Small Intestinal Microbiota of Low Body Mass Index (BMI) & Normal BMI Women of Reproductive Age and Microbiota-directed Balanced Energy Protein (MD-BEP) Supplementation in Maternal Environmental Enteric Dysfunction (EED)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 180
- 试验地点
- 2
- 主要终点
- Change of weight in women of reproductive age before and after nutritional intervention
研究概览
简要总结
Undernutrition among women of reproductive age is more common in South Asia than in any other region. In South Asia, the prevalence of maternal undernutrition varies between 10 and 40%. There is a scarcity of data on the contribution of small intestinal (SI) microbiota to pathogenesis of Environmental Enteric Dysfunction (EED) of malnutrition, as it is difficult to obtain gut biopsy specimens from malnourished individuals, especially children. The Bangladesh Environmental Enteric Dysfunction (BEED) study, involving participants who live in an urban slum (Mirpur) in Dhaka, provided an opportunity to examine the role of the duodenal microbiota in the pathogenesis of EED in children and also performed esophagogastroduodenoscopy (EGD) on thirty-eight 18-45-year-old malnourished (BMI<18.5 kg/m2) women residing in the same resource-poor setting of Mirpur, Dhaka who failed to respond to an egg/milk/micronutrients- based nutritional intervention comparable to that given to children. In this intervention component, beginning at the end of the first trimester, low-BMI (<18.5 kg/m2) pregnant women (aged 18-35 years) will be randomly assigned to receive either Microbiota-directed Balanced Energy Protein (MD-BEP) or Ready-to-Use-Supplementary Food Balanced Energy Protein (RUSF-BEP) for the duration of their pregnancy and during the first 3 postnatal months, in addition to standard antenatal care. A parallel cohort of age-matched normal-BMI pregnant women who will not receive any nutritional intervention will serve as a reference control group.
详细描述
Specific Objectives:
AIM 1 - Human studies component Comparative assessment of low BMI & normal BMI small intestinal (SI) and fecal microbiomes plus feature of SI mucosal, plasma and fecal proteomes prior to intervention.
Intervention with MD-BEP to access effect on EED microbiome and physiologic state of low BMI women.
Identify candidate mediators/surrogate biomarkers of EED (fecal/plasma) that can be deployed in future clinical studies.
AIM 1A will compare the SI and fecal microbiota and the plasma, duodenal and fecal proteomes/ metabolomes of non-pregnant, young malnourished Bangladeshi women (BMI<18.5kg/m2) who have histopathologic evidence of SI enteropathy versus those with normal BMIs (20-24.9kg/m2) and no histopathologic evidence of enteropathy who have undergone routine endoscopic evaluation for dyspepsia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
盲法说明
The participants will be randomly assigned either RUSF or MDCF-2 (as dietary supplements). The participants will be made unaware of the supplement they are receiving; however, the field staff and investigators will be made aware of the dietary supplement allocation.
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Inclusion criteria for pregnant low-BMI women
- •Bangladeshi female, age 18-35 years
- •BMI 20-24.9 kg/m2
- •Middle-upper socioeconomic class (≥ $11/day family income)
- •Functional dyspepsia
- •Willing to sign the consent form
- •Willing to provide biological samples during the study period of 6 months
- •Inclusion criteria for non-pregnant low-BMI women
- •Bangladeshi female, age 18-35 years
- •BMI <18.5 kg/m2
- •No antibiotics for 1 month
- •Willing to sign the consent form
- •Willing to undergo endoscopy and biopsy
- •Willing to provide biological samples during the study period of 6 months
- •Willing to receive food supplementation for 3 months
- •Inclusion criteria for normal-BMI non-pregnant women
- •Bangladeshi female, age 18-35 years
- •BMI 20-24.9 kg/m2
- •Middle-upper socioeconomic class (≥ $11/day family income)
- •Functional dyspepsia
- •Willing to sign the consent form
- •Willing to provide biological samples during the study period of 6 months
- •Inclusion criteria for normal-BMI pregnant women
- •Bangladeshi female, age 18-35 years
- •BMI 20-24.9 kg/m2
- •Middle-upper socio-economic class (≥ $11/day family income)
- •Enrolled at the end of first-trimester of pregnancy (before 14 weeks of gestation)
- •Willing to sign the consent form
- •Willing to undergo endoscopy and biopsy
- •Willing to provide biological samples during the study period
- •Willing to let anthropometry and biological sample collection from her newborn for the first 6 months of life
排除标准
- •Exclusion criteria for pregnant low-BMI women
- •Received antibiotics during the last one month
- •Presence of any chronic disease including diabetes mellitus or any congenital disorder or deformity
- •Ongoing episode of diarrhea, history of persistent diarrhea in the past month or history of acute diarrhea in the past 7 days
- •Exclusion criteria for non-pregnant low-BMI women
- •Severe anemia (<8 g/dl), TB and other chronic diseases, including diabetes mellitus, urogenital infections or any congenital disorder or deformity
- •Pregnancy, lactation, drug abuse, known psychiatric disorders
- •High clinical suspicion of cancer or other chronic or acute diseases that may cause malnutrition. Adult participants who fulfill the inclusion criteria and are not excluded through history and clinical examination will undergo following screening tests based on clinical judgement:
- •Chest x-ray
- •Urine for R/E
- •Ultrasonography of whole abdomen
- •Fasting blood glucose/ HbA1c
- •Stool for OBT (occult blood test)
- •Cancer markers (ie. CEA, CA 15.3, CA 19.9)
- •Known allergy to any components of nutrition intervention
- •Nugent Score/Amsel Criteria to exclude bacterial vaginosis: A Nugent score 3-4 is consistent with Bacterial vaginosis (BV). The modified Amsel criteria with a cut-off value of 2 (pH+VD; sensitivity 71%, specificity 90%, accuracy 88% or KOH+VD; sensitivity 75%, specificity 91%, accuracy 89%) might be considered for this purpose
- •Ongoing episode of diarrhea, history of persistent diarrhea in the past month or history of acute diarrhea in the past 7 days
- •Exclusion criteria for non-pregnant normal-BMI women
- •Received antibiotics during the last one month
- •Presence of any chronic disease including diabetes mellitus or any congenital disorder or deformity
- •Ongoing episode of diarrhea, history of persistent diarrhea in the past month or history of acute diarrhea in the past 7 days
- •Exclusion criteria for pregnant normal-BMI women
- •Multiple pregnancy (carrying two or more fetuses)
- •Threatened abortion, persistent pervaginal bleeding, or cervical incompetence
- •History of three or more consecutive abortions
- •History of gestational diabetes, macrosomia, gestational hypertension, preeclampsia/eclampsia in a prior pregnancy
- •Active disease/complications requiring acute phase treatment in a hospital
- •Tuberculosis
- •Severe anemia (Hb concentration < 8 mg/dl)
- •Antibiotic use (ongoing or within last two weeks before the onset of intervention)
- •Taking medications such as insulin, thyroid hormones, glucocorticoids
- •Chronic diseases, such as hypertension, heart disease, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, pancreatic diseases, Crohn's disease, ulcerative colitis, diabetes mellitus, thyroid dysfunction, immunological diseases, malignancy, or any congenital disorder or other diseases which could impede compliance with the study protocol
- •Known case of serious psychiatric or behavioral disorders, such as schizophrenia, bipolar disorder
- •Having known history of allergy to the therapeutic agents
- •Having a plan to move or deliver outside the study area
- •Known allergy to any components of nutrition intervention.
结局指标
主要结局
Change of weight in women of reproductive age before and after nutritional intervention
时间窗: Enrolment to 360 days for non-pregnant cohort, and up to 540 days for pregnant cohort
In this study, nutritional status will be assessed through anthropometry. Body weight will be collected in kg using a standard weighing machine, and determined at the time of enrolment for all groups, days 30, 60, 90, 120, 180, 210, 270, and 360 for non-pregnant cohort; and days 30, 60, 90, 120, 164, 178, 180, 210, 280, 360, 390, 450, and 540 for pregnant cohort.
Validated plasma biomarker (AGP)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. alpha-1-acid glycoprotein (AGP) will serve as a marker for Systemic inflammation and it will be measured by ELISA method.
Hormonal regulators of appetite and satiety (Leptin)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Leptin will serve as a marker for Hormonal regulators of appetite and satiety and it will be measured by ELISA method from plasma.
Height of women of reproductive age before and after nutritional intervention
时间窗: Enrolment to 360 days for non-pregnant cohort, and up to 540 days for pregnant cohort
In this study, nutritional status will be assessed through anthropometry. Height will be collected in centimeters using stadiometer. Anthropometry will be collected at the time of enrolment for all groups, days 30, 60, 90, 120, 180, 210, 270, and 360 for non-pregnant cohort; and days 30, 60, 90, 120, 164, 178, 180, 210, 280, 360, 390, 450, and 540 for pregnant cohort.
Change in body composition of total fat and fat-free mass of women of reproductive age before and after nutritional intervention before and after nutritional intervention
时间窗: Enrolment to 360 days for non-pregnant, up to 540 days for pregnant cohort
Bioelectric Impedance Analysis (BIA) will be used to measure total fat and fat-free mass before, during and after the intervention. BIA is a method of assessing the body composition by measuring the body fat in relation to lean body mass. It is an integral part of a health and nutrition assessment. BIA will be used to measure total fat and fat-free mass before and after intervention with each of the three arms. 60 low-BMI women (18-35 years) provided with MD-BEP/RUSF-BEP intervention, with an age-matched cohort of 30 healthy (normal-BMI) women and subsequent serial fecal and plasma sampling (without nutritional intervention) serving as a control group will be selected for this analysis. Data will be collected on days 1, 180, and 360 days for non-pregnant women and days 0, 180, 360, and 540 days for pregnant women, and the unit of measurement will be the percentage of fat.
Validated plasma biomarker (sCD14)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, , to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Plasma sCD14 will be measured by ELISA method and it serves as a marker for Systemic inflammation
Hormonal regulators of appetite and satiety (Ghrelin)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, , to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Ghrelin will serve as a marker for Hormonal regulators of appetite and it will be measured by ELISA method from Plasma.
Hormonal regulators of appetite and satiety (IGF-1)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort, , to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Insulin-like growth factor 1 (IGF-1) will serve as a marker for Hormonal regulators of appetite and satiety and it will be measured from plasma using ELISA method.
Micronutrients level in plasma (Ferritin)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at baseline (at the time of EGD),enrolment, and days 30, 90 and, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort,, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Ferritin will serve as a marker for micronutrient level in the blood and it will be measured by ELISA method from Plasma.
Change in BMI of women of reproductive age before and after nutritional intervention
时间窗: Enrolment to 360 days for non-pregnant cohort, and up to 540 days for pregnant cohort
In this study, nutritional status will be assessed through anthropometry. Body weight in kilogram and height in cm will be determined at the time of enrolment for all groups, days 30, 60, 90, 120, 180, 210, 270, and 360 for non-pregnant cohort; and days 30, 60, 90, 120, 164, 178, 180, 210, 280, 360, 390, 450, and 540 for pregnant cohort.
Validated plasma biomarker (CRP)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at enrolment and on days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for the offspring cohort to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Plasma c-reactive protein (CRP) will be measured by the ELISA method.
Hormonal regulators of appetite and satiety (Glucagon-like peptide-2 (GLP-2))
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at enrolment, and days 30, 90, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort,, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Glucagon-like peptide-2 (GLP-2)will serve as a marker for Hormonal regulators of appetite and satiety and it will be measured from plasma using ELISA method.
Micronutrients level in plasma (Zinc)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Blood will be collected at baseline (at the time of EGD),enrolment, and days 30, 90 and, 180, 270, 360 for non-pregnant women; days 0, 30, 90, 180, 270, 360, 450, and 540 for pregnant women; and days 30, 180, 270, and 360 for offspring cohort,, to determine changes in the representation of plasma biomarkers of EED as a function of treatment. Zinc will serve as a marker for micronutrient level in the blood and the plasma zinc will be measured by atomic absorption spectrometry method.
Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden, stool pH
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Fecal samples will be collected at the time Of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Stool pH will be measured on freshly collected stool samples by portable stool pH meter from Hanna instruments, USA.
15. Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/ enteropathogenic burden) (Myeloperoxidase)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Myeloperoxidase will be measured from fecal samples using ELISA method.
Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden (neopterin)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Neopterin will be measured from fecal sample using ELISA method
Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden (Oxidation-Reduction Potential (Redox potential))
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Redox potential will be measured in millivolt (mV)
Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden (calprotectin)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Calprotectin will be measured from fecal sample using ELISA method.
Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden (Dual oxidase 2 (DUOX2)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Fecal DUOX2 will be measured by ELISA method.
Validated fecal biomarkers of health status including mediators of growth, systemic inflammation, gut inflammation/enteropathogenic burden Lipocalin 2 (Lcn2)
时间窗: Enrolment to 360 days for non-pregnant and children, up to 540 days for pregnant cohort
Fecal samples will be collected at the time of enrolment, days 30, 60, 90, 120, 180, 210, 270, 360 for non-pregnant women; days 0, 30, 60, 90, 120, 180, 210, 270, 360, 390, 450, and 540 for pregnant women; and days 0, 30, 90, 180, 210, 270, and 360 for offspring cohort, for analysis of the effects of intervention on the microbiota-microbiome. Lipocalin 2 (Lcn2) will be measured by ELISA method using fecal sample.
Pregnancy-related change in weight
时间窗: Enrolment to pregnancy termination and three months post-birth
Pregnant women will be enrolled and followed up over a period of 9 months. Enrolment will be done before 2nd trimester. Low-BMI pregnant women will be provided with daily supplementation of supplemental food (MD-BEP/RUSF-BEP) and normal-BMI women will be followed without any intervention. For the low-BMI pregnant women, antenatal care (ANC) services from nearby healthcare facility will be ensured by study staff. Trained Health Workers (HWs) will visit the homes of all enrolled pregnant women once a month. During the follow up, the investigators will collect anthropometry data from each participant every four-weekly. The unit of data collection for pregnant women is kg. Relevant laboratory investigation that will be done among pregnant women will follow previously described methods.
次要结局
未报告次要终点