Publications by authors named "Timon E Adolph"

33 Publications

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Apolipoprotein A5 controls fructose-induced metabolic dysregulation in mice.

Nutr Metab Cardiovasc Dis 2021 03 17;31(3):972-978. Epub 2020 Nov 17.

Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria; Christan Doppler Laboratory for Metabolic Crosstalk, Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Background And Aims: Western dietary habits are partially characterized by increased uptake of fructose, which contributes to metabolic dysregulation and associated liver diseases. For example, a diet enriched with fructose drives insulin resistance and non-alcoholic fatty liver disease (NAFLD). The molecular hubs that control fructose-induced metabolic dysregulation are poorly understood. Apolipoprotein A5 (apoA5) controls triglyceride metabolism with a putative role in hepatic lipid deposition. We explored apoA5 as a rheostat for fructose-induced hepatic and metabolic disease in mammals.

Methods And Results: ApoA5 knock out (-/-) and wildtype (wt) mice were fed with high fructose diet or standard diet for 10 weeks. Afterwards, we conducted a metabolic characterization by insulin tolerance test as well as oral glucose tolerance test. Additionally, hepatic lipid content as well as transcription patterns of key enzymes and transcription factors in glucose and lipid metabolism were evaluated. Despite comparable body weight, insulin sensitivity was significantly improved in high fructose diet fed apoA5 (-/-) when compared to wildtype mice on the same diet. In parallel, hepatic triglyceride content was significantly lower in apoA5 (-/-) mice than in wt mice. No difference was seen between apoA5 (-/-) and wt mice on a standard diet.

Conclusion: ApoA5 is involved in fructose-induced metabolic dysregulation and associated hepatic steatosis suggesting that apoA5 may be a novel target to treat metabolic diseases.
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http://dx.doi.org/10.1016/j.numecd.2020.11.008DOI Listing
March 2021

Increased Fecal Neopterin Parallels Gastrointestinal Symptoms in COVID-19.

Clin Transl Gastroenterol 2021 01 12;12(1):e00293. Epub 2021 Jan 12.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria.

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.
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http://dx.doi.org/10.14309/ctg.0000000000000293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806232PMC
January 2021

Cardioprotective effects of short-term empagliflozin treatment in db/db mice.

Sci Rep 2020 11 12;10(1):19686. Epub 2020 Nov 12.

Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.

Sodium glucose transporter (SGLT)-2 inhibitors have consistently shown cardioprotective effects independent of the glycemic status of treated patients. In this study we aimed to investigate underlying mechanisms of short-term empagliflozin treatment in a mouse model of type II diabetes. Male db/db mice were fed a western type diet with or without enrichment with empagliflozin for 7 days. While glucose tolerance was significantly improved in empagliflozin treated mice, body weight and fasting insulin levels were comparable in both groups. Cardiac insulin signaling activity indicated by reduced proteinkinase B (AKT) phosphorylation was significantly decreased in the empagliflozin treated group. Remarkably, mitochondrial mass estimated by citrate synthase activity was significantly elevated in empagliflozin treated mice. Accordingly, mitochondrial morphology was significantly altered upon treatment with empagliflozin as analysed by transmission electron microscopy. Additionally, short-term empagliflozin therapy was associated with a changed cardiac tissue cytokine expression in favor of an anti-inflammatory pattern. Our data suggest that early cardioprotection in empagliflozin treated mice is independent of a reduction in body weight or hyperinsulinemia. Ameliorated mitochondrial ultrastructure, attenuated cardiac insulin signaling and diminished cardiac inflammation might contribute to the cardioprotective effects of empagliflozin.
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http://dx.doi.org/10.1038/s41598-020-76698-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665199PMC
November 2020

Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade.

Hepatology 2021 Feb 6;73(2):833-842. Epub 2021 Feb 6.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1002/hep.31518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898624PMC
February 2021

Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans.

Gut 2021 Mar 22;70(3):585-594. Epub 2020 Jul 22.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria

Objective: Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by ) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.

Design: An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.

Results: Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.

Conclusion: Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.
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http://dx.doi.org/10.1136/gutjnl-2020-321375DOI Listing
March 2021

Gastric banding-associated weight loss diminishes hepatic Tsukushi expression.

Cytokine 2020 09 19;133:155114. Epub 2020 May 19.

Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria.

Obesity has emerged as a substantial global healthcare issue that is frequently associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD). Tsukushi (TSK), a liver-derived molecule, was recently identified as a major driver of NAFLD. Laparoscopic adjustable gastric banding (LAGB) has proven effective in reducing body weight and improving NAFLD. We therefore aimed to investigate the relation between LAGB-induced weight loss and TSK expression. Twenty-six obese patients undergoing LAGB were included in the study and metabolic parameters were assessed before (t0) and six months after LAGB (t6). The expression of TSK in liver and subcutaneous adipose tissue (AT) specimens was determined at both time points. To unravel regulatory mechanisms of TSK expression, human peripheral blood mononuclear cells (PBMCs) were stimulated with pro-inflammatory cytokines and TSK mRNA levels were analyzed by quantitative polymerase chain reaction. LAGB induced pronounced weight loss which was paralleled by amelioration of metabolic disturbances and histologically defined NAFLD. While hepatic TSK expression was markedly decreased after LAGB, adipose tissue TSK expression remained comparable to baseline. The decline in hepatic TSK expression after LAGB positively correlated with weight loss and the reduction in BMI, and negatively correlated with NAFLD activity score (NAS). In human PBMCs, pro-inflammatory cytokines such as IL-1β and TNFα induced the expression of TSK. In conclusion, LAGB-induced weight loss reduces hepatic TSK expression. Inhibiting TSK might represent a promising target for treating NAFLD in the future.
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http://dx.doi.org/10.1016/j.cyto.2020.155114DOI Listing
September 2020

Dimethyl fumarate ameliorates hepatic inflammation in alcohol related liver disease.

Liver Int 2020 07 6;40(7):1610-1619. Epub 2020 May 6.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Background & Aims: Alcohol-related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl-fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD.

Methods: Dimethyl-fumarate or vehicle was orally administered to wild-type mice receiving a Lieber-DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical- and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol-induced intestinal barrier disruption.

Results: Dimethyl-fumarate protected against ethanol-induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines (Tnf-α, Il-1β, Cxcl1) and reduced abundance of neutrophils and macrophages in ethanol-fed and DMF-treated mice when compared to vehicle. DMF protected against ethanol-induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS-induced cytokine responses of KCs.

Conclusions: Dimethyl-fumarate counteracts ethanol-induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited.
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http://dx.doi.org/10.1111/liv.14483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383968PMC
July 2020

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.

Nat Commun 2020 04 14;11(1):1775. Epub 2020 Apr 14.

Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.
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http://dx.doi.org/10.1038/s41467-020-15646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156516PMC
April 2020

A role for IL-1 inhibitors in the treatment of non-alcoholic fatty liver disease (NAFLD)?

Expert Opin Investig Drugs 2020 Feb 24;29(2):103-106. Epub 2019 Oct 24.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1080/13543784.2020.1681397DOI Listing
February 2020

Pancreas-Microbiota Cross Talk in Health and Disease.

Annu Rev Nutr 2019 08;39:249-266

Department of Internal Medicine I (Gastroenterology, Hepatology, Endocrinology and Metabolism), Medical University Innsbruck, Innsbruck 6020, Austria; email:

The pancreas controls metabolism through endocrine and exocrine functions. Pancreatic diseases comprise a spectrum of mild to life-threatening conditions, including acute and chronic pancreatitis, diabetes, and pancreatic cancer, which affect endocrine and exocrine pancreatic function and impose a substantial disease burden on individuals. Increasing experimental evidence demonstrates that the intestinal microbiota has an important impact on pancreatic function and diseases. This influence may be conferred by bacterial metabolites, such as short-chain fatty acids, or the modulation of immune responses. In turn, pancreatic factors, such as the excretion of antimicrobials, might have a substantial impact on the composition and functional properties of the gut microbiota. Here, we summarize experimental and clinical approaches used to untie the intricate pancreas-microbiota cross talk. Future advances will allow clinicians to manipulate the intestinal microbiota and guide patient management in pancreatic diseases.
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http://dx.doi.org/10.1146/annurev-nutr-082018-124306DOI Listing
August 2019

The intestinal microbiota fuelling metabolic inflammation.

Nat Rev Immunol 2020 01 6;20(1):40-54. Epub 2019 Aug 6.

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation.
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http://dx.doi.org/10.1038/s41577-019-0198-4DOI Listing
January 2020

Weight Loss Induced by Bariatric Surgery Restricts Hepatic Expression.

J Obes 2018 8;2018:7108075. Epub 2018 Nov 8.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck 6020, Austria.

Introduction: Obesity and related nonalcoholic fatty liver disease (NAFLD) are an emerging health care issue that imposes substantial morbidity to individuals. Growth and differentiation factor 15 () limits food uptake, body weight, and energy balance by modulation of GDNF-family receptor -like (GFRAL) signalling in the hindbrain. However, the regulation of expression in obesity and NAFLD is incompletely understood. We sought to define the impact of weight loss achieved by laparoscopic adjustable gastric banding (LAGB) on hepatic and adipose expression in a cohort of severely obese patients.

Methods: We analysed expression of liver and subcutaneous adipose tissue before and 6 months after LAGB in severely obese patients undergoing LAGB by quantitative real-time PCR. To assess the role of inflammation on expression, we analysed Hep G2 hepatocytes stimulated with cytokines such as IL-1, TNF, IL-6, LPS, or cellular stressors such as tunicamycin.

Results: expression was mostly confined to the liver compared to adipose tissue in severely obese patients. Weight loss induced by LAGB was associated with reduced hepatic (but not adipose tissue) expression of . Stimulation with IL-1 or tunicamycin induced hepatic expression in hepatocytes. In line with this, hepatic expression directly correlated with IL-1 expression and steatosis severity in NAFLD. These data demonstrated that amelioration of metabolic inflammation and weight loss reduced hepatic expression.

Conclusion: Based on recent mechanistic findings, our data suggest that hepatic may serve as a negative feedback mechanism to control energy balance in NAFLD.
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http://dx.doi.org/10.1155/2018/7108075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250003PMC
July 2019

How our understanding of the microbiome has changed the way we look at liver diseases.

Biomark Med 2018 11 16;12(11):1203-1206. Epub 2018 Nov 16.

Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.2217/bmm-2018-0266DOI Listing
November 2018

Gut microbiota as gatekeeper of anti-tumour responses in the liver.

Nat Rev Gastroenterol Hepatol 2018 10;15(10):584-586

Department of Internal Medicine I, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1038/s41575-018-0046-1DOI Listing
October 2018

Liver-Microbiome Axis in Health and Disease.

Trends Immunol 2018 09 26;39(9):712-723. Epub 2018 May 26.

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Austria. Electronic address:

The intestinal and hepatobiliary tract exhibits host-specific commensal colonization. The resident microbiota has emerged as a key player in intestinal and hepatic diseases. Alcoholic and nonalcoholic fatty liver diseases (ALD/NAFLD), primary sclerosing cholangitis (PSC), liver cirrhosis, and some of their clinical complications, such as hepatic encephalopathy (HE), have been linked to a microbial signature, as also observed for severe liver inflammation in alcoholic hepatitis. In turn, the liver impacts, and communicates with, the microbiota through hepatic mediators, such as bile acids or inflammatory signals. Therefore, a liver-microbiome bidirectional crosstalk appears to be critical in health and various liver diseases and could be therapeutically targeted, such as by fecal microbiota transplantation.
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http://dx.doi.org/10.1016/j.it.2018.05.002DOI Listing
September 2018

Food, microbiome and colorectal cancer.

Dig Liver Dis 2018 07 3;50(7):647-652. Epub 2018 Apr 3.

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Austria. Electronic address:

You are what you eat. This adage has been confirmed by many studies demonstrating the high impact of nutrition on risk of cardiovascular diseases, many malignancies and other diseases. Dietary factors are of major relevance in the evolution of colorectal carcinoma. Various aspects are involved in colorectal carcinoma pathogenesis including genetics, lifestyle, age, chronic inflammation and others. It has only recently been recognized that the gut microbiota might reflect an important missing link in the interaction between diet and subsequent colorectal carcinoma development. Dietary factors are a major confounding factor affecting the composition of the intestinal microbiota. Several preclinical and clinical studies have recently suggested a role for the intestinal microbiota in potentially initiating and driving colorectal carcinoma. Therefore it is increasingly acknowledged that dietary factors might favor carcinogenesis via manipulation of the gut microbiota via potential outgrowth of certain bacterial populations, such as Fusobacterium nucleatum, Escherichia coli or Bacteroides fragilis. Excitingly, recent large clinical studies also highlighted a role for the gut microbiota and in particular Akkermansia muciniphila in tumor response toward chemotherapeutic agents and immune checkpoint inhibitors. This review will concentrate on the role of dietary factors in affecting the microbiota and implications in colorectal carcinoma.
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http://dx.doi.org/10.1016/j.dld.2018.03.030DOI Listing
July 2018

The Intestinal Microbiota in Colorectal Cancer.

Cancer Cell 2018 06 12;33(6):954-964. Epub 2018 Apr 12.

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory of Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria.

Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future.
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http://dx.doi.org/10.1016/j.ccell.2018.03.004DOI Listing
June 2018

Paneth Cells and their Antimicrobials in Intestinal Immunity.

Curr Pharm Des 2018 ;24(10):1121-1129

Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Since the initial description of granular-rich small-intestinal crypt-based epithelial cells in 1872, today referred to as Paneth cells, a plethora of recent studies underlined their function in intestinal homeostasis. Paneth cells are evolutionary conserved highly secretory cells that produce antimicrobials to control gut microbial communities. Moreover, Paneth cells emerged as stem cell regulators that translate environmental cues into intestinal epithelial responses. Paneth cell disturbances may instigate intestinal inflammation and provide susceptibility to infection. Altered Paneth cell functions have been associated with a variety of inflammatory disease models and were linked to human intestinal disease processes including inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. This review summarizes our current understanding of Paneth cells and their antimicrobials in health and disease.
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http://dx.doi.org/10.2174/1381612824666180327161947DOI Listing
October 2019

Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease.

Liver Int 2018 06 16;38(6):1095-1101. Epub 2017 Dec 16.

Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Background & Aims: Chronic alcohol consumption and alcoholic liver disease (ALD) afflicts individuals with substantial morbidity and mortality with limited treatment options available. Hepatic inflammation, triggered by activated Kupffer cells, is a driving force in alcoholic liver disease. Interleukin 37 (IL-37) exerts anti-inflammatory effects in hepatic diseases, however, the impact of Interleukin 37 on alcoholic liver disease is unknown. In this study, we addressed the role of Interleukin 37 in alcoholic liver disease.

Methods: We utilized Interleukin 37 expressing transgenic mice and human recombinant Interleukin 37 in models of alcoholic liver disease. Interleukin 37 expression was measured in liver samples of 20 alcoholic steatohepatitis and 36 non-alcoholic fatty liver disease patients.

Results: Interleukin 37 transgenic mice are not protected against hepatic injury and inflammation in alcoholic liver disease. Ethanol suppressed Interleukin 37 expression in transgenic mice. Alcoholic steatohepatitis (ASH) patients similarly exhibited reduced Interleukin 37 expression when compared to non-alcoholic fatty liver disease (NAFLD) patients. Human recombinant Interleukin 37 ameliorated hepatic inflammation in a binge drinking model of alcoholic liver disease.

Conclusion: We provide evidence for an exogenous noxae that suppresses Interleukin 37 expression which limits its anti-inflammatory effects in alcoholic liver disease.
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http://dx.doi.org/10.1111/liv.13642DOI Listing
June 2018

NAD metabolism fuels human and mouse intestinal inflammation.

Gut 2018 10 6;67(10):1813-1823. Epub 2017 Sep 6.

Division of Internal Medicine I, Department of Medicine, Medical University Innsbruck, Innsbruck, Austria.

Objective: Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD . NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism.

Design: We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.

Results: FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1 mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10.

Conclusion: Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.
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http://dx.doi.org/10.1136/gutjnl-2017-314241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145287PMC
October 2018

Adipokines and Non-Alcoholic Fatty Liver Disease: Multiple Interactions.

Int J Mol Sci 2017 Jul 29;18(8). Epub 2017 Jul 29.

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, A-6020 Innsbruck, Austria.

Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD). Whereas adiponectin deficiency might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is associated with a substantial risk for developing hepatocellular carcinoma (HCC) also in the non-cirrhotic stage of disease. Both adiponectin and leptin have been related to liver tumorigenesis especially in preclinical models. This review covers recent advances in our understanding of some adipokines in NAFLD and associated HCC.
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http://dx.doi.org/10.3390/ijms18081649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578039PMC
July 2017

Recovery of ethanol-induced depletion ameliorates alcoholic liver disease.

Gut 2018 05 26;67(5):891-901. Epub 2017 May 26.

Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Objective: Alcoholic liver disease (ALD) is a global health problem with limited therapeutic options. Intestinal barrier integrity and the microbiota modulate susceptibility to ALD. , a Gram-negative intestinal commensal, promotes barrier function partly by enhancing mucus production. The aim of this study was to investigate microbial alterations in ALD and to define the impact of administration on the course of ALD.

Design: The intestinal microbiota was analysed in an unbiased approach by 16S ribosomal DNA (rDNA) sequencing in a Lieber-DeCarli ALD mouse model, and faecal abundance was determined in a cohort of patients with alcoholic steatohepatitis (ASH). The impact of on the development of experimental acute and chronic ALD was determined in a preventive and therapeutic setting, and intestinal barrier integrity was analysed.

Results: Patients with ASH exhibited a decreased abundance of faecal when compared with healthy controls that indirectly correlated with hepatic disease severity. Ethanol feeding of wild-type mice resulted in a prominent decline in abundance. Ethanol-induced intestinal depletion could be restored by oral supplementation. Furthermore, administration when performed in a preventive setting decreased hepatic injury, steatosis and neutrophil infiltration. also protected against ethanol-induced gut leakiness, enhanced mucus thickness and tight-junction expression. In already established ALD, used therapeutically ameliorated hepatic injury and neutrophil infiltration.

Conclusion: Ethanol exposure diminishes intestinal abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from supplementation.
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http://dx.doi.org/10.1136/gutjnl-2016-313432DOI Listing
May 2018

Beyond Digestion: The Pancreas Shapes Intestinal Microbiota and Immunity.

Cell Metab 2017 03;25(3):495-496

Department of Internal Medicine I, Gastroenterology, Hepatology, & Endocrinology, Medical University Innsbruck, Innsbruck 6020, Austria. Electronic address:

Our understanding of the regulatory mechanisms that shape the gut microbiota is rapidly emerging. The intestinal microbial landscape is modulated by a plethora of host-extrinsic and host-intrinsic factors. In this issue of Cell Metabolism, Ahuja and colleagues (2017) demonstrate that mediators secreted by pancreatic acini shape the intestinal microbiota and intestinal immunity.
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http://dx.doi.org/10.1016/j.cmet.2017.02.018DOI Listing
March 2017

Lipocalin-2: A Master Mediator of Intestinal and Metabolic Inflammation.

Trends Endocrinol Metab 2017 05 15;28(5):388-397. Epub 2017 Feb 15.

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology and Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria. Electronic address:

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by various cell types and is an attractive biomarker of inflammation, ischemia, infection, and kidney damage. Both intestinal and metabolic inflammation, as observed in obesity and related disorders, are associated with increased LCN2 synthesis. While LCN2 in the intestinal tract regulates the composition of the gut microbiota and shows anti-inflammatory activities, it also exhibits proinflammatory activities in other experimental settings. In animal models of metabolic inflammation, type 2 diabetes mellitus (T2DM), or nonalcoholic steatohepatitis (NASH), increased LCN2 expression favors inflammation via the recruitment of inflammatory cells, such as neutrophils, and the induction of proinflammatory cytokines. A better understanding of this crucial marker of innate immunity might pave the way for targeting this pathway in future therapies.
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http://dx.doi.org/10.1016/j.tem.2017.01.003DOI Listing
May 2017

Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.

J Exp Med 2017 02 12;214(2):401-422. Epub 2017 Jan 12.

Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK

ATG16L1, a major risk polymorphism in Crohn's disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age-dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1α. IRE1α accumulates in Paneth cells of Atg16l1 mice, and humans homozygous for ATG16L1 exhibit a corresponding increase of IRE1α in intestinal epithelial crypts. In contrast to a protective role of the IRE1β isoform, hyperactivated IRE1α also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1 mice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1α, and optineurin deficiency amplifies IRE1α levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1 mice as predicted from impaired Paneth cell antimicrobial function, such structural alteration of the microbiota does not trigger ileitis but, rather, aggravates dextran sodium sulfate-induced colitis. Hence, we conclude that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1α aggregates during ER stress at this site.
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http://dx.doi.org/10.1084/jem.20160791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294857PMC
February 2017

Weight loss induced by bariatric surgery restores adipose tissue PNPLA3 expression.

Liver Int 2017 02 29;37(2):299-306. Epub 2016 Aug 29.

Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Background & Aims: Obesity and its related co-morbidities such as non-alcoholic fatty liver disease (NAFLD) are increasing dramatically worldwide. The genetic variation in Patatin-like phospholipase domain-containing protein 3 (PNPLA3), which is also called adiponutrin (ADPN), in residue 148 (I148M, rs738409) has been associated with NAFLD. However, the regulation and function of PNPLA3 in metabolic diseases remains unclear. Laparoscopic gastric banding (LAGB) of severely obese patients reduces body weight, liver and adipose tissue inflammation. In this study, we investigated whether weight loss induced by LAGB affected PNPLA3 expression in hepatic and adipose tissue.

Methods: Liver and subcutaneous adipose tissue samples were collected from 28 severely obese patients before and 6 months after LAGB. PNPLA3 expression was assessed by quantitative real-time PCR. To understand whether inflammatory stimuli regulated PNPLA3 expression, we studied the effect of tumour necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) on PNPLA3 expression in human adipocytes and hepatocytes.

Results: PNPLA3 was strongly expressed in the liver and clearly detectable in subcutaneous adipose tissue of obese patients. Weight loss induced by LAGB of severely obese patients led to significantly increased adipose, but not hepatic, tissue expression of PNPLA3. Subcutaneous PNPLA3 expression negatively correlated with body-mass-index, fasting glucose and fasting insulin. TNFα potently suppressed PNPLA3 expression in adipocytes but not hepatocytes.

Conclusions: Weight loss induced by LAGB restored adipose tissue PNPLA3 expression which is suppressed by TNFα. Further studies will be required to determine the functional impact of PNPLA3 and its related genetic variation on adipose tissue inflammation and NAFLD.
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http://dx.doi.org/10.1111/liv.13222DOI Listing
February 2017

Lipocalin 2 Protects from Inflammation and Tumorigenesis Associated with Gut Microbiota Alterations.

Cell Host Microbe 2016 Apr;19(4):455-69

Division of Internal Medicine I (Gastroenterology, Endocrinology and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck 6020, Austria. Electronic address:

High mucosal and fecal concentrations of the antimicrobial siderophore-binding peptide Lipocalin-2 (Lcn2) are observed in inflammatory bowel disease. However, Lcn2 function in chronic intestinal inflammation remains unclear. Here, we demonstrate that Lcn2 protects from early-onset colitis and spontaneous emergence of right-sided colonic tumors resulting from IL-10 deficiency. Exacerbated inflammation in Lcn2(-/-)/Il10(-/-) mice is driven by IL-6, which also controls tumorigenesis. Lcn2(-/-)/Il10(-/-) mice exhibit profound alterations in gut microbial composition, which contributes to inflammation and tumorigenesis, as demonstrated by the transmissibility of the phenotype and protection conferred by antibiotics. Specifically, facultative pathogenic Alistipes spp. utilize enterobactin as iron source, bloom in Lcn2(-/-)/Il10(-/-) mice, and are sufficient to induce colitis and right-sided tumors when transferred into Il10(-/-) mice. Our results demonstrate that Lcn2 protects against intestinal inflammation and tumorigenesis associated with alterations in the microbiota.
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http://dx.doi.org/10.1016/j.chom.2016.03.007DOI Listing
April 2016

Reversal of murine alcoholic steatohepatitis by pepducin-based functional blockade of interleukin-8 receptors.

Gut 2017 05 8;66(5):930-938. Epub 2016 Feb 8.

Christian Doppler Research Laboratory for Gut Inflammation, Medical University Innsbruck, Innsbruck, Austria.

Objective: Alcoholic steatohepatitis is a life-threatening condition with short-term mortality up to 40%. It features hepatic neutrophil infiltration and blood neutrophilia, and may evolve from ethanol-induced breakdown of the enteric barrier and consequent bacteraemia. Signalling through CXCR1/2 G-protein-coupled-receptors (GPCRs), the interleukin (IL)-8 receptors, is critical for the recruitment and activation of neutrophils. We have developed short lipopeptides (pepducins), which inhibit post-ligand GPCR activation precisely targeting individual GPCRs.

Design: Experimental alcoholic liver disease was induced by administering alcohol and a Lieber-DeCarli high-fat diet. CXCR1/2 GPCRs were blocked via pepducins either from onset of the experiment or after disease was fully established. Hepatic inflammatory infiltration, hepatocyte lipid accumulation and overall survival were assessed as primary outcome parameters. Neutrophil activation was assessed by myeloperoxidase activity and liver cell damage by aspartate aminotransferase and alanine aminotransferase plasma levels. Chemotaxis assays were performed to identify chemoattractant signals derived from alcohol-exposed hepatocytes.

Results: Here, we show that experimental alcoholic liver disease is driven by CXCR1/2-dependent activation of neutrophils. CXCR1/2-specific pepducins not only protected mice from liver inflammation, weight loss and mortality associated with experimental alcoholic liver disease, but therapeutic administration cured disease and prevented further mortality in fully established disease. Hepatic neutrophil infiltration and triglyceride accumulation was abrogated by CXCR1/2 blockade. Moreover, CXCL-1 plasma levels were decreased with the pepducin therapy as was the transcription of hepatic IL-1β mRNA.

Conclusions: We propose that high circulating IL-8 in human alcoholic hepatitis may cause pathogenic overzealous neutrophil activation, and therapeutic blockade via pepducins merits clinical study.
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http://dx.doi.org/10.1136/gutjnl-2015-310344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531226PMC
May 2017

Influence of the human intestinal microbiome on obesity and metabolic dysfunction.

Curr Opin Pediatr 2015 Aug;27(4):496-501

Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.

Purpose Of Review: Recent studies have suggested that there may be a strong link between the gut microbiota, energy extraction and body metabolism.

Recent Findings: Evidence is accumulating that the intestinal microbiota, in addition to other major factors such as diet and host genetics, contributes to obesity, metabolic dysfunction and diabetes. Both preclinical experimental and human studies have shown that obesity and metabolic dysfunction are characterized by a profound dysbiosis. Several human metagenome-wide association studies have demonstrated highly significant correlations of certain members of intestinal microbiota with obesity and type 2 diabetes. In addition dietary factors that substantially affect microbial composition, microbiota disruption, and the consequence of early-life antibiotic use, may contribute to childhood obesity and metabolic dysfunction. Further evidence for an association between microbiota and metabolic dysfunction has been derived from studies in pregnancy demonstrating that major gut microbial shifts occur during pregnancy thereby affecting host metabolism. In particular, the high rate of obesity following caesarean section could be partially explained by functional alterations in the intestinal microbiota.

Summary: Obesity and associated metabolic dysfunction emerge from disturbed interactions between the intestinal microbiota, dietary changes and host immune functions. A better understanding of this relationship might lead to better therapies for human metabolic and inflammatory diseases in the future.
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http://dx.doi.org/10.1097/MOP.0000000000000234DOI Listing
August 2015