Bifidobacterium infantis treatment promotes weight gain in Bangladeshi infants with severe acute malnutrition

Abstract

Disrupted development of the gut microbiota is a contributing cause of childhood malnutrition. Bifidobacterium longum subspecies infantis is a prominent early colonizer of the infant gut that consumes human milk oligosaccharides (HMOs). We found that the absolute abundance of Bifidobacterium infantis is lower in 3- to 24-month-old Bangladeshi infants with severe acute malnutrition (SAM) compared to their healthy age-matched counterparts. A single-blind, placebo-controlled trial (SYNERGIE) was conducted in 2- to 6-month-old Bangladeshi infants with SAM. A commercial U.S. donor–derived B. infantis strain (EVC001) was administered daily with or without the HMO lacto- N -neotetraose for 28 days. This intervention increased fecal B. infantis abundance in infants with SAM, although to levels still 10- to 100-fold lower than in untreated healthy controls. EVC001 treatment promoted weight gain that was associated with reduced intestinal inflammation markers in infants with SAM. We cultured fecal B. infantis strains from Bangladeshi infants and colonized gnotobiotic mice with these cultured strains. The gnotobiotic mice were fed a diet representative of that consumed by 6-month-old Bangladeshi infants, with or without HMO supplementation. One B. infantis strain, Bg_2D9, expressing two gene clusters involved in uptake and utilization of N -glycans and plant-derived polysaccharides, exhibited superior fitness over EVC001. The fitness advantage of Bg_2D9 was confirmed in a gnotobiotic mouse model of mother-to-infant gut microbiota transmission where dams received a pretreatment fecal community from a SAM infant in the SYNERGIE trial. Whether Bg_2D9 is superior to EVC001 for treating malnourished infants who consume a diet with limited breastmilk requires further clinical testing.

Human Milk Oligosaccharide Utilization in Intestinal Bifidobacteria is Governed by a Global Transcriptional Regulator NagR

“…This model explains the similarity of transcriptomic responses of B. infantis ATCC 15697 during growth in media supplemented with LNT or LNnT (39, 40) and suggests that utilization of any GlcNAc-containing glycan by this bacterium will result in upregulation of NagR-controlled genes. Among these glycans might be particular fucosylated HMOs (e.g., LNFP I) and milk N -glycans imported by different ABC transport systems (34, 73). Consistent with this notion, a previous study demonstrated that B. infantis upregulates nag and H1 cluster genes (53) when utilizing N -glycosylated human lactoferrin.…”

“…Interestingly, different GlcNAc derivatives serve as effector molecules of these TFs: GlcNAc for NahR and GlcNAc-6S for AtsR (44, 59). Another NagR paralog in B. infantis 2D9, NglR, potentially controls a genomic locus involved in utilizing complex N -glycans (73) ( Table 2 ). Overall, these observations illustrate how bifidobacteria adapted to regulate the foraging of host glycans during colonization of mammalian hosts and shed more light on how complex regulatory networks emerge and evolve.…”

“…Decreased Bifidobacterium abundance is characteristic of stunted GMs observed in preterm infants (14) and children suffering from severe acute malnutrition (73). Therapeutic approaches aimed at restoring the bifidobacterial population in these affected groups include administering exogenous Bifidobacterium species (e.g., B. infantis ) as probiotics or/and food formulas containing prebiotics that would selectively stimulate the growth of endogenous bifidobacteria in the gut and thus confer beneficial properties to the infant (14–16, 73). Since the prevalence of bifidobacteria in the neonatal gut is often attributed to their ability to selectively utilize dietary human milk oligosaccharides (HMOs) (2, 17–21), these milk glycans are considered “natural” prebiotics and added to infant formulas.…”

“…B. infantis , which is widely used in probiotic and synbiotic formulations (8, 15, 16, 73), possesses several unique genomic clusters (e.g., HMO cluster I or H1) that encode the most elaborate HMO uptake (33, 34) and intracellular degradation machinery (35–38) among bifidobacteria ( Fig. 1A-B ).…”

The Future of Synbiotics: Rational Formulation and Design

“…In addition to the complementary synbiotics described above for reducing sepsis and modulating microbiome composition in infants, other potentially synergistic synbiotics have also been developed using B. infantis. In a recent report (Barratt et al, 2022), infants with acute malnutrition were given B. infantis with or without HMO lacto-N-neotetraose. Although both treatments led to engraftment of the B. infantis strain and promoted weight gain in the infants, the synbiotic did not enhance the effect compared to the B. infantis-only treatment.…”