The Importance of the Gut Microbiota in Body Weight Control and Insulin Sensitivity

Obesity Clinical Trial

— ANTIBIOTICS  

Official title:

The Effect of the Knock Down of Gut Microbiota by Antibiotics on Parameters of Body Weight Control and Insulin Sensitivity

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02241421
• Other study ID #: 11-3-072
• Status: Completed
• Phase: N/A
• Start date: April 2012
• Est. completion date: November 2014

Study information

• Verified date: September 2020
• Source: Maastricht University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

BACKGROUND: The relation between gut microbiota and obesity originates from animal studies, showing that the change of gut microbiota can induce changes in both insulin resistance and body composition. In addition, these studies have shown changes in gut permeability inducing a pro-inflammatory state, changes in adipose tissue function and inflammation, effects on energy harvesting and metabolism, skeletal muscle fatty acid partitioning and fat oxidation. Human data is lacking, although several studies suggested that the composition of the gut microbiota differs between lean and obese, and between diabetic and non-diabetic individuals.

OBJECTIVE: To provide insight in the physiological significance and underlying mechanisms involved in the relation between gut microbiota, energy balance and insulin sensitivity in overweight men with impaired glucose homeostasis.

Description:

The view on the putative significance of gut microbiota in metabolism emerged from animal studies. Bäcked et al. showed that germ free mice had 40% less body fat compared to conventionally raised mice. Transplantation of a cecum-derived microbial community of conventional mice into germ free mice, resulted in a significant increase of body weight and insulin resistance within 2 weeks. Application of metagenomic techniques in leptin-deficient ob/ob mice showed a different proportion of bacteria belonging when compared to lean, wild-type or heterozygous mice, with a greater representation of Firmicutes and fewer Bacteroidetes. This obese gut microbiome showed an enrichment in genes involved in energy extraction from food, less energy left over in the faeces and higher contents of the short-chain fatty acids (SCFAs) propionate, acetate and butyrate in the cecum.

Furthermore, microbiota composition may alter gut permeability, and may play a role in the development of metabolic endotoxemia (inflammation) and related impairments in glucose metabolism. In addition, the gut microbiota may determine AMP-activated protein kinase (AMPK) levels in muscle and liver, thereby affecting fatty acid oxidation (substrate metabolism) and fat storage. However, underlying mechanisms are not completely understood.

Therefore, researchers within the Top Institute Food and Nutrition (TIFN) have designed a multidisciplinary project ('Microbiota, energy balance and metabolism'), to fill the unmet gap between gut microbiota and human energy metabolism. The current protocol is designed to clarify the role of the gut microbiota in host energy metabolism and insulin sensitivity, with the main focus on underlying mechanisms.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: November 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 35 Years to 70 Years

Eligibility

Inclusion Criteria:

• male

• 35-70 years

• caucasian

• overweight/obese (BMI 25-35 kg/m2)

• insulin resistant (Homeostasis Model of Assessment - Insulin Resistance (HOMA_IR) > 2.2)

• impaired glucose tolerance (IGT: 2h plasma glucose during 75g Oral Glucose Tolerance Test(OGTT) 7.8-11.1 mmol/l) and/or impaired fasting glucose (plasma glucose = 5.6 mmol/l)

• body weight stable for at least three months (±3 kg)

Exclusion Criteria:

• known allergic reaction to vancomycin, teicoplanin, amoxicillin and other ß-lactam antibiotics (penicillins and cefalosporins) or related antibiotics

• diabetes mellitus

• hearing disorders

• cardiovascular disease

• kidney disease

• gastrointestinal disease

• cancer

• asthma or bronchitis

• liver malfunction

• major illness with a life expectancy < 5 years

• diseases affecting glucose tolerance (e.g. pheochromocytoma, Cushing's syndrome, acromegaly), - - use of antibiotics in the past 3 months

• plans to lose weight and participation in organized sports activities for >3 hours per week

• The use of ß-blockers, lipid lowering-drugs, glucose-lowering agents (including all sulfonylureas, biguanides, a-glucosidase inhibitors, thiazolidinediones, repaglinide, nateglinide and insulin), anti-oxidants or chronic corticosteroids treatment (> 7 consecutive days of treatment)

Related Conditions & MeSH terms

• Body Weight
• Insulin Resistance
• Obesity

Intervention

Drug:
• Amoxicillin

• Vancomycin

Other:
• Placebo

Locations

Country	Name	City	State
Netherlands	Maastricht University	Maastricht

Sponsors (2)

Lead Sponsor	Collaborator
Maastricht University Medical Center	Top Institute Food and Nutrition

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Insulin sensitivity	Before and after the intervention, insulin sensitivity will be measured by using the hyperinsulinemic-euglycemic clamp technique including a glucose tracer to accurately quantify glucose fluxes at the whole body level. Glucose and Insulin levels will be determined.	up to two weeks
Secondary	Fatty Acid Handling in the muscle	Because skeletal muscle is responsible for almost 80% of insulin-stimulated glucose disposal, and comprises up to 40% of total body mass, it can be considered to be a major tissue in the etiology of insulin resistance. Therefore, it is important to study the role of skeletal muscle substrate metabolism (fatty acid handling)in the context of this study. Fatty acids, glycerol, triacylglycerol and labelled palmitate in the chylomicron fraction will be measured.	up to two weeks
Secondary	Markers of inflammation	Low-grade inflammation seems to contribute to insulin resistance in obese insulin resistant subjects. Therefore, muscle and adipose tissue expression/secretion of inflammatory molecules (i.e. TNFa, IL-6) will be measured.	up to two weeks
Secondary	Energy expenditure	Indirect calorimetry measurements will be done to determine energy expenditure (O2 and CO2). While the gut microbiota plays an important role in nutrient metabolism and energy extraction from the diet, the determination of energy expenditure and energy content in faeces will provide important insight into the role of the gut microbiota in body weight regulation.	up to two weeks
Secondary	Microbiota composition and energy content in faecal samples	The composition of bacteria in the gut will be determined before and after intervention to link the composition to the primary and other secondary parameters. The energy content in the faeces will provide insight in the energy extraction capacity of the bacteria present.	up to two weeks
Secondary	Gut wall permeability	A proposed hypothesis is that gut permeability plays an important role in the induction of inflammation in obese insulin resistant subjects. A multi-sugar whole gut permeability assay will be performed.	up to two weeks