Clinical trial NCT03322449: APOA2 Gene, Diet, Inflammation and Gut Health
Official title: APOA2 Gene, Diet, Inflammation and Gut Health
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Inflammation
Keywords: APOA2
Inflammation
gene
diet
Lead sponsor: Tufts University
Sponsor class: OTHER
First posted: 2017-10-26
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: randomized crossover dietary intervention
Primary purpose: PREVENTION

Brief summary: Nutrients and chemicals in food are able to regulate expression of genetic elements. Gene-nutrient interaction in response to unhealthy diets can increase an individual's risk, shifting the individual from health toward the development of chronic disease. The apolipoprotein A2 (APOA2) gene may either put individuals at risk for or protect from obesity in the presence of certain fats in food. The main purpose of this four-week study is to examine diet induced gene-nutrient interaction, with a focus on gut health, gut microbiota and inflammation in individuals who have either the CC or the TT form within a specific variant of the APOA2 Gene. The (2) one-week study diets, one plant based and the other animal based are separated by a (1) week return to your regular habitual without probiotic or prebiotic food products.

Detailed description: The primary objectives of this application are 1. To use a diet intervention setting to rigorously evaluate the mechanisms responsible for the previously observed effects, focusing on gut microbiota and markers of gut health and inflammation and 2. To prove that targeted dietary intervention based on genes can provide additional, tailored benefit to genetically vulnerable individuals. The overall hypothesis proposes that significant cross-talk between the human host genome, the microbiome, and the diet, defines the observed inter-individual variation in metabolic and physiological responses. Accordingly, the investigators propose the following specific aims and hypotheses.

AIM 1: To catalog the response of the plasma metabolome to diets differing in saturated fat and prebiotics content (animal-based diet versus plant-based diet) in individuals from the USA carrying CC (n=20) and TT (n=20) genotypes at the common APOA2 -265T\>C SNP using a crossover, randomized dietary intervention study.

Our primary hypothesis states: A significant and biologically relevant proportion of the individual variation in changes in the plasma metabolome in response to dietary saturated fat and prebiotic intake will be due to APOA2-265T\>C genotypes. Specifically, subjects homozygous (CC) for the less common C allele will respond to decreases in total dietary saturated fat and increases in prebiotics (i.e., plant-based diet) with significantly greater improvement of metabolites related to gut health, inflammation and other cardiometabolic traits than subjects homozygous (TT) for the common T allele.

AIM 2: To characterize differential impacts of low SFA/high prebiotic (plant-based) diet vs. high SFA/low prebiotic (animal-based) diets on gut microbiota patterns between CC and TT persons at APOA2-265T\>C.

Our primary hypothesis states: CC subjects have a preference for high-fat and -protein foods and therefore high levels of Bacteroidetes, Actinobacteria and similar species in the gut are expected. Moreover, reducing intake of saturated fat and increasing prebiotics will be more effective in inducing a healthier gut microflora profile in CC subjects than in those with the TT genotype, with opposite effects observed when the diet is switched to one high in saturated fat.

AIM 3: To integrate the metabolomic and gut microflora taxonomic information generated in AIM1 and AIM2 in order to elucidate the physiological mechanism(s) by which diet impinges on metabolic pathways through APOA2 genotypes.

Our primary hypothesis states: A diet low in saturated fat and high in prebiotics induces beneficial changes in gut microbiota, metabolic processes and inflammation, which are significantly more pronounced in CC than in TT subjects.

Eligibility criteria: Inclusion Criteria:

* Men and women
* 18 years or older
* Women who are not pregnant
* A BMI ranging between 27 and 34

Exclusion Criteria:

* Unexplained elevation in serum transaminases (i.e. \>1.5 times the upper limit of normal) or with evidence of active liver disease, including primary biliary cirrhosis or pre-existing gallbladder disease
* Severe renal dysfunction (serum creatinine \>2.0mg/dL)
* Excessive alcohol consumption (\>2 drinks/day)
* Preexisting cardiovascular disease (CVD)
* Stable exertional angina pectoris requiring sublingual nitroglycerin within the prior 3 months
* Uncontrolled tyoe 2 diabetes (T2D) (fasting glucose \>126 mg/dl) or other significant endocrine disease.
* Uncontrolled hypertension (systolic blood pressure \>180 mmHg or diastolic blood pressure \>100 mmHg).
* History of pancreatitis within 1 yr. prior to screening.
* Subjects on lipid lowering or diabetes medications.
* Smoking
* Pregnancy
* Body mass index (BMI) below 27 or greater than 34 kg/m2
* Participants will also be excluded for drug abuse, extreme dietary habits, multiple food allergies, extreme levels of physical or athletic activity, or by changes in body weight \>20 lbs. during the last 6 months
* Current use of antibiotics or during the previous 4 weeks.
* Inability to follow any of the experimental diets (including being vegetarian) or to perform the sampling required for this study
* Use of herbal supplements that may alter the gut microflora
* Autoimmune diseases
* Recent colonoscopy (within the previous two months)
* Use of antidiarrheal medication
* Thyroid diseases
* Use of omega-3 supplements (unless it is discontinued one month prior to the beginning of the study).

Primary outcomes:
measure: tryptophan metabolism
timeFrame: 1 week per intervention arm
Secondary outcomes:
measure: Satiety assessment using plasma levels of leptin
timeFrame: 1 week per intervention arm
measure: adipose tissue metabolism
timeFrame: 1 week per intervention arm
measure: Plasma Lipoproteins
timeFrame: 1 week per intervention arm
measure: Gut microbiota diversity and composition
timeFrame: 1 week per intervention arm
measure: Plasma levels of Interleukin 6 to assess inflammatory status
timeFrame: 1 week per intervention arm
measure: Plasma levels of tumor necrosis factor alpha to assess regulation of immune cells
timeFrame: 1 week per intervention arm
measure: Plasma levels of C-reactive to assess regulation of inflammation
timeFrame: 1 week per intervention arm
measure: Plasma levels of Lipopolysaccharides to assess gut inflammation
timeFrame: 1 week per intervention arm
Other outcomes:
Locations:
city: Boston
country: United States
facility: Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University
state: Massachusetts
Study officials:
affiliation: JM-USDA HNRCA at Tufts University
name: Jose M Ordovas, PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Corella D, Arnett DK, Tsai MY, Kabagambe EK, Peacock JM, Hixson JE, Straka RJ, Province M, Lai CQ, Parnell LD, Borecki I, Ordovas JM. The -256T>C polymorphism in the apolipoprotein A-II gene promoter is associated with body mass index and food intake in the genetics of lipid lowering drugs and diet network study. Clin Chem. 2007 Jun;53(6):1144-52. doi: 10.1373/clinchem.2006.084863. Epub 2007 Apr 19.
citation: Corella D, Peloso G, Arnett DK, Demissie S, Cupples LA, Tucker K, Lai CQ, Parnell LD, Coltell O, Lee YC, Ordovas JM. APOA2, dietary fat, and body mass index: replication of a gene-diet interaction in 3 independent populations. Arch Intern Med. 2009 Nov 9;169(20):1897-906. doi: 10.1001/archinternmed.2009.343.
citation: Smith CE, Tucker KL, Arnett DK, Noel SE, Corella D, Borecki IB, Feitosa MF, Aslibekyan S, Parnell LD, Lai CQ, Lee YC, Ordovas JM. Apolipoprotein A2 polymorphism interacts with intakes of dairy foods to influence body weight in 2 U.S. populations. J Nutr. 2013 Dec;143(12):1865-71. doi: 10.3945/jn.113.179051. Epub 2013 Oct 9.