Demonstration of the Prebiotic-like Effects of Camu-camu Consumption Against Obesity-related Disorders in Humans

Study Overview
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Brief Summary
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Previous work of the investigators demonstrated the anti-obesity and anti-steatosis potential of the Amazonian fruit camu-camu (CC) in a mouse model of diet-induced obesity [1]. It was demonstrated that the prebiotic role of CC was directly linked to higher energy expenditure stimulated by the fruit since fecal transplantation from CC-treated mice to germ-free mice was sufficient to reproduce the effects. The full protection against hepatic steatosis observed in CC-treated mice is of particular importance since nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease. Thirty percent of adults in developed countries have excess fat accumulation in the liver, and this figure can be as high as 80% in obese subjects. NAFLD is an umbrella term encompassing simple steatosis, as well as non-alcoholic steatohepatitis which can lead to cirrhosis and hepatocellular carcinoma in up to 20% of cases. Up to now, except for lifestyle changes, no effective drug treatment are available. Previous work has suggested that CC possesses anti-inflammatory properties and could acutely reduce blood pressure and glycemia after a single intake. While CC could represent a promising treatment for obesity and fatty liver, no studies have thoroughly tested this potential in humans. Therefore, a robust clinical proof of concept study is needed to provide convincing evidence for a microbiome-based therapeutic strategy to counteract obesity and its associated metabolic disorders. The mechanism of action of CC could involve bile acid (BA) metabolism. BA are produced in the liver and metabolized in the intestine by the gut microbiota. Conversely, they can modulate gut microbial composition. BA and particularly, primary BA, are powerful regulators of metabolism. Indeed, mice treated orally with the primary BA α, β muricholic (αMCA, βMCA) and cholic acids (CA) were protected from diet-induced obesity and hepatic lipid accumulation. Interestingly, the investigators reported that administration of CC to mice increased the levels of αMCA, βMCA and CA. Primary BA are predominantly secreted conjugated to amino acids and that deconjugation rely on the microbial enzymatic machinery of gut commensals. The increased presence of the deconjugated primary BA in CC-treated mice indicate that a cluster of microbes selected by CC influence the BA pool composition. These data therefore point to an Interplay between BA and gut microbiota mediating the health effects of CC. Polyphenols and in particular procyanidins and ellagitannins in CC can also be responsible for the modulation of BA that can impact on the gut microbiota. Indeed, it has been reported that ellagitannins containing food like walnuts modulate secondary BA in humans whereas procyanidins can interact with farnesoid X receptors and alter BA recirculation to reduce hypertriglyceridemia. These effects are likely mediated by the remodeling of the microbiota by the polyphenols. In accordance with the hypothesis that the ultimate effect of CC is directly linked to a modification of the microbiota, fecal transplantation from CC-treated mice to germ-free mice was sufficient to recapitulate the lower weight gain and the higher energy expenditure seen in donor mice.

Official Title
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Demonstration of the Prebiotic-like Effects of Camu-camu Consumption Against Obesity-related Disorders in Humans

Conditions
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Overweight, Microtia, Endotoxemia, Metabolic Syndrome, Insulin Resistance, Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Dietary Supplement: Camu camu
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI between 25 and 40 kg/m2 Fasting triglyceride > 1,35 mmol/L Understanding of spoken and written french Accept to follow study instructions Exclusion Criteria: Smoking Medication affecting glucose metabolism, blood lipid levels or blood pressure Metabolic disorders requiring treatment Diabetic subjects presenting HbA1c >6.5% or fasting glycemia >7 mmol/L Consumption of fruit or polyphenol supplements in the last 3 months Allergy or intolerance for camu camu or for an ingredient of the placebo Alcohol consumption of > 2 drinks / day Weight change > 5% of body weight in the last 3 months Major surgical operation in the last 3 months or planned in the next months Pregnant or breastfeeding women or women planning pregnancy in the next months Antibiotics intake in the last 3 months Regular probiotics intake in the last 3 months Gastrointestinal malabsorption Cirrhosis Chronic kidney disease Concomitant participation in another clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Camu camu<br> | Dietary Supplement: Camu camu<br>* 3 capsules of camu camu powder (500 mg / capsule) daily during 12 weeks<br>|
| Placebo Comparator: Placebo<br> | Dietary Supplement: Placebo<br>* 3 capsules of placebo daily during 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Gut Microbiota Composition and Diversity | Global variation of the fecal microbiota | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in fat accumulation in the liver | Evaluation of fat accumulation by magnetic resonance imaging (MRI) | Change between the beginning and the end of each treatment (12 weeks each) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Endotoxemia | Plasma Lipopolysaccharides (LPS) and Lipopolysaccharide Binding Protein (LBP) | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in Intestinal permeability | Plasma zonulin | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in Inflammation state of the tissue | Fecal calprotectin and chromogranin | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in Short chain and branched chain fatty acids in the feces | Measure short chain fatty acids in the feces | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in gut health | Evaluation of gastrointestinal symptoms using a standardized questionnaire (the gastrointestinal symptom rating scale (GSRS)) | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in stool consistency | Evaluation of stool consistency using a standardized questionnaire (Bristol stool chart) | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in Glucose homeostasis | Evaluation of plasma glucose using a 3-hour oral glucose tolerance test | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in Glucose homeostasis | Evaluation of insulin concentration using a 3-hour oral glucose tolerance test | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in Glucose homeostasis | Evaluation of c-peptide concentration using a 3-hour oral glucose tolerance test | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in Glucose homeostasis | Evaluation of glycated haemoglobin | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in Lipid profile | Evaluation of plasma triglycerides (TG), Total cholesterol, LDL, HDL, Apolipoprotein B and free fatty acids | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in anthropometric measurements | Evaluation of BMI (measured with weight change and height throughout the protocol) | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in anthropometric measurements | Evaluation of waist circumference | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in body composition | Evaluation of body composition by osteodensitometry | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in chronic inflammation | Evaluation of plasma high sensitive C-Reactive Protein (hs-CRP) | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in liver health | Evaluation of aspartate transaminase and alanine aminotransferase (AST and ALT) | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in gene expression levels | Transcriptomic analyses to investigate underlying mechanisms of action | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in circulating levels of plasma metabolites | Evaluation of camu-camu derived metabolites, short chain fatty acids, branched chain fatty acids, bile acids, phenolic compounds | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in camu camu-derived metabolites present in stool | Evaluation of metabolome: camu-camu derived metabolites, short chain fatty acids, branched chain fatty acids, bile acids, phenolic compounds | Change between the beginning and the end of each treatment (12 weeks each) | 
| Change in blood pressure | Evaluation of systolic and diastolic blood pressure | Change between the beginning and the end of each treatment (12 weeks each) |