Safety and efficacy of a probiotic-containing infant formula supplemented with 2’-fucosyllactose: a double-blind randomized controlled trial

Abstract

Background Human milk oligosaccharides (HMOs) have important and diverse biological functions in early life. This study tested the safety and efficacy of a starter infant formula containing Limosilactobacillus (L.) reuteri DSM 17938 and supplemented with 2’-fucosyllactose (2’FL). Methods Healthy infants < 14 days old (n = 289) were randomly assigned to a bovine milk-based formula containing L. reuteri DSM 17938 at 1 × 107 CFU/g (control group; CG) or the same formula with added 1.0 g/L 2’FL (experimental group; EG) until 6 months of age. A non-randomized breastfed group served as reference (BF; n = 60). The primary endpoint was weight gain through 4 months of age in the formula-fed infants. Secondary endpoints included additional anthropometric measures, gastrointestinal tolerance, stooling characteristics, adverse events (AEs), fecal microbiota and metabolism, and gut immunity and health biomarkers in all feeding groups. Results Weight gain in EG was non-inferior to CG as shown by a mean difference [95% CI] of 0.26 [-1.26, 1.79] g/day with the lower bound of the 95% CI above the non-inferiority margin (-3 g/day). Anthropometric Z-scores, parent-reported stooling characteristics, gastrointestinal symptoms and associated behaviors, and AEs were comparable between formula groups. Redundancy analysis indicated that the microbiota composition in EG was different from CG at age 2 (p = 0.050) and 3 months (p = 0.052), approaching BF. Similarly, between sample phylogenetic distance (weighted UniFrac) for BF vs EG was smaller than for BF vs CG at 3-month age (p = 0.045). At age 1 month, Clostridioides difficile counts were significantly lower in EG than CG. Bifidobacterium relative abundance in EG tracked towards that in BF. Fecal biomarkers and metabolic profile were comparable between CG and EG. Conclusion L. reuteri-containing infant formula with 2’FL supports age-appropriate growth, is well-tolerated and may play a role in shifting the gut microbial pattern towards that of breastfed infants. Trial Registration The trial was registered on ClinicalTrials.gov (NCT03090360) on 24/03/2017.

Functional effects of human milk oligosaccharides (HMOs)

“…A formula including 2′-FL and LNnT showed softer stool consistency in another investigation 118 . Stool consistency in infants fed 2′-FL and FOS-containing formula was found to be comparable to that of breast-fed infants 157 , 158 .…”

“…Infant formula supplemented with 2′FL alone, 2′FL combined with LNnT, and a blend of five HMOs (2′-FL, 3-FL, LNT, 3′-SL, 6′-SL) in formula with intact and hydrolyzed protein have all been shown to be well tolerated in clinical trials 118 , 149 , 150 , 153 , 155–157 . Stool consistency, flatulence, and the frequency of spitting up/vomiting were similar in infants given formula containing with or without HMOs 149 , 157 , 158 . In an RCT testing, a mix of 5 HMOs in infant formula, the stools in the HMO supplemented formula group were more soft, frequent, and yellow.…”

High-Level De Novo Biosynthesis of 2′-Fucosyllactose by Metabolically Engineered Escherichia coli

“…4 The safety evaluation and clinical trials of 2′-FL have widely been studied, and it is suggested that 2′-FLcontaining infant formula is safe and well-tolerant for infants. 5 2′-FL has been approved as Generally Recognized As Safe (GRAS) by American Food and Drug Administration (FDA) and commercially added to infant formula. These confirmed health benefits and promising applications have driven the extensive researches of 2′-FL, particularly in the field of biosynthesis.…”

“…The health benefits of 2′-FL have been thoroughly investigated and confirmed, especially for infants, including prebiotic effect, immune modulators, and maintaining barrier function of gut epithelial cells . The safety evaluation and clinical trials of 2′-FL have widely been studied, and it is suggested that 2′-FL-containing infant formula is safe and well-tolerant for infants . 2′-FL has been approved as Generally Recognized As Safe (GRAS) by American Food and Drug Administration (FDA) and commercially added to infant formula.…”

Limosilactobacillus reuteri FN041 prevents atopic dermatitis in pup mice by remodeling the ileal microbiota and regulating gene expression in Peyer’s patches after vertical transmission

“…This may be due to the better adherence of FN041 (unpublished data). The addition of DSM17938 to neonatal formula promoted growth in children and was well-tolerated ( 48 , 49 ), implying that FN041 could be used in the maternal formula and infant formula during the late trimester and lactation for the prevention of neonatal AD.…”