Clinical Evaluation of 16-Week Supplementation with 5HMO-Mix in Healthy-Term Human Infants to Determine Tolerability, Safety, and Effect on Growth

Abstract

Human milk oligosaccharides (HMOs) are complex sugars that occur naturally in human breast milk and provide many beneficial functions. Most formula products lack HMOs or contain only the most abundant HMO, 2′-fucosyllactose; however, benefits of HMOs come from multiple sugars. We therefore developed a mixture of five HMOs (5HMO-Mix) mimicking the natural concentrations of the top five HMOs (5.75 g/L total, comprising 52% 2′-fucosyllactose, 13% 3-fucosyllactose, 26% lacto-N-tetraose, 4% 3′-sialyllactose, and 5% 6′-sialyllactose) representing the groups of neutral, neutral-fucosylated, and sialylated HMOs. We conducted the first multicenter, randomized, controlled, parallel-group clinical study assessing the safety, tolerability, and effect on growth of formula containing the 5HMO-Mix in healthy infants. We enrolled 341 subjects aged ≤14 days; 225 were randomized into groups fed either with infant formula containing 5HMO-Mix (5HMO-Mix) or infant formula without HMOs (IF) for 4 months, with the others exclusively breastfed. There were no differences in weight, length, or head circumference gain between the two formula groups. The 5HMO-Mix was well tolerated, with 5HMO-Mix and breastfed infants producing softer stools at a higher stool frequency than the control formula group. Adverse events were equivalent in all groups. We conclude that the 5HMO-Mix at 5.75 g/L in infant formula is safe and well tolerated by healthy term infants during the first months of life.

Studies and Application of Sialylated Milk Components on Regulating Neonatal Gut Microbiota and Health

“…Sialylated HMOs are mainly composed of 3′-sialyllactose (3′-SL), 6′-sialyllactose (6′-SL), LS-tetra-saccharide a (LSTa), LS-tetra-saccharide b (LSTb), LS-tera-saccharide c (LSTc), and disialyllacto-N-tetraose (DSLNT) ( 17 , 18 ) ( Figure 2A ), and the concentration of them is about 1,000–3,300 mg/L in the colostrum and droped to about 135–2,150 mg/L in the matured human milk ( Table 1 ). Among all sialylated HMOs, the content of sialyllactose (SL) is the highest, with an estimated concentration of 170–500 μg/mL for 6′-SL in mature breast milk ( 6 , 22 – 24 ). SL play important roles in neonatal gut maturation, prevention of pathogen invasion, immune regulation, and prebiotic function ( 33 ).…”

Multifunctional Benefits of Prevalent HMOs: Implications for Infant Health

“…The core set of HMOs proposed in Figure 1, composed of 2 -FL, 3-FL, 3 -SL, 6 -SL, and LNT, would encompass a majority of the benefits described above and come closer than ever before to delivering a wide portion of the protection associated with breastfeeding. Indeed, this set of HMOs has been demonstrated to be safe and well tolerated in a recent multicenter clinical trial conducted in healthy full term infants up to four months of age [16].…”

“…Only very recently have advances in the large-scale production of HMOs made fortification of infant formula feasible [11,12]. There exists a growing body of scientific literature on the safety and benefits of HMO fortification [13][14][15][16], notably 2 -fucosyllactose (2 -FL) [17][18][19][20][21], the first HMO to be widely added to commercial infant formula, which is now available from several manufacturers. Researchers have identified as many as 150 unique HMOs occurring naturally in human milk at widely varying concentrations and prevalence [22,23].…”

Untangling human milk oligosaccharides and infant gut microbiome

“…Administration of these HMOs also shifted the developing gut microbiome toward a composition more similar to breastfed infants, and decreased medication use was reported compared to non-supplemented formula fed infants ( Berger et al., 2020 ). Very recently, a European trial involving multiple centers across different countries, reported the outcome of supplementation of 5 HMOs - 2′FL, 3FL, LNT, 3′-sialyllactose (3′SL), and 6′SL ( Parschat et al., 2021 ). Overall, the 5-HMOs blend was well-tolerated by term infants enrolled and no difference in growth rates were observed when compared to non-supplemented formula ( Parschat et al., 2021 ).…”

“…Very recently, a European trial involving multiple centers across different countries, reported the outcome of supplementation of 5 HMOs - 2′FL, 3FL, LNT, 3′-sialyllactose (3′SL), and 6′SL ( Parschat et al., 2021 ). Overall, the 5-HMOs blend was well-tolerated by term infants enrolled and no difference in growth rates were observed when compared to non-supplemented formula ( Parschat et al., 2021 ).…”