Children are what they eat: Shaping their growth & immunity

Gut microbiome trajectory, immunity, and clinical implications

Norbert Sprenger, PhD Nestlé Institute of Health Sciences, Lausanne, Switzerland

Key Messages

• Early life gut microbiome maturation is characterized by a temporal acquisition, colonization, and selection of microbes with different functionalities.
• The timely and age appropriate microbiome maturation represent important windows of opportunity for immune competence development.
• Different nutrition components are important in different phases to drive an age appropriate microbiome maturation.

Abstract:

Developmental milestones are achieved sequentially in specific time windows. Similarly, the early gut microbiome matures sequentially and progressively. This maturation process can be described based on microbial taxa and their key metabolic functions. It is characterized by a specific temporal microorganism acquisition, colonization, and selection with differential functional features. This orchestrated maturation occurs from birth during the first years before the microbiome reaches an adult-like composition and function. Overall, age and nutrition are at the center of microbiome variation. Yet, microbiome disruptors, namely C-section birth and antibiotic use can have profound effects. Both are generally related to a higher risk to develop allergies as well as overweight and obesity. Early life nutrition is an important microbiome modulator and with breastmilk we have an optimal reference at least during the first 6 months of age, while dietary choices during and after the weaning period are to a large extent guided by tradition and culture. Human milk is very rich in oligosaccharides and some of these HMOs drive a Bifidobacterium species dominance during the exclusive breastfeeding period. Increasingly, specific Bifidobacterium species and their HMO boosted metabolites are recognized as important factors for immune competence development.

Following this Bifidobacterium peak, with timely introduction of solid food, the microbiome maturation sees a marked diversification with many immune-active taxa and their metabolites, like butyrate and propionate, increasing in abundance. This diversification with several microbial taxa is repeatedly observed to be important to reduce the risk to become sensitized and develop allergies. Today, an age appropriate gut microbiome maturation is generally acknowledged to be important and observations indicate that an accelerated microbiome maturation during the first months or a delayed maturation after 6 months of age affects long term immune health of a child. The role of individual microbial taxa and their metabolites as well as that of different microbiome relevant nutrient components at different phases during early life are emerging. 

Further reading:

1. Berger, B.; Porta, N.; Foata, F.; Grathwohl, D.; Delley, M.; Moine, D.; Charpagne, A.; Siegwald, L.; Descombes, P.; Alliet, P.; et al. Linking Human Milk Oligosaccharides, Infant Fecal Community Types, and Later Risk To Require Antibiotics. mBio 2020, 11, doi:10.1128/mBio.03196-19.
2. Korpela, K.; de Vos, W.M. Early life colonization of the human gut: microbes matter everywhere. Curr Opin Microbiol 2018, 44, 70-78, doi:10.1016/j.mib.2018.06.003.
3. Roswall, J.; Olsson, L.M.; Kovatcheva-Datchary, P.; Nilsson, S.; Tremaroli, V.; Simon, M.C.; Kiilerich, P.; Akrami, R.; Kramer, M.; Uhlen, M.; et al. Developmental trajectory of the healthy human gut microbiota during the first 5 years of life. Cell Host Microbe 2021, 29, 765-776 e763, doi:10.1016/j.chom.2021.02.021.
4. Stewart, C.J.; Ajami, N.J.; O’Brien, J.L.; Hutchinson, D.S.; Smith, D.P.; Wong, M.C.; Ross, M.C.; Lloyd, R.E.; Doddapaneni, H.; Metcalf, G.A.; et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 2018, 562, 583-588, doi:10.1038/ s41586-018-0617-x.
5. Tsukuda, N.; Yahagi, K.; Hara, T.; Watanabe, Y.; Matsumoto, H.; Mori, H.; Higashi, K.; Tsuji, H.; Matsumoto, S.; Kurokawa, K.; et al. Key bacterial short-chain fatty acid profiles in early life. ISME J 2021, doi:10.1038/s41396-021-00937-7.
6. Galazzo, G.; van Best, N.; Bervoets, L.; Dapaah, I.O.; Savelkoul, P.H.; Hornef, M.W.; consortium, G.-M.; Lau, S.; Hamelmann, E.; Penders, J. Development of the Microbiota and Associations With Birth Mode, Diet, and Atopic Disorders in a Longitudinal Analysis of Stool Samples, Collected From Infancy Through Early Childhood. Gastroenterology 2020, 158, 1584- 1596, doi:10.1053/j.gastro.2020.01.024.
7. Roduit, C.; Frei, R.; Ferstl, R.; Loeliger, S.; Westermann, P.; Rhyner, C.; Schiavi, E.; Barcik, W.; Rodriguez-Perez, N.; Wawrzyniak, M.; et al. High levels of butyrate and propionate in early life are associated with protection against atopy. Allergy 2019, 74, 799-809, doi:10.1111/all.13660.
8. Tun, H.M.; Peng, Y.; Chen, B.; Konya, T.B.; Morales-Lizcano, N.P.; Chari, R.; Field, C.J.; Guttman, D.S.; Becker, A.B.; Mandhane, P.J.; et al. Ethnicity Associations With Food Sensitization Are Mediated by Gut Microbiota Development in the First Year of Life. Gastroenterology 2021, 161, 94-106, doi:10.1053/j.gastro.2021.03.016.

Nutrition support over the first 1000 days: how can nutrition influence the immune system?

Rosan Meyer, RD, PhD Imperial College of London & University of Winchester, London, United Kingdom

Key Messages

• A healthy diet during the first 1000 days for the mother and the young child has been shown to have a positive impact on the immune system
• Optimizing growth and avoiding either under or overnutrition has a positive impact on the immune system
• Healthy eating can also have an anti-inflammatory impact on the child
• There may be certain conditions where probiotics may be beneficial
• Vitamin and mineral supplementation in well-nourished children do not prevent coughs and colds. However healthcare professionals should keep to local guidance for vitamin D, iron, zinc, vitamin A and iodine supplementation.

Abstract: 

The first 1000 days have been shown to be critical in building the foundation for good health for later life. This involves optimal nutritional support for the pregnant mothers to ensure healthy foetal development and a diet that supports both nutritive and non-nutritive composition of breastmilk.^1,2 Nutritional status, in particular growth status plays a role in the immune system. Whilst immune dysfunction and the pathophysiology has been well-established in undernutrition there is only a recent acknowledgement that overnutrition also has a negative impact on the immune system.³ When undernutrition is present, both adaptive and innate immune system is involved in the following way:

Innate immune function³

• Impaired epithelial barrier function
• Lower granulocyte microbicidal act.
• Lower circulating dendritic cells
• Reduced complement proteins

Adaptive immune function³

• reduced levels of soluble IgA
• lymphoid organ atrophy
• fewer circulating B cells
• a shift from Th1-associated to Th2-associated cytokines
• lymphocyte hyporesponsiveness to phytohemagglutinin

When overnutrition occurs, adipose tissue takes on the role of an endocrine organ and secretes cytokines, also known as adipokines.⁴ This promotes chronic low-grade inflammation and whilst less is known on the pathophysiology of the inflammation in overnutrition, it is thought that similar to undernutrition, there is a direct impact on the innate and adaptive immune function. Supporting the microbiome through breastfeeding has also been shown to have a positive impact on the immune system.^5,6 Current guidelines for healthy infants do not recommend routine supplementation with probiotics, however the European Society for Paediatric Gastroenterology, Hepatology and Nutrition have guidelines, including specific strains, on the use of probiotics for acute gastroenteritis and preterm infants.^7,8 In addition, several publications exist on the consideration of probiotics also for functional gastrointestinal disorders.^9,10 Food itself, during the complementary feeding stage and
throughout life, has an impact on the immune system. Data from the LEAP study on early introduction of peanuts, has indicated that this has a significant impact on reduction of peanut allergy.¹¹ Whilst the early introduction of peanut as an allergen should always be seen within the context of local prevalence and advice on complementary feeding, there is good evidence that dietary diversity from 6 months of age, has a positive impact on the microbiome and has been linked to lower levels of food allergies.¹²

Food does not only provide macro and micronutrients, that are supportive of growth and maintaining vitamin and mineral status but has a pro/anti-inflammatory role. Anti-inflammatory diets have now been studied in children and adults with inflammatory bowel disease, irritable bowel disease and allergic disorders.^13,14 Diets that have an anti-inflammatory effect include the Mediterranean and Okinawa diet, which are rich in fruit/vegetables, high in LCPUFA, high in fibre and low in sugar and low with processing ingredients. A healthy diet for young children will therefore have a positive impact on the child’s immune system. In the current climate of the COVID 19 pandemic, the question on vitamin and mineral supplementation on prevention of viral coughs and colds from parents are frequent. A recent systematic review and meta-analysis has found no evidence of vitamin C, A, D zinc in well-nourished children preventing coughs and colds. However, in populations where deficiencies are common and where poor nutritional status is present, healthcare professional will need to consider targeted supplements.

References:

1. Days, Why 1000 Days, 2021, pp. https://thousanddays.org/why-1000-days/.
2. M. de Waard, B. Brands, S.M.P. Kouwenhoven, J.C. Lerma, P. Crespo-Escobar, B. Koletzko, B.M. Zalewski, and J.B. van Goudoever, Optimal of current evidence and recommendations (EarlyNutrition project). Critical reviews in food science and nutrition 57 (2017) 4003-4016.
3. C.D. Bourke, J.A. Berkley, and A.J. Prendergast, Immune Dysfunction as a Cause and Consequence of Malnutrition. Trends Immunol 37 (2016) 386-398.
4. G.R. Umano, C. Pistone, E. Tondina, A. Moiraghi, D. Lauretta, E. Miraglia Del Giudice, and I. Brambilla, Pediatric Obesity and the Immune System. Frontiers in pediatrics 7 (2019) 487.
5. C. Milani, S. Duranti, F. Bottacini, E. Casey, F. Turroni, J. Mahony, C. Belzer, S. Delgado Palacio, S. Arboleya Montes, L. Mancabelli, G.A. Lugli, J.M. Rodriguez, L. Bode, W. de Vos, M. Gueimonde, A. Margolles, D. van Sinderen, and M. Ventura, The First Microbial Colonizers of the Human Gut: Composition, Activities, and Health Implications of the Infant Gut Microbiota. Microbiol Mol Biol Rev 81 (2017).
6. K.M. Hunt, J.A. Foster, L.J. Forney, U.M. Schutte, D.L. Beck, Z. Abdo, L.K. Fox, J.E. Williams, M.K. McGuire, and M.A. McGuire, Characterization of the diversity and temporal stability of bacterial communities in human milk. PLoS One 6 (2011) e21313.
7. H. Szajewska, A. Guarino, I. Hojsak, F. Indrio, S. Kolacek, R. Orel, S. Salvatore, R. Shamir, J.B. van Goudoever, Y. Vandenplas, Z. Weizman, B.M. Zalewski, P. Working Group on, H. Prebiotics of the European Society for Paediatric Gastroenterology, and Nutrition, Use of Probiotics for the Management of Acute Gastroenteritis in Children: An Update. J Pediatr Gastroenterol Nutr 71 (2020) 261-269.
8. C.H.P. van den Akker, J.B. van Goudoever, R. Shamir, M. Domellof, N.D. Embleton, I. Hojsak, A. Lapillonne, W.A. Mihatsch, R. Berni Canani, J. Bronsky, C. Campoy, M.S. Fewtrell, N. Fidler Mis, A. Guarino, J.M. Hulst, F. Indrio, S. Kolacek, R. Orel, Y. Vandenplas, Z. Weizman, and H. Szajewska, Probiotics and Preterm Infants: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric
Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr 70 (2020) 664-680.
9. Y. Vandenplas, B. Hauser, and S. Salvatore, Functional Gastrointestinal Disorders in Infancy: Impact on the Health of the Infant and Family. Pediatr Gastroenterol Hepatol Nutr 22 (2019) 207-216.
10. N. Thapar, M.A. Benninga, M.D. Crowell, C. Di Lorenzo, I. Mack, S. Nurko, M. Saps, R.J. Shulman, H. Szajewska, M.A.L. van Tilburg, and P. Enck, Paediatric functional abdominal pain disorders. Nat Rev Dis Primers 6 (2020) 89.
11. G. DuToit, P.H. Sayre, G. Roberts, M.L. Sever, K. Lawson, H.T. Bahnson, H.A. Brough, A.F. Santos, K.M. Harris, S. Radulovic, M. Basting, V. Turcanu, Peanut Allergy after Early Peanut Consumption. N.Engl.J Med (2016).
12. C. Venter, M. Greenhawt, R.W. Meyer, C. Agostoni, I. Reese, G. du Toit, M. Feeney, K. Maslin, B.I. Nwaru, C. Roduit, E. Untersmayr, B. Vlieg-Boerstra, I. Pali-Scholl, G.C. Roberts, P. Smith, C.A. Akdis, I. Agache, M. Ben-Adallah, Muraro, L.K. Poulsen, H. Renz, M. Sokolowska, C. Stanton, and L. O’Mahony, EAACI position paper on diet diversity in pregnancy, infancy and childhood: Novel concepts and implications for studies in allergy and asthma. Allergy (2019).
13. N.H. Shafiee, Z.A. Manaf, N.M. Mokhtar, and R.A. Raja Ali, Anti-inflammatory diet and inflammatory bowel disease: what clinicians and patients should know? Intest Res 19 (2021) 171-185.
14. M.R. Mascarenhas, Pediatric Anti-Inflammatory Diet. Pediatr Ann 48 (2019) e220-e225