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How does protein intake in infancy influence risk of obesity in later life?

Supervisors: Professor Atul Singhal, Associate Professor Mona Bajaj-Elliott / Professor Joe Standing

Background:

Breast-feeding has been consistently shown to protect against the development of later obesity. The most widely researched hypothesis suggests that higher protein content of infant formula (14g/L) compared to breast milk (10-11g/L) increases the risk of later obesity possibly by endocrine mechanisms that lead to adipose tissue deposition -the ‘low protein’ hypothesis (1). This hypothesis has been confirmed in a large, randomised, controlled trial (RCT) in which infants fed formulas with a higher protein concentration for the first year had greater BMI at age 6 years compared to those receiving a standard protein formula (1). The biological basis for the low protein hypothesis has yet to be elucidated. 

Recent research has begun to focus on the contribution of the gut microbiome to the development of long-term obesity. Studies suggest that differences in the colonisation and maturation of the gut microbiome may partly explain the observed health benefits seen in breast-fed (versus formula-fed), such as reduced risk of obesity (2). These benefits are suggested to be mediated by factors unique to breast milk (e.g., oligosaccharides) but could also be related to the lower protein content of human milk. For instance, feeding a lower protein formula to Rhesus monkey infants, led to a lower risk of obesity and increased abundance of Bifidobacteria, bacteria associated with lower risk of obesity in human infants (3). Formula fed infants also have greater abundance of Clostridia (2), a class of bacteria involved in amino-acid fermentation previously associated with greater obesity risk. Studies also highlight the role of specific amino acids, including tryptophan and proline and their derivatives on gut motility, gut-brain and gut-immune axis (4). 

Previous studies investigating the impact of protein intake in infants on gut microbiota have been small (n<10) and non-randomised. The current proposal, to the best of our knowledge, will be the first randomised study to test the impact of a lower protein formula on the developing infant gut microbiome. These data could help us better understand the protective effects of both breast-feeding and a lower protein intake on the risk of developing obesity later in life and support the use of a lower protein formula in infancy. 

Aims:

To test the hypothesis that consumption of a lower protein formula leads to a gut microbial structure and function similar to breast-fed infants, consequently mitigating the risk of obesity. 

Methods:

The study will be extension of an active RCT in which 84 infants have been randomised to standard protein formula (1.5 g/100 ml) and 84 to low protein formula (1.01 g/100 ml) between 3-12 months of age. There is also a breast-fed reference group of 78 infants. At age 1 year, the low protein formula was shown to be safe and well tolerated. It is planned to continue to follow up these infants to age 4 years (in 2023) which will be the age of the primary analysis. Mothers will be asked to collect a stool specimen from her child using standard techniques.  Longitudinal investigation on gut microbial structure (16S rRNA/metagenomics) and function (metabolomics) and immune axis (faecal cytokines) will be conducted (5). Linear/non-linear modelling will be performed to integrate the various parameters and the risk of obesity.

References:
1.    Koletzko B, et al.  High protein intake in young children and increased weight gain and obesity risk.  Am J Clin Nutr 2016;103 (2):303-4. doi: 10.3945/ajcn.115.128009
2.    He X, et al. The Role of Protein and Free Amino Acids on Intake, Metabolism, and Gut Microbiome: A Comparison Between Breast-Fed and Formula-Fed Rhesus Monkey Infants. Front Pediatr. 2020 Jan 24;7:563. doi: 10.3389/fped.2019.00563. 
3.    Vandenplas Y et al. Factors affecting early-life intestinal microbiota development. Nutrition. 2020 Oct;78:110812. doi: 10.1016/j.nut.2020.110812. 
4.    Wu L, et al. Mutual interaction between gut microbiota and protein/amino acid metabolism for host mucosal immunity and health. Anim Nutr. 2021 Mar;7(1):11-16. doi: 10.1016/j.aninu.2020.11.003. 
5.    Vaitkute G et al.  Linking gastrointestinal microbiota and metabolome dynamics to clinical outcomes in paediatric hematopoietic stem cell transplantation. Microbiome in press.