies in industrialized countries. Post-translational modifications can alter the immunological properties of proteins, but the underlying mechanisms and effects are not well understood. In this st...

Wheat is an important staple crop since its proteins contribute to human and animal nutrition and are important for its end-use quality. However, wheat proteins can also cause adverse human reactions for a large number of people. We performed a genome wide association study (GWAS) on 114 proteins quantified by LC-MS-based proteomics and expressed i...

The single nucleotide polymorphism I148M of the lipase patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an unfavorable prognosis in alcoholic and non-alcoholic steatohepatitis (ASH, NASH), with progression to liver cirrhosis and development of hepatocellular carcinoma. In this study, we investigated the mechanistic interac...

Introduction: Via pleiotropic targeting of membrane and nuclear fatty acid receptors regulating key metabolic and inflammatory pathways in the liver, long-chain omega-3 fatty acids could offer a unique therapeutic approach for the treatment of metabolic-inflammatory diseases such as NASH. However, they lack efficacy for the treatment of NASH, like...

Wheat is an important staple food and its processing quality is largely driven by proteins. However, there is a sizable number of people with inflammatory reactions to wheat proteins, namely celiac disease, wheat allergy and the syndrome of non-celiac wheat sensitivity. Thus, proteome profiles should be of high importance for stakeholders along the...

Background & Aims Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. Methods FAP expression was analyzed in mice and patients with fi...

Biomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalized medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and co...

Background COVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9–20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of se...

Background Primary sclerosing cholangitis (PSC) is a progressive bile duct disease associated with inflammatory bowel disease (PSC‐IBD). Aim To investigate whether patients with PSC‐IBD benefit from a gluten‐free and amylase trypsin inhibitor (ATI)‐free diet (GFD). Methods We performed a prospective clinical pilot study administering an eight‐wee...

Probiotic bacteria and their metabolites, particularly short chain fatty acids (SCFA), have been shown to prevent or ameliorate allergic inflammation in OVA- or house dust mice-driven allergy mouse models. The aim of this study was to investigate the role of SCFA and a defined probiotic formulation (PF) containing 10 different Lactobacilli species...

Timely detection of portal hypertension as a manifestation in a subgroup of patients with common variable immunodeficiency (CVID) represents a challenge since it is usually not associated with liver cirrhosis. To identify relevant markers for portal hypertension, we evaluated clinical history, laboratory parameters, and abdominal ultrasound includi...

Objective: Celiac disease (CeD) is an autoimmune enteropathy triggered by dietary gluten, with a prevalence around 1%. Since many patients show heterogeneous symptoms, it is vastly underdiagnosed and yet without any treatment option besides lifelong gluten restriction. Vascular function in CeD patients compared to healthy controls has been assessed...

Significance Fibrosis is a consequence of most chronic liver diseases, but currently no approved antifibrotic treatment is available. M2-type macrophages drive fibrosis progression and prevent regression, even when effective causal therapies have been employed. M2-type macrophages activate a cascade of fibrogenic effector cells and can prevent remo...

Defined conjugation of functional molecules to block copolymer end groups is a powerful strategy to enhance the scope of micellar carriers for drug delivery. In this study, we have established an approach to access well‐defined polycarbonate‐based block copolymers by labeling their end groups with single fluorescent dye molecules. Following control...

Probiotic bacteria and their metabolites, particularly short chain fatty acids (SCFA), have been shown to prevent or ameliorate allergic inflammation in OVA- or house dust mite-driven allergy mouse models. The aim of this study was to investigate the role of SCFA and a defined probiotic formulation (PF) in a recently developed humanized mouse model...

Background & aims: Growing evidence suggests an important role of B cells in the development of non-alcoholic fatty liver disease (NAFLD). However, a detailed functional analysis of B cell subsets in NAFLD pathogenesis is lacking. Approach & results: In wildtype mice, 21 weeks of high fat diet (HFD) feeding resulted in NAFLD with massive macrove...

Probiotic bacteria and their metabolites, particularly short chain fatty acids (SCFA), have been shown to prevent or ameliorate allergic inflammation in OVA- or house dust mice-driven allergy mouse models. The aim of this study was to investigate the role of SCFA and the probiotic formulation BactoFlor® 10/20 in a recently developed humanized mouse...

Background/aims: Osteoprotegerin (OPG) is a profibrotic mediator produced by myofibro-blasts under influence of transforming growth factor β (TGFβ). Its expression in experimental models of liver fibrosis correlates well with disease severity and treatment responses. The regulation of OPG in liver tissue is largely unknown and we therefore set out...

The use of nanoparticles as carriers to deliver pharmacologically active compounds to specific parts of the body via the bloodstream is a promising therapeutic approach for the effective treatment of various diseases. To reach their target sites, nanocarriers (NCs) need to circulate in the bloodstream for prolonged periods without aggregation, degr...

Reactive oxygen species and reactive nitrogen species (RONS) are involved in programmed cell death in the context of numerous degenerative and chronic diseases. In particular, the ability of cells to maintain redox homeostasis is necessary for an adaptive cellular response to adverse conditions that can cause damage to proteins and DNA, resulting i...

Objectives Serum propeptides of type III and type VI collagen (PRO-C3 and PRO-C6) are elevated in advanced nonalcoholic fatty liver disease, but their value in patients with severe obesity and their evolution after bariatric surgery (BS) is unknown. It is unclear if these markers of fibrogenesis are affected by adipose tissue fibrosis (ATF). We stu...

Background and Aims Although long-chain omega-3 fatty acids (LCn-3FAs) regulate inflammatory pathways of relevance to non-alcoholic steatohepatitis (NASH), their susceptibility to peroxidation may limit their therapeutic potential. We compared the metabolism of eicosapentaenoic acid (EPA) with an engineered EPA derivative (icosabutate) in human hep...

Background & Aims Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods We profiled 2,083 serum miRNAs in a discovery cohort (183 NAFLD cases representing the complete NAFLD spectrum and 10 po...

Key message Wheat cultivars largely differ in the content and composition of ATI proteins, but heritability was quite low for six out of eight ATIs. The genetic architecture of ATI proteins is built up of few major and numerous small effect QTL. Abstract Amylase trypsin inhibitors (ATIs) are important allergens in baker’s asthma and suspected trig...

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-te...

The interaction of extracellular matrix (ECM) components with hepatic stellate cells (HSCs) is thought to perpetuate fibrosis by stimulating signaling pathways that drive HSC activation, survival and proliferation. Consequently, disrupting the interaction between ECM and HSCs is considered a therapeutical avenue although respective targets and unde...

Accumulating evidence suggests that both the nature of oncogenic lesions and the cell‐of‐origin can strongly influence cancer histopathology, tumor aggressiveness and response to therapy. Although oncogenic Kras expression and loss of Trp53 tumor suppressor gene function have been demonstrated to initiate murine lung adenocarcinomas (LUADs) in alve...

Was ist neu? Therapie mit Givosiran Givosiran ist ein kleines synthetisches doppelsträngiges siRNA-Fragment mit 20 Basenpaaren Länge. Eine prospektive, randomisierte multizentrische Studie (Envision) zeigte erstmalig die klinische Wirksamkeit von monatlich subkutan applizierten synthetischen RNA-Molekülen („small interfering“ RNA, siRNA) zur Präven...

Celiac disease (CeD) is a frequent immune-mediated disease that affects not only the small intestine but also many extraintestinal sites. The role of gluten proteins as dietary triggers, HLA-DQ2 or DQ8 as major necessary genetic predisposition, and tissue transglutaminase (TG2) as mechanistically involved autoantigen, are unique features of CeD. Re...