Pilot of a Prebiotic and Probiotic Trial in Young Infants With Severe Acute Malnutrition

Summary

Malnutrition is an ever-present problem worldwide. It is estimated that over 18 million children under the age of 5 are affected by the most extreme form of undernutrition, severe acute malnutrition (SAM). In spite of having standardized management protocols, in many hospitals, inpatient mortality reaches up to 30%. Infectious morbidity is common among survivors. Diarrhea, severe intestinal inflammation, low concentrations of fecal short-chain fatty acids (SCFAs), and severe systemic inflammation are significantly associated with mortality in SAM. Investigators of this study have earlier shown that the gut microbiota in children with SAM is immature and is causally related to SAM.

Human milk contains between 10 and 20 g/liter of oligosaccharides (human milk oligosaccharides-HMOs) which is the third most abundant solid component after lactose and lipids. HMOs are resistant to gastrointestinal digestion in host infants, and thus the greater part of HMOs reached the colon and may act as prebiotics to shape a healthy gut ecosystem by stimulating the growth of useful microorganisms by acting as receptor analogs to inhibit the binding of various pathogens and toxins to epithelial cells. Probiotics are live organisms beneficial for a healthy life. The human digestive tract possesses a diverse microbial community throughout its extent, which supports their hosts generally for healthy living. Bifidobacterium spp. is dominant microbiota in infants who are exclusively breastfed and these infants are less likely to suffer from diarrhea. According to recent studies among the most common probiotics genera Lactobacillus and Bifidobacterium, the latter is more abundant in the gut. To carry out their functional activities, Bifidobacteria must be able to survive the gastrointestinal tract transit and persist, at least transiently, in the host. The population of Bifidobacteria in the gut community drastically decreases after weaning. Certain Bifidobacteria possess the metabolic capabilities to break down the HMOs. Consequently, it is observed that HMOs support the growth of select Bifidobacteria in the gut of the infant.

Research done at icddr,b and Washington University indicates that gut microbes are related to undernutrition and that children with SAM have gut dysbiosis that mediates some of the pathologies of their condition. The standard of care in these children should be reinforced by an intervention that corrects the gut dysbiosis, improves weight gain during nutritional rehabilitation, and reduces infectious morbidity. Investigators do not have any published data on the microbiome response to probiotic supplementation (with and without prebiotics) in malnourished infants or preserving the microbiome with probiotics in non-malnourished children.

A short-term pilot study should be conducted to evaluate the microbiome response to probiotic supplementation (with and without prebiotics) in malnourished populations to justify a larger study of clinical outcomes. Additionally, non-malnourished infants who are hospitalized for infectious conditions face challenges related to gut dysbiosis caused by antibiotic usage. Here the investigators will evaluate the ability of a probiotic intervention to rescue the microbiome of primarily breastfed non-malnourished infants.

Intervention: Bifidobacterium longum subspecies infantis (EVC001) with and without prebiotic supplementation for 28 days.

Objectives: To evaluate the microbiome response to probiotic supplementation (with and without prebiotics) in infants under 6 months with severe acute malnutrition and to compare the microbiome response with healthy infants with a probiotic.

Methods: Single-blind RCT, stratified randomization will be based on infant age at the time of transfer to the Nutritional Rehabilitation Unit (NRU).

3 treatment arms for infants with SAM

1. Placebo (Lactose)
2. Bifidobacterium infantis alone (Bif)
3. Bifidobacterium infantis + prebiotic Lacto-N-neotetraose \[LNnT\] (Bif+prebiotic) Age at enrollment

1. 2-3.9 months of age
2. 4-5.9 months of age 1 open-label treatment arm for 18 non-malnourished primarily breastfed infants: Bifidobacterium infantis alone (Bif)

Population:

1. Group 1 (SAM): Infants between 2 and \<6 months old with SAM as defined by weight-for-length Z score \< -3 either sex, caregiver willing to provide consent for enrolment of the infant, caregiver willing to stay in the NRU for about 15 days, residence within 15 km from icddr,b
2. Group 2 (non-malnourished): Non-malnourished infants (WLZ ≥ -1) \<6 months old who are hospitalized for treatment with antibiotics for the infection, infants receiving at least 50% of nutritional intake from breast milk at the time of hospitalization, either sex, residence within 15 km from icddr,b

Primary Outcome measures/variables:

Bifidobacterium infantis colonization measured by qPCR during and after supplementation (with and without prebiotics)

Conditions

• Severe Acute Malnutrition

Interventions

OTHER

Bifidobacterium infantis

Bifidobacterium longum subsp. infantis (EVC001)

OTHER

Bifidobacterium infantis with prebiotic Lacto-N-neotetraose [LNnT]

Bifidobacterium infantis with prebiotic Lacto-N-neotetraose \[LNnT\]

OTHER

Placebo (Lactose)

Placebo (Lactose)

Sponsors & Collaborators

• International Centre for Diarrhoeal Disease Research, Bangladesh

  lead OTHER

Principal Investigators

• Tahmeed Ahmed, MBBS, PhD · International Centre for Diarrhoeal Disease Research, Bangladesh

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

2 Months

Max Age

6 Months

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2018-09-21

Primary Completion

2019-08-26

Completion

2020-03-18

Countries

• Bangladesh

Study Locations