title: Early Benefits of a Starter Formula Enriched in Prebiotics and Probiotics on the Gut Microbiota of Healthy Infants Born to HIV+ Mothers: A Randomized Double-Blind Controlled Trial.
abstract: The gut microbiota of infants is shaped by both the mode of delivery and the type of feeding. The gut of vaginally and cesarean-delivered infants is colonized at different rates and with different bacterial species, leading to differences in the gut microbial composition, which may persist up to 6 months. In a multicenter, randomized, controlled, double-blind trial conducted in South Africa, we tested the effect of a formula supplemented with a prebiotic (a mixture of bovine milk-derived oligosaccharides [BMOS] generated from whey permeate and containing galactooligosaccharides and milk oligosaccharides such as 3'- and 6'-sialyllactose) and the probioticBifidobacterium animalissubsp.lactis(B. lactis) strain CNCM I-3446 on the bifidobacteria levels in the gut of infants born vaginally or via cesarean section in early life. Additionally, the safety of the new formulation was evaluated. A total of 430 healthy, full-term infants born to HIV-positive mothers who had elected to feed their child beginning from birth (≤3 days old) exclusively with formula were randomized into this multicenter trial of four parallel groups. A total of 421 infants who had any study formula intake were included in the full analysis set (FAS). The first two groups consisted of cesarean-delivered infants assigned to the Test formula (n = 92) (a starter infant formula [IF] containing BMOS at a total oligosaccharide concentration of 5.8 ± 1.0 g/100 g of powder formula [8 g/L in the reconstituted formula] +B. lactis[1 × 107colony-forming units {cfu}/g]) or a Control IF (n = 101); the second two groups consisted of vaginally delivered infants randomized to the same Test (n = 115) or Control (n = 113) formulas from the time of enrollment to 6 months. The primary efficacy outcome was fecal bifidobacteria count at 10 days, and the primary safety outcome was daily weight gain (g/d) between 10 days and 4 months. At 10 days, fecal bifidobacteria counts were significantly higher in the Test formula than in the Control formula group among infants with cesarean birth (median [range] log: 9.41 [6.30-10.94] cfu/g versus 6.30 [6.30-10.51] cfu/g;P= 0.002) but not among those with vaginal birth (median [range] log: 10.06 [5.93-10.77] cfu/g versus 9.85 [6.15-10.79] cfu/g;P= 0.126). The lower bound of the two-sided 95% confidence interval of the difference in the mean daily weight gain between the Test and Control formula groups was more than -3 g/d in both the vaginally and cesarean-delivered infants, indicating that growth in the Test formula-fed infants was not inferior to that of Control formula-fed infants. At 10 days and 4 weeks, the fecal pH of infants fed the Test formula was significantly lower than in those fed the Control formula, irrespective of mode of delivery: for vaginal delivery: 4.93 versus 5.59;P< 0.001 (10 days) and 5.01 versus 5.71;P< 0.001 (4 weeks); for cesarean delivery: 5.14 versus 5.65,P= 0.009 (10 days) and 5.06 versus 5.75,P< 0.001 (4 weeks). At 3 months, this acidification effect only persisted among cesarean-born infants. IF supplemented with the prebiotic BMOS and probioticB. lactisinduced a strong bifidogenic effect in both delivering modes, but more explicitly correcting the low bifidobacteria level found in cesarean-born infants from birth. The supplemented IF lowered the fecal pH and improved the fecal microbiota in both normal and cesarean-delivered infants. The use of bifidobacteria as a probiotic even in infants who are immunologically at risk is safe and well tolerated.
authors.affiliation: University of Witwatersrand & Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa.
authors.forename: Peter
authors.initials: P
authors.lastname: Cooper
authors.affiliation: University of Witwatersrand & Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Bolton
authors.affiliation: University of Witwatersrand & Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.
authors.forename: Sithembiso
authors.initials: S
authors.lastname: Velaphi
authors.affiliation: Nestlé Nutrition, Nestec Ltd, Vevey, Switzerland.
authors.forename: Nanda
authors.initials: N
authors.lastname: de Groot
authors.affiliation: Nestlé Research Center, Lausanne, Switzerland.
authors.forename: Shahram
authors.initials: S
authors.lastname: Emady-Azar
authors.affiliation: Nestlé Nutrition, Nestec Ltd, Vevey, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Pecquet
authors.affiliation: Nestlé Health Science, Vevey, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Steenhout
keywords: B. lactis; Infant formula; bifidogenic; cesarean; gut microbiota; oligosaccharides