Wirksamkeit von Ghrelin bei Darmbarrierefunktionsstörungen im Rahmen cholestatischer Lebererkrankungen

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Introduction: Cholestatic liver disease (CLD) is associated with intestinal barrier dysfunction. The peptide hormone ghrelin may exert both hepatoprotective and barrierstrengthening effects. Here, we have evaluated these effects under the conditions of experimental cholestasis. Methods: C57BL/6J mice with bile duct ligation (BDL) or sham surgery were treated with ghrelin or solvent for 9 days. Liver injury was assessed by histological and laboratory analyses. Paracellular macromolecule permeability and transmural electrical resistance (TMER) of colonic tissues were measured using a Ussing chamber. Expression of tight junction (TJ) genes was quantified by real-time PCR. Amplicon metagenomic sequencing was employed to analyze bacterial 16S rRNA from colonic stool samples. Results: Mice with BDL exhibited weight loss and signs of severe liver injury. These changes were unaffected by ghrelin treatment. FITC-4-kDa-dextran flux was increased and TMER decreased after BDL. Treatment with ghrelin tended to reduce these effects. Furthermore, application of ghrelin was associated with higher mRNA levels of claudin-4, occludin, and ZO-1 in colonic tissues of mice with BDL. Reduced alpha-diversity of the microbiome was observed in solvent-treated mice with BDL but not in ghrelin-treated animals. Conclusion: Ghrelin treatment did not improve weight loss and liver damage but increased gene expression of colonic TJ proteins and restored the alpha-diversity of the microbiome. Since protective effects of ghrelin might be masked by the severity of the model, we suggest follow-up studies in models of milder CLD.

Programme: Forschungsförderung der Medizinischen Fakultät der Rostocker Universität (FORUN)

SEEK ID: https://ldh.mediz-rostock.imise.uni-leipzig.de/projects/6

Public web page: Not specified

Organisms: Mus musculus

NFDI4Health PIs: No PIs for this Project

Project start date: 1st Jan 2021

Project end date: 31st Dec 2021

Extended Metadata (Nfdi4Health MDS 3.3)

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Id of the project(*) : 29329

Resource classification(*)

Type of the resource(*) : Study

Title(s)/name(s) of the Project

Title/name(*) : Präklinische Studien zur Wirksamkeit von Ghrelin bei Störungen der Darmbarrierefunktion im Rahmen einer cholestatischen Lebererkrankung
Language of the title/name(*) : German

Title/name(*) : Preclinical studies on the efficacy of ghrelin in the context of intestinal barrier dysfunction in cholestatic liver disease
Language of the title/name(*) : English

Acronym(s) of the Project

Acronym(*) : Ghrelin
Language of the acronym(*) : German

Acronym(*) : Ghrelin
Language of the acronym(*) : English

Description(s) of the Project

Description(*) : Abflussbehinderungen der Galle (Cholestase) können zu Lebererkrankungen führen, die in eine teilweise lebensbedrohliche Leberzirrhose münden können. Einen wichtigen Teilaspekt der komplexen Pathophysiologie der cholestatischen Lebererkrankungen stellt die Störung der Darmbarrierefunktion dar. Mit dem Peptidhormon Ghrelin steht eine potenziell Barriere-stärkende Substanz mit praktischen Anwendungsperspektiven zur Verfügung. Allerdings ist unbekannt, ob diese Effekte auch unter den Rahmenbedingungen cholestatischer Lebererkrankungen auftreten. Im Rahmen des Projekts sollen an Mäusen mit einer Gallengangligatur Effekte von Ghrelin auf die Darmbarrierefunktion erfasst und mechanistisch untersucht werden. Die Hypothese der Antragstellerin lautet, dass Ghrelin unter den gegebenen Rahmenbedingungen die Darmbarrierefunktion verbessert. Das Untersuchungsprogramm am lebenden Tier umfasst Gewichtsmessungen und Protokollierung des Befindens nach einem etablierten Schema. Nach der Euthanasie der Mäuse erfolgen histologische, elektrophysiologische, proteinanalytische und molekularbiologische Analysen am Darmgewebe zur Charakterisierung der Darmbarrierefunktion; Assays zur Quantifizierung einer bakteriellen Translokation und begleitende Routineuntersuchungen an Blut, Leber und weiteren Geweben der Tiere. Als Kontrollen dienen Tiere ohne Gallengangligatur (Sham-Operation), Mäuse mit Gallengangligatur ohne Ghrelintherapie und Mäuse, die zusätzlich zum Ghrelin einen Rezeptorantagonisten erhalten. Dessen Wirkung wird Aufschluss über die Spezifität der Ghrelineffekte geben. Die Realisierung des Arbeitsprogramms wird zu neuen Einblicken in die molekularen Mechanismen der Ghrelinwirkung am Darm führen. Zugleich werden präklinische Erkenntnisse zur Wirksamkeit bei Barrierefunktionsstörungen im Kontext chronischer Lebererkrankungen erwartet, die in Drittmittel-geförderten Anschlussprojekten vertieft werden sollten.
Language of the description(*) : German

Description(*) : Obstruction of the bile ducts (cholestasis) can lead to liver diseases, which may result in potentially life-threatening liver cirrhosis. An important aspect of the complex pathophysiology of cholestatic liver disease is the dysfunction of the intestinal barrier. The peptide hormone ghrelin is a potentially barrier-strengthening substance with practical application perspectives. However, it is unknown whether these effects also occur under the conditions of cholestatic liver disease. In this project, effects of ghrelin on intestinal barrier function will be assessed and mechanistically investigated in mice with bile duct ligation. The hypothesis of the applicant is that ghrelin improves intestinal barrier function under the given conditions. Investigations in living animals include weight measurements and recording of the condition according to an established scheme. After euthanasia of the mice, histological, electrophysiological, protein analytical and molecular biological analyses of the bowel will be performed in order to characterize intestinal barrier function. Additionally, assays for quantification of bacterial translocation and accompanying routine examinations of blood, liver and other tissues will be conducted. As controls, animals without bile duct ligation (sham), mice with bile duct ligation without ghrelin therapy and mice that receive a receptor antagonist in addition to ghrelin are planned. The effect of the receptor antagonist will provide information on the specificity of the ghrelin effects. The implementation of the described program will lead to new insights into the molecular mechanisms of ghrelin in the gut. Simultaneously, preclinical findings on the efficacy in barrier dysfunction in the context of chronic liver disease are expected, which will be deepened in externally funded follow-up studies.
Language of the description(*) : English

Keyword(s) describing the Project

Keyword(*) : cholestasis

Keyword(*) : Ghrelin

Keyword(*) : Experimental Liver Injury

Keyword(*) : Intestinal Barrier

Keyword(*) : Mouse

Language(s) of the project : English, German

Contributor(s) of the Project

Is it a personal or organisational contribution?(*) : Personal
Details about the contributing organisation(s)/institution(s)/group(s)
Contributor type(*) : Not specified
Funding identifier(s) : Not specified
Name of the organisation/institution/group(*) : Not specified
Details about the contributing person(s)
Contributor type(*) : Creator/Author
Given name(*) : Luise
Family name(s)(*) : Ehlers
Digital identifier(s)
Identifier(*) : 0000-0001-8565-0560
Scheme(*) : ORCID
Email address : Luise.Ehlers@med.uni-rostock.de
Phone number : +49 (0)381 4947349
Organisation(s) associated with the contributor
Name(*) : Rostock University Medical Center
Address : Schillingallee 35, 18057 Rostock
Web page : https://www.med.uni-rostock.de/
Digital identifier(s)
Identifier(*) : 0000 0000 9737 0454
Scheme(*) : ISNI
Identifier(*) : grid.413108.f
Scheme(*) : GRID
Identifier(*) : 04dm1cm79
Scheme(*) : ROR
Name(*) : Rudolf-Zenker-Institut für Experimentelle Chirurgie
Address : Schillingallee 69a, 18057 Rostock
Web page : https://experimentelle-chirurgie.med.uni-rostock.de/
Digital identifier(s)
Identifier(*) : Not specified
Scheme(*) : Not specified

Is it a personal or organisational contribution?(*) : Personal
Details about the contributing organisation(s)/institution(s)/group(s)
Contributor type(*) : Not specified
Funding identifier(s) : Not specified
Name of the organisation/institution/group(*) : Not specified
Details about the contributing person(s)
Contributor type(*) : Principal investigator
Given name(*) : Robert
Family name(s)(*) : Jaster
Digital identifier(s)
Identifier(*) : 0000-0002-8220-4570
Scheme(*) : ORCID
Email address : Not specified
Phone number : +49 (0)381 4947349
Organisation(s) associated with the contributor
Name(*) : Rostock University Medical Center
Address : Schillingallee 35, 18057 Rostock
Web page : https://www.med.uni-rostock.de/
Digital identifier(s)
Identifier(*) : 0000 0000 9737 0454
Scheme(*) : ISNI
Identifier(*) : grid.413108.f
Scheme(*) : GRID
Name(*) : Rudolf-Zenker-Institut für Experimentelle Chirurgie
Address : Schillingallee 69a, 18057 Rostock
Web page : https://experimentelle-chirurgie.med.uni-rostock.de/
Digital identifier(s)
Identifier(*) : Not specified
Scheme(*) : Not specified

Is it a personal or organisational contribution?(*) : Organisational
Details about the contributing organisation(s)/institution(s)/group(s)
Contributor type(*) : Research group
Funding identifier(s) : Not specified
Name of the organisation/institution/group(*) : Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center
Details about the contributing person(s)
Contributor type(*) : Not specified
Given name(*) : Not specified
Family name(s)(*) : Not specified
Digital identifier(s)
[]
Email address : Not specified
Phone number : Not specified
Organisation(s) associated with the contributor
Name(*) : Not specified
Address : Not specified
Web page : Not specified
Digital identifier(s)
Identifier(*) : Not specified
Scheme(*) : Not specified
Identifier(*) : Not specified
Scheme(*) : Not specified
Name(*) : Not specified
Address : Not specified
Web page : Not specified
Digital identifier(s)
Identifier(*) : Not specified
Scheme(*) : Not specified
Identifier(*) : Not specified
Scheme(*) : Not specified

Alternative identifiers

Type of the registry(*) : Other
Identifier(*) : 889005

Characteristics of the Project

Is it an interventional or non-interventional Project? : Interventional
Specification of the type of the Project
Interventional Project type : Unknown, Other
Non-interventional Project type : []
Primary health condition(s) or disease(s) considered in the Project
Primary health condition or disease name(*) : Liver Fibrosis
Terminology/classification(*) : ICD-10
Code of the health condition or disease : K74.0
Groups of diseases or conditions(*)
Which groups of diseases or conditions were the data collected on? : Diseases of the digestive system (XI)
On which diseases or conditions were the data collected? : []
Collects mortality data? : Not specified
Administrative information about the Project
Status of the ethics committee approval : Request for approval submitted, approval granted
Overall Project status : Completed: Recruitment, data collection, and data quality management completed normally
Participants enrolled by invitation? : Not applicable
Start date : 1 January 2021
End date : 31 December 2021
Mono- or multicentric? : Monocentric
Number of centers : Not specified
One or more data providers? : Not specified
Number of data providers : Not specified
Primary subject(*) : Animal
Eligibility criteria for Project participants
Eligibility criteria: Minimum age
Minimum eligible age(*) : 2
Unit of age(*) : Months
Eligibility criteria: Maximum age
Maximum eligible age(*) : 4
Unit of age(*) : Months
Eligible gender : Male, Female
Inclusion criteria : Not specified
Exclusion criteria : Not specified
Population of the Project(*)
Coverage : Regional
Country(ies) : Germany
Region(s) and/or city(ies) : Rostock
Interventions of the Project
Name of the intervention(*) : Ghrelin
Type of the intervention : Drug (including placebo)
Additional information about the intervention : daily injection, 200 µg/kg body weight in NaCl 0.9%, volume 2 µl/g body weight, i.p., LOT: 433573 (Phoenix Pharmaceuticals)
Name(s) of the arm(s) associated with the given intervention : Not specified
Name of the intervention(*) : NaCl 0.9%
Type of the intervention : Drug (including placebo)
Additional information about the intervention : daily injection, volume 2 µl/g body weight, i.p.
Name(s) of the arm(s) associated with the given intervention : Not specified
Exposures of the Project
Name of the exposure : Not specified
Type of the exposure : Not specified
Additional information about the exposure : Not specified
Name(s) of the group(s) associated with the given exposure : Not specified
Outcome measures in the Project
Name of the outcome measure(*) : Transmural Electrical Resistance (TMER) of jejunum
Description of the outcome measure : Resistance [Ohm * cm^2]
Type of the outcome measure : Primary
Time point(s) of assessment : day 10
Name of the outcome measure(*) : body weight
Description of the outcome measure : [g]
Type of the outcome measure : Secondary
Time point(s) of assessment : day 0 - day 10
Name of the outcome measure(*) : histology
Description of the outcome measure : of gut and liver
Type of the outcome measure : Secondary
Time point(s) of assessment : day 10
Additional information about the Project : Not specified
Additional assessments/measurements in the Project : []
Data sharing strategy of the Project(*)
Is it planned to share the data?(*) : Yes, there is a plan to make data available
Supporting documents available in addition to the data : Study protocol, Statistical analysis plan, Manual of operations (SOP)
When and for how long will the data be available? : 10 years
Criteria for data access : reasonable request
Additional information about data sharing : Not specified
DataSHIELD/Opal infrastructure available? : No
Link to data request application : Not specified
Web page with additional information about data sharing : Not specified
Record linkage possible? : Not specified
Non-interventional aspects of the Project
Temporal design : []
Target follow-up duration of the Project
Target follow-up duration(*) : Not specified
Unit of time(*) : Not specified
Number of follow-ups conducted : Not specified
Biosamples retained in a biorepository : []
Specific types of retained biosamples : Not specified
Interventional aspects of the Project
Numerical phase : Not applicable
Masking of intervention(s) assignment
Masking implemented? : Not specified
Who is masked? : []
Additional information about masking : Not specified
Type of allocation of participants to an arm : Randomized
Off-label use of a drug product : Not applicable

Annotated Properties

Topic annotations

Medicines research and development, Animal study, Laboratory animal science, Mouse clinic, Sample collections

Wirksamkeit von Ghrelin bei Darmbarrierefunktionsstörungen im Rahmen cholestatischer Lebererkrankungen

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