Characterization of Human Intestinal Macrophages in Metabolic Disease

Study Overview
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Brief Summary
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This is a prospective, observational study aiming at improving the understanding of the pathophysiology of metabolic disease. As inflammation has been recognized as a key characteristic of metabolic disease but its starting point is still unknown, the investigators' aim is to characterize intestinal macrophages from human gut biopsies taken in diagnostic endoscopies of the gastrointestinal tract or in bariatric surgeries for clinical reasons.

Detailed Description
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Metabolic disease including obesity and diabetes has reached epidemic proportions in the past years. Besides classical risk factors such as unhealthy diet and physical inactivity, smoking and air pollution have also emerged as unexpected risk factors for type 2 Diabetes. Inflammation has been reported as key characteristic of metabolic disease and is predictive of future cardiovascular events. However, the starting point of chronic low-grade inflammation is not known. As the gastrointestinal tract first comes into contact with dietary components, but potentially also air pollution/ smoke particles ingested upon mucociliary clearance from the lung, the gut could be the starting point of inflammation in metabolic disease. The aim of this study is to characterize intestinal macrophages in obese versus lean subjects and smokers versus non-smokers to translate the principal investigator's preclinical findings to human disease and assess whether an inflammatory shift prevails in human intestinal macrophages in metabolic disease. Additionally, to assess whether intestinal macrophage subpopulations can be altered deliberately by nutritional intervention, the investigators will assess intestinal macrophages from subjects scheduled for bariatric surgery that will be on a calorie-restricted diet during the last 2 to 4 weeks prior to surgery. The macrophages originate from human gut samples. As patients will undergo diagnostic endoscopy of the gastrointestinal tract or bariatric surgery for clinical reasons and the standard of care will not be changed by the study, there will be no additional interventions to patients by their participation in the study. Additionally, three EDTA and one serum blood tube for the analysis of inflammatory cells and markers in the blood will be taken as well as a single stool sample. The investigators' goal is to recruit in total 150 patients as it will be a pilot study in a first step.

Official Title
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Characterization of Human Intestinal Macrophages in Metabolic Disease - iMAC (Pilot) Study

Conditions
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Metabolic Disease

Intervention / Treatment
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* Procedure: tissue samples, blood and stool sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient undergoing colonoscopy: Obese (BMI > 32 kg/m2 ) and smoker (≥ 1 pack cigarettes/d) Obese (BMI > 32 kg/m2 ) and non-smoker (control group) Lean (BMI < 27 kg/m2 ) and smoker (≥ 1 pack cigarettes/d) Lean (BMI < 27 kg/m2 ) and non-smoker (control group) Patient undergoing gastroscopy: Obese (BMI > 35 kg/m2 ) and non-smoker planned for bariatric surgery Lean (BMI < 27 kg/m2 ) and non-smoker (control group) Exclusion Criteria: Inability to provide informed consent, e.g. mental impairment or insufficient knowledge of project language Intake of corticosteroids Anti-inflammatory/ immunosuppressive drugs Clinical signs of current infection Known anemia (e.g. hemoglobin < 110 g/L for males, < 100 g/L for females) Known neutropenia (e.g. leukocyte count < 1.5 × 10^9/L or ANC < 0.5 × 10^9/L) Known immunodeficiency, e.g. HIV Known vasculitis, collagenosis Known inflammatory bowel disease Known adrenal insufficiency and/or substitution with glucocorticoids Known clinically significant kidney or liver disease (e.g. creatinine > 1.5 mg/dL, AST/ALT > 2 × ULN, alkaline phosphatase > 2 × ULN, or total bilirubin [tBili] > 1.5 × ULN) Risky daily alcohol consumption (> 24g/d for males, > 12g for females), known liver cirrhosis Child B or C Known uncontrolled congestive heart failure Known uncontrolled malignant disease Currently pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| colonoscopy: obese and smoker<br>10 small tissue samples of the Colon transversum 3 EDTA blood samples and 1 Serum blood sample in some cases 1 single stool sample | Procedure: tissue samples, blood and stool sample<br>* Tissue samples from gastroscopy/colonoscopy.<br>|
| colonoscopy: obese and non-smoker<br>10 small tissue samples of the Colon transversum 3 EDTA blood samples and 1 Serum blood sample in some cases 1 single stool sample | Procedure: tissue samples, blood and stool sample<br>* Tissue samples from gastroscopy/colonoscopy.<br>|
| colonoscopy: lean and smoker<br>10 small tissue samples of the Colon transversum 3 EDTA blood samples and 1 Serum blood sample in some cases 1 single stool sample | Procedure: tissue samples, blood and stool sample<br>* Tissue samples from gastroscopy/colonoscopy.<br>|
| colonoscopy: lean and non-smoker<br>10 small tissue samples of the Colon transversum 3 EDTA blood samples and 1 Serum blood sample in some cases 1 single stool sample | Procedure: tissue samples, blood and stool sample<br>* Tissue samples from gastroscopy/colonoscopy.<br>|
| gastroscopy: obese and non-smoker undergoing bariatric surgery<br>6 small tissue samples of the gastric corpus and 6 of the Duodenum 3 EDTA blood samples and 1 Serum blood sample in some cases 1 single stool sample 1cm long piece of the jejunum, which is usually disposed during bariatric surgery. | Procedure: tissue samples, blood and stool sample<br>* Tissue samples from gastroscopy/colonoscopy.<br>|
| gastroscopy: lean and non-smoker<br>6 small tissue samples of the gastric corpus and 6 of the Duodenum 3 EDTA blood samples and 1 Serum blood sample in some cases 1 single stool sample | Procedure: tissue samples, blood and stool sample<br>* Tissue samples from gastroscopy/colonoscopy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of intestinal macrophages | Quantity (absolute and relative numbers) of intestinal macrophages in biopsies from the gastrointestinal tract in obese versus lean subjects and smokers versus non-smokers measured with flow cytometry. | 2 years | 
| Type and rate of subpopulations of intestinal macrophages | Quality (inflammatory versus non-inflammatory subpopulations) of intestinal macrophages in biopsies from the gastrointestinal tract in obese versus lean subjects and smokers versus non-smokers measured with flow cytometry. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of other intestinal immune cells | In case the investigators do not find clear differences in frequency of intestinal macrophages, they will assess other intestinal immune cells (e.g. B-, T-lymphocytes), and enteroendocrine cells (e.g. L-cells) as a secondary endpoint in an explorative manner. Additionally, the investigators aim to correlate their findings from the biopsy samples with inflammation markers and immune cells in the blood, with microbiota and immune cells in the stool and with the eating habits of the patients. | 2 years | 
| Type and rate of subpopulations of other intestinal immune cells | In case the investigators do not find clear differences in subpopulations of intestinal macrophages, they will assess other intestinal immune cells (e.g. B-, T-lymphocytes), and enteroendocrine cells (e.g. L-cells) as a secondary endpoint in an explorative manner. Additionally, the investigators aim to correlate their findings from the biopsy samples with inflammation markers and immune cells in the blood, with microbiota and immune cells in the stool and with the eating habits of the patients. | 2 years | 
| Gene expression profile of intestinal macrophages | Gene expression of intestinal macrophages in biopsies from the colon in obese versus lean non-smokers by RNA sequencing. | 2 years |