The purpose of this article is to provide an update on current knowledge regarding development of the infant gut microbiota, with particular focus on infant health and development, in addition to the different factors that influence gut microbiota composition and the developing immune system in early life. 

The role of early life nutrition will also be addressed, by comparing breastfeeding to infant formula feeding and discussing the role of probiotics, prebiotics and fermented dairy ingredients on the infant gastrointestinal (GI) and digestive systems.

Gastrointestinal microbial development from birth

The gut microbiota refers to the collection of microbes including bacteria, viruses, and fungi that reside in the human gut, although to date the majority of research has been conducted on bacteria. The gut microbiota has received significant research attention in recent times, with studies demonstrating the important and often central role of the gut microbiota in host health and disease status. 

The gut microbiota is established following birth, with microbial colonisation of infants occurring in concert with immune system maturation, then converging towards an adult-like microbiota during the first three to five years of life. Development of the gut microbiota has a profound impact on infant health and on health in later life. Gut microbiota composition is influenced by factors such as mode of delivery, gestational age at birth, feeding regime, perinatal antibiotic use and host genetics. 

The microbiota of vaginally born, exclusively breastfed infants at term, with no previous exposure to antibiotics either directly, or indirectly from the mother, could be considered the ‘gold standard’. Immune, endocrine, cognitive, as well as metabolic functions are influenced by the microbial communities present; subsequently impacting future health outcomes.^1,2

Many factors can cause fluctuations in the developing intestinal microbiome and early life disorders such as necrotising enterocolitis, childhood obesity and even autism have been associated with an altered/disturbed gut microbiome. 

The bacterial communities found in the gastrointestinal tract (GIT) during the first days of life originate mainly from the mother and the environment. The acquisition of microbial strains from mother to infant may occur through different pathways, including the birth canal for vaginally delivered infants, contact between mother and infant during parental care and through breast milk. 

In vaginally delivered infants, mode of delivery is the first major determinant of gut microbiota development, where faecal and vaginal bacteria from the mother primarily colonise the infant gut. On the other hand, infants born by Caesarean section are exposed initially to bacteria originating from the skin of the mother, the hospital environment and healthcare workers. 

We recently conducted a comprehensive analysis of the infant gut microbiome ranging from preterm birth to the age of 24 weeks, as part of the INFANTMET project, specifically investigating the effect of gestational age and birth mode on the gut microbiome. We found that vaginally delivered infants had a microbiota composition that was stable over 24 weeks and was dominated by the phylum Actinobacteria which consists predominantly of Bifidobacterium.³

However, the microbiota of infants who were delivered via Caesarean section was initially different to the vaginally delivered infants at week one. During the initial weeks of life, the gut microbiota of Caesarean-delivered infants became progressively more similar to that of vaginally delivered infants, such that by week 24 they had similar microbiota composition. 

We also found clear differences in gut microbiome composition between infants born preterm compared to term over the study period.³ Such differences were most likely a result of a number of factors unique to preterm infants, including feeding type, antibiotic exposure (maternal and infant), increased duration of hospital stay, in addition to gut and immune immaturity. Indeed, with respect to the progression of microbial development in preterm infants, another study found that the acquisition of microbes
correlated with the infant’s post-conceptual age.⁴

Bacilli were dominant in the earliest samples, followed by Gammaproteobacteria and Clostridia at 33-36 weeks postconceptual age.⁴ These results show that in infants born by Caesarean section and in premature infants, the development of the gut microbiota is delayed during the early postnatal period, a critical developmental window for the maturation of the newborn’s immune system, which may put the infant at increased risk for development of inflammatory and metabolic disorders. 

Impact of early life nutrition on gut microbiota

Breastfeeding is one of the most important factors from birth that contributes to significant GI health benefits. It is considered the gold standard in early infant nutrition and helps to protect the infant from respiratory and gastrointestinal infections, supports the growth of healthy gut microbiota, and furthermore facilitates the development of endogenous defences. 

It is well known that the infant feeding regime can have a strong influence on the composition of the intestinal microbiota of neonates⁵; for example, breastfed infants were reported to have reduced levels of Clostridium difficile and Escherichia coli in the faeces one month after birth compared to formula-fed infants.⁶

In the INFANTMET study, we found that prolonged breastfeeding (> four months) had a significant effect on the microbial composition of Caesarean-delivered full-term infants, a change not seen in the vaginally delivered full-term cohort, at 24 weeks of age.³ Thus, breastfeeding may be even more beneficial for Caesarean-delivered infants than those delivered via the vaginal route. 

In addition to the duration of breastfeeding, the introduction of formula feeds can play a significant role in shaping the infant gut microbiome in early life.^7,8,9,10 Selective proliferation of healthy intestinal bacteria is thought to be just one of the multiple benefits of exclusive breastfeeding. Numerous studies investigating the effects of breastfeeding versus formula-feeding have identified specific bifidobacterial species that correlate with feeding regime. This is important as Bifidobacteria can be associated with the production of a number of potentially health-promoting metabolites and numerous health-promoting effects based on their use as probiotics in human intervention studies. 

With respect to gut microbiota development in formula-fed infants, it was reported that bacteroides were dominant in the gut microbial population of six-week-old formula-fed infants¹¹ and it has also been noted that the microbiota of formula-fed infants is, in general, more diverse than that of their breastfed counterparts.¹²

Breastfeeding may also have additional advantages over formula feeding, as it may act as a source of bacteria to help colonise the immature infant gut. A limited number of studies has examined the microbial communities present within breast milk and tracked alterations in microbial diversity throughout the lactation period. 

However, in a recent study, our group reported the presence of a core breast milk microbiome using next-generation Illumina MiSeq sequencing to detect 12 dominant genera in lactating mothers (n = 10), constituting 81% of the taxa present over the first six weeks of life.⁷

A number of frequently shared taxa, including Bifidobacterium, Lactobacillus, Staphylococcus and Enterococcus were common in both breast milk and infant faeces during the first three months of life, and culture-dependent analysis identified identical strains of Bifidobacterium breve and Lactobacillus plantarum present in both breast milk and infant faeces, confirming the concept of maternal-infant transmission.¹⁰ Similar findings have been reported using alternative techniques to identify identical genomic patterns of Bifidobacterium and Lactobacillus present in breast milk and corresponding infant faeces.^13,14,15

Breast milk has been proven, both in vitro and in vivo, to increase bifidobacterial numbers with the proportion among the infant GIT microbiota decreasing with age. This is predominantly as a result of changes in feeding regime when milk is no longer the sole source of food. This, in turn, results in the development of a more diverse bacterial population which is required to metabolise a more varied diet. Human breast milk is a natural source of prebiotics containing the necessary nutrients, growth factors and proteins required for development of the neonatal gut. 

A recent study by Bäckhed¹⁷ demonstrated the influence of the microbiome phosphotransferase system (PTS) genes for carbohydrate uptake in an infant cohort. Genes encoding lactose-specific transporters were found most abundant at four months of age when the infant diet consisted mainly of breast milk. While breast milk oligosaccharides facilitate growth and survival of bifidobacteria in the GIT of breastfed infants, it is the inclusion of prebiotic ingredients, galactooligosaccharides (GOS) and fructooligosaccharides (FOS) that serve as energy sources for bifidobacteria in formula-fed infants. 

These prebiotic ingredients are selectively utilised by the bifidobacteria present in the GIT; thus, enhancing the bifidobacterial microbiota in a similar way to breast-milk oligosaccharides.¹⁶ This will be discussed in more detail below in the prebiotic section.  

Weaning

As the gut microbial community is not yet fully established until an infant reaches two to three years of age, it is important that we recognise the changes occurring in the gut microbiome during the transition from early infant feeding (breast- or bottle-fed) to solid foods. The appropriate age for complementary feeding stated by the WHO¹⁸ is six to 23 months; however this can change in exceptionally difficult circumstances (eg. low birth weight or malnourished infants). 

A recent study investigating the microbial populations in two Danish infant cohorts found a strong association in gut microbial composition with a dietary intake of foods high in protein and fibre, specifically meats, cheeses and Danish rye bread, in both groups.¹⁹ Correlations between macronutrient types and gut microbiota compositions revealed associations between breast milk/early infant feeding and Bifidobacteriaceae, Enterococcaceae, and Lactobacillaceae. Interestingly, Pasteurellaceae abundance was positively correlated with fibre and health-conscious food choices in both groups (high in vegetable fats, fruits or fish but low in sugary drinks, sweets/cakes). Overall, these data suggest that it is the transition from breastfeeding to foods rich in fibre and protein, independent of lifestyle and genetic disposition to obesity, that determines the progression of gut microbial development in early life.¹⁹

The role of prebiotics and probiotics on infant GIS

The current definition of ‘prebiotic’ is: “a substance that is selectively utilised by host microorganisms conferring a health benefit”.²⁰ Inulin-type fructans and FOS can be found readily available in foods such as cereals, chicory, bananas, and other fruits and vegetables, which are recommended for infants when weaning from breast milk or infant formulae. 

As previously discussed, breast milk is the gold standard ‘prebiotic’ food for the growth of beneficial microorganisms in the infant gut. While the prebiotic concept has previously focussed on Bifidobacterium and Lactobacillus, new prebiotic ingredients should be considered to influence the growth of other bacterial genera such as Roseburia, Faecalibacterium, Eubacterium and Bacteroides.²

Prebiotics

Prebiotics reduce pH and when present in infant milk formula, produce a similar short chain fatty acid (SCFA) profile to that of exclusively breast-fed infants.²² SCFAs benefit the host in multiple ways such as maintaining colonocyte health and in turn, improving intestinal barrier function.²³

Indeed, previous studies have reported dominance in Bifidobacterium longum in prebiotic formula-fed infant stool supplemented with GOS/FOS.^24,25 Haarman et al²⁵ found that the bifidobacterial communities prevalent in non-prebiotic standard formula-fed infants resembled a more adult-like microbiota. In addition, another study found that exclusively formula-fed infants were often colonised with E coli, C difficile, Bacteroides fragilis and Lactobacillus spp, which were less apparent in their exclusively breastfed counterparts.²⁶

Probiotics

Probiotics, described as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”,²⁷ have been investigated as potential prophylactics and/or treatments to re-establish gut homeostasis. In addition, the metabolism of indigestible oligosaccharides and plant polysaccharides by beneficial gut microbiota contributes to the production of microbial bioactive molecules (SCFAs). 

It is also known that bacteria such as Bifidobacterium have the ability to produce vitamins that are beneficial in maintaining a healthy diet (eg. folate, B12, B1, and K). Moreover, the enzymatic breakdown of particular complex polysaccharides is attributable to different species of bacteria, particularly those found in the Bacteroides genus.²⁸ For example, the complete genome sequence of Bacteroides thetaiotaomicron ATCC 29148 (isolated from healthy adult faeces) was found to contain a proteome with a large array of enzymes necessary for the digestion of otherwise indigestible dietary polysaccharides,²⁹ including glycosylhydrolases for polysaccharide degradation, as well as amylose, amylopectin and pullulan for the digestion of plant polysaccharides. 

Subsequently, due to the beneficial effects displayed by various microorganisms in the gut, probiotic treatment is being extensively studied in different disease states associated with microbial/metabolic alterations in the gut. Maternal-infant transmission of probiotic microorganisms has also been demonstrated; administration of the probiotic Lactobacillus rhamnosus GG to pregnant women prior to delivery (week 30-36), resulted in its presence in infant faeces six months after birth.³⁰

Fermented foods

Fermentation is a process that has been used for thousands of years, mainly for food preservation purposes. In terms of bacterial fermentation, lactic acid bacteria (LAB) are the main microorganisms used in food fermentations for the production of yoghurt, kimchi³¹ and kefir.³² Indeed, yoghurt, a fermented dairy product, is widely consumed by many infants and toddlers, and is a suitable vehicle for the delivery of probiotics and prebiotic ingredients. 

Many LAB produce a wide range of bioactive metabolites and vitamins during the fermentation process that have been shown to attribute to properties beneficial to health, such as cholesterol lowering, anti-diabetic and immuno-stimulatory health effects.^33-35 Recently, the importance of fermented foods and why they should be included in future food guides for different countries across the globe was reviewed.³⁶ This review, in combination with future research studies, will provide valuable knowledge for the inclusion of such fermented food guides and create an opportunity to refine future regulatory policies. For example, recent case-control studies have investigated the health benefits of fermented cereals – in addition to the consumption of fermented dairy products – for pregnant women to prevent the manifestation of allergy in childhood³⁷ and diabetes in pre-diabetic women.³⁸

 There is some clinical evidence to indicate fermented milk formula have benefits for infant nutrition, resulting in reductions in frequency and severity of gut discomfort,³⁹ infectious diarrhoea,⁴⁰ gut microbiota modulation⁴¹ and supporting adequate growth in early life.⁴² The ESPGHAN Committee on Nutrition recommends further clinical trials to prove the health benefits of fermented milk formula in infant nutrition.⁴³

Meeting the correct nutritional needs  

It is critical during early development that the correct nutritional needs of the infant are met to avoid complications later in life. Breastfeeding is the gold standard feeding regime in early infant nutrition, the true effects of which are still not fully understood. 

While significant advancements have been made in infant formula design – including the incorporation of microbiota-modulating ingredients, such as prebiotics, probiotics and fermented milk ingredients – further research is needed to confirm the health benefits of these in adequately powered, well designed clinical trials. Given that the microbiota has a major role in protection against pathogens, maturation of the immune system and metabolic welfare of the host, it is imperative to understand how early infant nutrition influences the development of a healthy gut microbiota during childhood. 

References

1. Kelly JR, Borre Y, O’ Brien CO, Patterson E, El Aidy S, Deane J, Kennedy PJ, Beers S, Scott K, Moloney G, Hoban AE, Scott L, Fitzgerald P, Ross P, Stanton C, Clarke G, Cryan JF, Dinan TG.Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016; 82: 109-118
2. Li D, Wang P, Wang P, Hu X, Chen F. The gut microbiota: a treasure for human health. Biotechnol Adv. 2016; 34 (7): 1210-1224
3. Hill CJ, Lynch DB, Murphy K, Ulaszewska M, Jeffery IB, O’Shea CA, Watkins C, Dempsey E, Mattivi F, Tuohy K, Ross RP, Ryan CA, O’Toole PW, Stanton C. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort. Microbiome. 2017; 5 (1): 21
4. La Rosa PS, Warner BB, Zhou Y, Weinstock GM, Sodergren E, Hall-Moore CM, Stevens HJ, Bennett WE Jr, Shaikh N, Linneman LA, Hamvas A, Deych E, Shands BA, Shannon WD, Tarr PI. Patterned progression of bacterial populations in the premature infant gut. Proc Natl Acad Sci USA. 2014; 111 (34): 12522-12527
5. Van Best N, Hornef MW, Savelkoul PHM, Penders J. On the origin of the species: Factors shaping the establishment of infant’s gut microbiota. Birth Defects Res C Embryo Today. 2015; 105: 240-251
6. Penders J, Vink C, Driessen C, London N, Thijs C, Stobberingh EE. Quantification of Bifidobacterium spp., Escherichia coli and Clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time PCR. FEMS Microbiol Lett. 2005; 243 (1): 141–147
7. Murphy K, Curley D, O’Callaghan TF, O’Shea CA, Dempsey EM, O’Toole PW, Ross RP, Ryan CA, Stanton C. The composition of human milk and infant faecal microbiota over the first three months of life: a pilot study. Sci Rep. 2017; 7: 40597
8. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014; 505 (7484): 559-563
9. O’Sullivan A, Farver M, Smilowitz JT. The influence of early infant-feeding practices on the intestinal microbiome and body composition in infants. Nutr Metab Insights. 2015; 8 (S1): 1-9
10. Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The infant microbiome development: mom matters. Trends Mol Med. 2015; 21 (2): 109-117
11. Fallani M, Young D, Scott J, et al; Other Members of the INFABIO Team. Intestinal microbiota of 6-week-old infants across Europe: geographic influence beyond delivery mode, breast-feeding, and antibiotics. J Pediatr Gastroenterol Nutr. 2010; 51(1):77-84. doi: 10.1097/MPG.0b013e3181d1b11e
12. Bezirtzoglou E, Tsiotsias A, Welling GW. Microbiota profile in feces of breast- and formula-fed newborns by using fluorescence in situ hybridization (FISH). Anaerobe. 2011 Dec;17(6):478-82. doi: 10.1016/j.anaerobe.2011.03.009
13. Martín R, Langa S, Reviriego C, Jimínez E, Martín ML, Xaus J, Fernández L, Rodríguez JM. Human milk is a source of lactic acid bacteria for the infant gut. J Pediatr. 2003; 143 (6): 754-758
14. Martín R, Jimínez E, Olivares M, Martín ML, Fernández L, Xaus J, Rodríguez JM. Lactobacillus salivarius CECT 5713, a potential probiotic strain isolated from infant feces and breast milk of a mother-child pair. Int J Food Microbiol. 2006; 112 (1): 35-43
15. Makino H, Martin R, Ishikawa E, Gawad A, Kuboto H, Sakai T, Oishi K, Tanaka R, Ben-Amor K, Knol J, Kushiro A. Multilocus sequence typing of bifidobacterial strains from infant’s faeces and human milk: are bifidobacteria being sustainably maintained during breastfeeding? Benef Microbes. 2015; 6(4): 563-572
16. Bakker-Zierikzee AM, Alles MS, Knol J, Kok FJ, Tolboom JJ, Bindels JG. Effects of infant formula containing a mixture of galacto- and fructo-oligosaccharides or viable Bifidobacterium animalis on the intestinal microflora during the first 4 months of life. Br J Nutr. 2005; 94 (5): 783-790
17. Bäckhed F, Roswall, J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, Li Y, Xia Y, Xie H, Zhong H, Khan MT, Zhang J, Li J, Xiao L, Al-Aama J, Zhang D, Lee YS, Kotowska D, Colding C, Tremaroli V, Yin Y, Bergman S, Xu X, Madsen L, Kristiansen K, Dahlgren J, Wang J. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe. 2015; 17 (5): 690-703
18. WHO. Infant and young child feeding. Model chapter for textbooks, for medical students and allied health professionals. World Health Organization. 2009. http://www.wpro.who.int/nutrition_wpr/publications/infantchildfeeding.pdf
19. Laursen MF, Andersen LBB, Michaelsen KF, Mølgaard C, Trolle E, Bahl MI, Licht TR. Infant gut microbiota development is driven by transition to family foods independent of maternal obesity. mSphere. 2016; 1 (1): pii: e00069-15
20. Bäckhed F, Roswall, J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, Li Y, Xia Y, Xie H, Zhong H, Khan MT, Zhang J, Li J, Xiao L, Al-Aama J, Zhang D, Lee YS, Kotowska D, Colding C, Tremaroli V, Yin Y, Bergman S, Xu X, Madsen L, Kristiansen K, Dahlgren J, Wang J. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe. 2015; 17 (5): 690-703
21. Conlon MA, Bird AR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2015; 7 (1): 17-44
22. Fanaro S, Boehm G, Garssen J, Knol J, Mosca F, Stahl B, Vigi V. Galacto-oligosaccharides and long-chain fructo-oligosaccharides as prebiotics in infant formulas: a review. Acta Paediatr Suppl. 2005; 94 (449): 22-26
23. Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de los Reyes-Gavilán CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. 2016; 7: 185
24. Barrett E, Deshpandey AK, Ryan CA, Dempsey EM, Murphy B, O’ Sullivan L, Watkins C, Ross RP, O’ Toole PW, Fitzgerald FG, Stanton C. The neonatal gut harbours distinct bifidobacterial strains.  Arch Dis Child – Fetal and Neonatal Ed. 2015; 100(5): F405-F410
25. Haarman M, Knol J. Quantitative real-time PCR assays to identify and quantify fecal Bifidobacterium species in infants receiving a prebiotic infant formula. Appl Environ Microbiol. 2005; 71 (5): 2318-2324
26. Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, van den Brandt PA, Stobberingh EE. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006; 118 (2): DOI: 10.1542/peds.2005-2824
27. FAO/WHO guidelines on probiotics: 10 years later. J Clin Gastroenterol. 2012; 46: doi: 10.1097/MCG.0b013e318269fdd5
28. Flint HJ, Scott KP, Duncan SH, Louis P, Forano E. Microbial degradation of complex carbohydrates in the gut. Gut Microbes. 2012; 3 (4): 289-306
29. Xu J, Bjursell MK, Himrod J, Deng S, Carmichael LK, Chiang HC, Hooper LV, Gordon GI. A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science. 2003; 299: 2074-2076
30. Schultz M, Göttl C, Young RJ, Iwen P, Vanderhoof JA. Administration of oral probiotic bacteria to pregnant women causes temporary infantile colonization. J Pediatr Gastroenterol Nutr. 2004; 38 (3): 293-297
31. Moon SH, Kim CR, Chang HC. Heterofermentative lactic acid bacteria as a starter culture to control kimchi fermentation. LWT - Food Science and Technology. 2017. doi.org/10.1016/j.lwt.2017.10.009
32. Linares DM, Gómez C, Renes E, et al. Lactic Acid Bacteria and Bifidobacteria with Potential to Design Natural Biofunctional Health-Promoting Dairy Foods. Frontiers in Microbiology. 2017;8:846. doi:10.3389/fmicb.2017.00846
33. Qian B, Xing M, Cui L, Deng Y, Xu Y, Huang M, et al. (2011). Antioxidant, antihypertensive, and immunomodulatory activities of peptide fractions from fermented skim milk with Lactobacillus delbrueckii ssp. bulgaricus LB340. J. Dairy Res. 78 72–79. doi:10.1017/S0022029910000889
34. Sosa-Castañeda J, Hernández-Mendoza A, Astiazarán-García H, Garcia HS, Estrada-Montoya MC, González-Córdova AF, et al. (2015). Screening of Lactobacillus strains for their ability to produce conjugated linoleic acid in milk and to adhere to the intestinal tract. J. Dairy Sci. 98 6651–6659. doi: 10.3168/jds.2014-8515
35. Linares D. M., O’Callaghan T. F., O’Connor P. M., Ross R. P., Stanton C. (2016a). Streptococcus thermophilus APC151 strain is suitable for the manufacture of naturally GABA-enriched bioactive yoghurt. Front. Microbiol. 7:1876
36. Chilton SN, Burton JP, Reid G. Inclusion of Fermented Foods in Food Guides around the World. Nutrients. 2015;7(1):390-404. doi:10.3390/nu7010390
37. West CE, Hammarström ML, Hernell O. Probiotics during weaning reduce the incidence of eczema. Pediatr. Allergy Immunol. 2009;20:430–437. doi: 10.1111/j.1399-3038.2009.00745.x
38. Asemi Z, Samimi M, Tabassi Z, Naghibi Rad M, Rahimi Foroushani A, Khorammian H., Esmaillzadeh A. Effect of daily consumption of probiotic yoghurt on insulin resistance in pregnant women: A randomized controlled trial. Eur. J. Clin. Nutr. 2013;67:71-74. doi: 10.1038/ejcn.2012.189
39. Roy P, Aubert-Jacquin C, Avart C, et al. Benefits of a thickened infant formula with lactase activity in the management of benign digestive disorders in newborns. Arch Pediatr 2004; 11:1546-1554
40. Thibault H, Aubert-Jacquin C, Goulet O. Effects of long-term consumption of a fermented infant formula (with Bifidobacterium breve c50 and Streptococcus thermophilus 065) on acute diarrhea in healthy infants. J Pediatr Gastroenterol Nutr 2004; 39:147-152
41. Mullie C, Yazourh A, Thibault H, et al. Increased poliovirus-specific intestinal antibody response coincides with promotion of Bifidobacterium longum-infantis and Bifidobacterium breve in infants: a randomized, double-blind, placebo-controlled trial. Pediatr Res 2004; 56:791-795
42. Frédéric Huet, Marieke Abrahamse-Berkeveld, Sebastian Tims, Umberto Simeoni, Gérard Beley, Christoph Savagner, Yvan Vandenplas, and Jonathan O’B. Hourihane (2016). Partly Fermented Infant Formulae With Specific Oligosaccharides Support Adequate Infant Growth and Are Well-Tolerated. J Pediatr Gastroenterol Nutr. 63(4): e43–e53. PMCID: PMC5051523
43. Agostoni C, Goulet O, Kolacek S, Koletzko B, Moreno L, Puntis J, Rigo J, Shamir R, Szajewska H, Turck D; ESPGHAN Committee on Nutrition.(2007). Fermented infant formulae without live bacteria. J Pediatr Gastroenterol Nutr.44(3):392-7