AUTHOR=Bosheva Miroslava , Tokodi Istvan , Krasnow Aleksander , Pedersen Helle Krogh , Lukjancenko Oksana , Eklund Aron C. , Grathwohl Dominik , Sprenger Norbert , Berger Bernard , Cercamondi Colin I. ,  5 HMO Study Investigator Consortium , Bauer Viktor , Arciszewska Malgorzata , Tarneva Maria , Popova Irina , Dosev Svilen , Dimitrova Sirma , Nikolova Olga , Nowak Marzena , Szuflinska-Sidorowicz Magdalena , Korczowski Bartosz , Karcheva-Beloeva Rositsa , Banov Stefan , Cimoszko Boguslawa , Olechowski Wieslaw , Simko Robert , Tengelyi Zsuzsanna , Korbal Piotr , Zolnowska Marta , Bilev Anton , Vasilopoulos Georgios , Korzynska Sylwia , Laki István , Koleva-Syarova Margarita , Grigorov Toni , Kraeva Steliyana , Kovács Éva , Markova Rada , Jasieniak-Pinis Grazyna , Fister Katalin , Stoeva Tatyana 

TITLE=Infant Formula With a Specific Blend of Five Human Milk Oligosaccharides Drives the Gut Microbiota Development and Improves Gut Maturation Markers: A Randomized Controlled Trial

JOURNAL=Frontiers in Nutrition

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2022.920362

DOI=10.3389/fnut.2022.920362

ISSN=2296-861X

ABSTRACT=<sec><title>Background</title><p>Human milk oligosaccharides (HMOs) have important biological functions for a healthy development in early life.</p></sec><sec><title>Objective</title><p>This study aimed to investigate gut maturation effects of an infant formula containing five HMOs (2′-fucosyllactose, 2′,3-di-fucosyllactose, lacto-N-tetraose, 3′-sialyllactose, and 6′-sialyllactose).</p></sec><sec><title>Methods</title><p>In a multicenter study, healthy infants (7–21 days old) were randomly assigned to a standard cow’s milk-based infant formula (control group, CG); the same formula with 1.5 g/L HMOs (test group 1, TG1); or with 2.5 g/L HMOs (test group 2, TG2). A human milk-fed group (HMG) was enrolled as a reference. Fecal samples collected at baseline (<italic>n</italic>∼150/formula group; HMG <italic>n</italic> = 60), age 3 (<italic>n</italic>∼140/formula group; HMG <italic>n</italic> = 65) and 6 (<italic>n</italic>∼115/formula group; HMG <italic>n</italic> = 60) months were analyzed for microbiome (shotgun metagenomics), metabolism, and biomarkers.</p></sec><sec><title>Results</title><p>At both post-baseline visits, weighted UniFrac analysis indicated different microbiota compositions in the two test groups (TGs) compared to CG (<italic>P</italic> &lt; 0.01) with coordinates closer to that of HMG. The relative abundance of <italic>Bifidobacterium longum</italic> subsp. <italic>infantis</italic> (<italic>B. infantis</italic>) was higher in TGs vs. CG (<italic>P</italic> &lt; 0.05; except at 6 months: TG2 vs. CG <italic>P</italic> = 0.083). <italic>Bifidobacterium</italic> abundance was higher by ∼45% in TGs vs. CG at 6-month approaching HMG. At both post-baseline visits, toxigenic <italic>Clostridioides difficile</italic> abundance was 75–85% lower in TGs vs. CG (<italic>P</italic> &lt; 0.05) and comparable with HMG. Fecal pH was significantly lower in TGs vs. CG, and the overall organic acid profile was different in TGs vs. CG, approaching HMG. At 3 months, TGs (vs. CG) had higher secretory immunoglobulin A (sIgA) and lower alpha-1-antitrypsin (<italic>P</italic> &lt; 0.05). At 6 months, sIgA in TG2 vs. CG remained higher (<italic>P</italic> &lt; 0.05), and calprotectin was lower in TG1 (<italic>P</italic> &lt; 0.05) vs. CG.</p></sec><sec><title>Conclusion</title><p>Infant formula with a specific blend of five HMOs supports the development of the intestinal immune system and gut barrier function and shifts the gut microbiome closer to that of breastfed infants with higher bifidobacteria, particularly <italic>B. infantis</italic>, and lower toxigenic <italic>Clostridioides difficile</italic>.</p></sec><sec><title>Clinical Trial Registration</title><p>[<ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/" xmlns:xlink="http://www.w3.org/1999/xlink">https://clinicaltrials.gov/ct2/show/</ext-link>], identifier [NCT03722550].</p></sec>