Impact of sugars and human milk oligosaccharides on infant microbiome and obesity

Funder: NIDDK
Funding Period: April 2017 for 4 years

Hispanic children are at high risk for obesity, a disparity that is already established by 2 years of age. Our prior work found that high dietary sugars in early-life contributes to this increased risk and that this adverse effect was obliterated in children who were exposed to extended (not exclusive) breastfeeding for >12 months. Thus, sugars and extended breastfeeding exert opposing effects on early obesity-risk, but the mechanisms are unclear. One way that dietary sugars and extended breastfeeding could impact infants’ obesity-risk is by affecting gut microbiome development, which is rapidly evolving during the first 24 months of life. This is a plausible mechanism given that the gut microbiome is implicated in the development of obesity, and that gut microbial changes have been documented in response to dietary sugars and factors in breast milk. One factor in breast milk that may be directly relevant is the mixture of different human milk oligosaccharides (HMOs), which reach the colon intact and serve as prebiotics, shaping the diversity of the gut microbiota. Therefore, the effects of HMOs on microbiome development could be one mechanism by which breastfeeding protects against obesity in infants, a novel concept supported by our preliminary data. Exposure to high dietary sugars in infancy could also impact obesity risk by disrupting cognitive function and appetite regulation, and evidence suggests that these effects might also be mediated by the gut microbiome, and that HMOs, can protect against these impairments, but human studies are lacking. We propose to examine these concepts in a cohort study in 240 Hispanic women and their newborn infants. Participants will be followed from birth to 24 months, with frequent sampling and assessment of breast milk for HMO composition, maternal and infant microbiota, maternal and infant diet, and infant eating behaviors. The primary outcome will be infant body fat by DEXA and secondary outcomes will be infant cognition and appetite regulation, including gut-derived appetite hormones in a sub-set. We have 4 aims: 1) Determine the effects of dietary sugars and HMOs on infant gut microbiome development. 2) Determine whether the effects of dietary sugars and HMOs on body fat changes over the first 24 months of life are mediated by gut microbiome changes. 3) Determine the effects of dietary sugars and HMOs on cognitive outcomes, eating behavior and appetite regulation and whether this is mediated by gut microbiome changes. 4) Determine whether extended breastfeeding offsets the negative effects of dietary sugars via delivery of specific HMOs that contribute to a beneficial microbiome and improved cognition and appetite regulation. This study will move the field forward by identifying how early-life dietary exposures (focusing on dietary sugars, breastfeeding and HMOs) affect gut microbiome development, and how this affects development of obesity, cognition and appetite regulation. Findings are expected to have significant implications for identifying specific HMOs and/or gut microbial changes that will be protective for obesity and inform future novel intervention modalities applicable to Hispanic women and their infants.

Nutrigenetic intervention to reduce liver fat in Hispanics

Funder: NIMHD (RO1)
Funding Period: March 2016 for 4 years

The prevalence of pediatric non-alcoholic fatty liver disease (NAFLD) has doubled in the last 20 years and affects obese Hispanics most severely. We have found that 40% of obese Hispanic children and adolescents have a liver fat fraction above 5.5%, a clinical criteria for NAFLD diagnosis Over time, NAFLD can lead to cirrhosis, liver disease and eventually liver cancer. This increased susceptibility to high liver fat in Hispanics is due in part to a genetic predisposition based on the 50% frequency in this population of a C>G (Ile148Met) polymorphism in the PNPLA3 gene. Our prior studies, as well as recent studies in animal models, provide compelling evidence that the impact of the PNPLA3 variant on liver fat is exacerbated by high dietary sugar. Current approaches to reducing liver fat however are limited to general advice on weight loss and healthy eating but do not directly address the mechanism of excess fat accumulation in the liver, especially as it relates to this genetic predisposition in Hispanics. Therefore, the overall objective of this proposal is to develop innovative strategies, with potential for long-term sustainability, for addressing elevated liver fat in obese Hispanic children and adolescents based on genetic predisposition. We propose a randomized nutrigenetic clinical trial of dietary sugar reduction in children with clinically diagnosed NAFLD, to examine whether there are differential treatment responses based on PNPLA3 genotype. We will recruit 180 overweight and obese Hispanic children (12 – 18 years) with clinically verified NAFLD and randomize them to one of two 16-week interventions: 1) standard of care for healthy eating (control/placebo group); and 2) reduction of dietary sugars to 10% of total calories (treatment group). The following will be measured before and after intervention: total liver fat, liver fibrosis, visceral and subcutaneous abdominal adipose tissue volume by magnetic resonance imaging methods at 3T; total body fat by DEXA; plasma liver enzymes, fasting insulin, glucose, lipids, free fatty acids, and inflammatory markers, and insulin and glucose response to an oral glucose challenge. The hypotheses are: a) liver fat content and metabolic outcomes, such as lipids and inflammatory biomarkers, will show significantly greater improvements with sugar reduction relative to control; and b) a treatment*genotype interaction whereby the reduction in liver fat will be significantly greater in GG relative to CC/CG subjects. These results will provide efficacy data for a novel treatment strategy to reduce liver fat in obese Hispanic children and adolescents with NAFLD. Furthermore, this study has the potential to impact personalized dietary recommendations for treatment and prevention of NAFLD in Hispanics, as a function of genetic predisposition.

Home intervention for reducing sugary drinks and obesity in Hispanic women and infants

Funder: NIDDK
Funding Period: September 2016 for 5 years

Consumption of sugar sweetened beverages and juices (SSB/J) in infancy is associated with obesity in early childhood. This is a significant public health issue requiring family based solutions. Yet interventions aimed at SSB/J reduction remain controversial based on limited effects in prior studies and concerns whether targeting a single factor will have an impact on the multi-factorial problem of obesity. However, while a prior trial in obese teenagers showed no effect of SSB/J reduction in Caucasians, there was a large significant effect in Hispanics. Furthermore, no study has examined the effects of SSB/J reduction during infancy when consumption begins and adipose tissue is rapidly developing. We therefore propose a trial aimed at reducing SSB/J consumption in low-income, Hispanic post-partum mothers and infants, a segment of the population at high risk for obesity. Although maternal-infant interventions are needed, they present many challenges including compliance and retention. We propose an innovative solution that merges components of effective interventions for SSB/J reduction and maternal-infant nutrition, into an existing home visit program (HVP), which are federally supported nationwide for promoting child development in high-risk populations. The 24-month intervention will focus on replacing mothers’ intake of SSB/J with water, and delaying introduction and limiting access to SSB/J in infants using home visits, telephone calls and in one group, home delivery of water/non-caloric beverages. Hispanic mothers who were overweight/obese prior to pregnancy (n=240) will be randomized with their newborn infants to one of three groups. Group 1 (efficacy) will receive a modified HVP incorporating a focus on SSB/J reduction plus home delivery. Group 2 (translation) will be identical to Group 1 without home delivery. Group 3 (control) will receive standard of care HVP. The main outcome will be body fat by DEXA in mothers and infants. Aim 1 tests whether the intervention will reduce obesity and metabolic risk in post-partum mothers. Aim 2 tests whether the intervention reduces the trajectory for body fat and weight-for-length in infants. We will also examine if these effects are maintained without home delivery, thus supporting scalability of the intervention approach. Aim 3 tests whether the effects on infants are mediated via maternal transmission related to changes in maternal sweet taste preference, use of SSB/J to sooth infants, use of sugary foods during weaning, and the profile of sugars in breast milk.

Human milk oligosaccharides, gut microbiome and obesity in infants

Funder: Gerber Foundation Grant
Funding PeriodL January 2016 for 3 years

This study aims to identify novel factors in human breast milk that affect development of the infant gut bacterial profile (the microbiome), and in turn contribute to infant growth and/or accumulation of excess body fat by 24 months of age. By comparing infants of mothers who were overweight/obese versus normal weight before pregnancy, we will also gain important insights into infant growth and development for infants at higher-risk versus lower-risk of developing obesity in early-life. Our main outcomes are significant because rapid infant growth and excess body fat by 24 months of age are well-established risk factors for future obesity and metabolic complications like type 2 diabetes. We will focus on human milk oligosaccharides (HMOs), complex sugars that are present in high and variable amounts in breast milk and are known to significantly contribute to establishing the infant immune system. Since HMOs cannot be digested and reach the colon intact, another less well studied effect of HMOs is that they can also act as prebiotics, promoting the growth of beneficial microorganisms in the intestine, potentially contributing to development of the infant gut microbiome. The gut microbiome is now known to play an important role in establishing long-term predisposition to a wide variety of diseased states, including obesity. We hypothesize that individual differences in HMOs in breast milk contribute to differences in infant growth rates and/or the development of early-onset obesity through their effects on the developing infant gut microbiome. We have established preliminary evidence in support of this novel theory in a small pilot study that followed infants to 6 months of age. In this new study, we will extend our initial observation to a larger sample of 80 mothers and infants, measure infant body fat out to 24 months of age, and examine whether the effect of HMOs on infant obesity is explained by their effect on the developing infant gut microbiota. In addition, we will examine whether differences in HMOs and/or the developing infant gut microbiota can explain the greater propensity for early onset obesity in infants born to mothers who were overweight/obese before pregnancy, as compared to infants on healthy weight mothers.

We will recruit 80 mother-infant pairs, with an even split of women who were overweight/obese versus normal weight before pregnancy. Mothers and infants will be monitored during the first 24 months of life, with frequent sampling of breast milk as well as infant and maternal stool. Maternal and infant dietary intake will also be determined using 24-hour recalls in mothers and validated maternal questionnaires for infant intake. The main outcome measures will be infant body weight-for-length trajectory during this period, as well as infant body composition (fat and lean mass), measured by dual energy x-ray absorptiometry (DEXA). To achieve our goal of integrating complex metabolic, physiological and nutritional outcomes using the most advanced technology possible, we have assembled a diverse multi-disciplinary research team of internationally recognized leaders in the field. This team has established a unique collaborative working group that provides expertise in infant and child obesity/nutrition and human clinical studies (Michael Goran, USC), human milk oligosaccharides (Lars Bode, UCSD), gut microbiome (Rob Knight, UCSD), and breast milk composition/infant body composition (David Fields, OUHSC).