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Impact of Probiotic B. infantis EVC001 Feeding in Premature Infants on the Gut Microbiome, Nosocomially Acquired Antibiotic Resistance, and Enteric Inflammation.

ABSTRACT: Background: Preterm birth is a major determinant of neonatal survival and morbidity, but the gut microbiome and associated enteric inflammation are also key factors in neonatal development and the risk of associated morbidities. We prospectively and longitudinally followed two cohorts of preterm infants, one of which was fed activated Bifidobacterium longum subsp. infantis (B. infantis) EVC001 8 × 10⁹ CFU daily, and the other was not fed a probiotic. Hospital feeding protocol assigned all infants born at <1500 g and/or < 32 weeks corrected gestational age to the probiotic feeding protocol, whereas infants born at >1500 g and/or >32 weeks corrected gestational age were not fed a probiotic. Fecal samples were opportunistically collected from 77 infants throughout the hospital stay, and subjected to shotgun metagenomic sequencing and quantification of enteric inflammation. De-identified metadata was collected from patient medical records. Results: The gut microbiome of preterm infants was typified by a high abundance of Enterobacteriaceae and/or Staphylococcaceae, and multivariate modeling identified the probiotic intervention, rather than degree of prematurity, day of life, or other clinical interventions, as the primary source of change in the gut microbiome. Among infants fed B. infantis EVC001, a high abundance of total Bifidobacteriaceae developed rapidly, the majority of which was B. infantis confirmed via subspecies-specific qPCR. Associated with this higher abundance of Bifidobacteriaceae, we found increased functional capacity for utilization of human milk oligosaccharides (HMOs), as well as reduced abundance of antibiotic resistance genes (ARGs) and the taxa that harbored them. Importantly, we found that infants fed B. infantis EVC001 exhibited diminished enteric inflammation, even when other clinical variables were accounted for using multivariate modeling. Conclusion: These results provide an important observational background for probiotic use in a NICU setting, and describe the clinical, physiological, and microbiome-associated improvements in preterm infants associated with B. infantis EVC001 feeding.

SUBMITTER: Nguyen M

PROVIDER: S-EPMC7921802 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Impact of Probiotic B. infantis EVC001 Feeding in Premature Infants on the Gut Microbiome, Nosocomially Acquired Antibiotic Resistance, and Enteric Inflammation.

Nguyen Marielle M Holdbrooks Heaven H Mishra Prasanthi P Abrantes Maria A MA Eskew Sherri S Garma Mariajamiela M Oca Cyr-Geraurd CG McGuckin Carrie C Hein Cynthia B CB Mitchell Ryan D RD Kazi Sufyan S Chew Stephanie S Casaburi Giorgio G Brown Heather K HK Frese Steven A SA Henrick Bethany M BM

Frontiers in pediatrics 20210216

Background: Preterm birth is a major determinant of neonatal survival and morbidity, but the gut microbiome and associated enteric inflammation are also key factors in neonatal development and the risk of associated morbidities. We prospectively and longitudinally followed two cohorts of preterm infants, one of which was fed activated Bifidobacterium longum subsp. infantis (B. infantis) EVC001 8 × 109 CFU daily, and the other was not fed a probiotic. Hospit ...[more]

PMID: 33665175

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Project description:Attempts to alter intestinal dysbiosis via administration of probiotics have consistently shown that colonization with the administered microbes is transient. This study sought to determine whether provision of an initial course of Bifidobacterium longum subsp. infantis (B. infantis) would lead to persistent colonization of the probiotic organism in breastfed infants. Mothers intending to breastfeed were recruited and provided with lactation support. One group of mothers fed B. infantis EVC001 to their infants from day 7 to day 28 of life (n = 34), and the second group did not administer any probiotic (n = 32). Fecal samples were collected during the first 60 postnatal days in both groups. Fecal samples were assessed by 16S rRNA gene sequencing, quantitative PCR, mass spectrometry, and endotoxin measurement. B. infantis-fed infants had significantly higher populations of fecal Bifidobacteriaceae, in particular B. infantis, while EVC001 was fed, and this difference persisted more than 30 days after EVC001 supplementation ceased. Fecal milk oligosaccharides were significantly lower in B. infantis EVC001-fed infants, demonstrating higher consumption of human milk oligosaccharides by B. infantis EVC001. Concentrations of acetate and lactate were significantly higher and fecal pH was significantly lower in infants fed EVC001, demonstrating alterations in intestinal fermentation. Infants colonized by Bifidobacteriaceae at high levels had 4-fold-lower fecal endotoxin levels, consistent with observed lower levels of Gram-negative Proteobacteria and Bacteroidetes. IMPORTANCE The gut microbiome in early life plays an important role for long-term health and is shaped in large part by diet. Probiotics may contribute to improvements in health, but they have not been shown to alter the community composition of the gut microbiome. Here, we found that breastfed infants could be stably colonized at high levels by provision of B. infantis EVC001, with significant changes to the overall microbiome composition persisting more than a month later, whether the infants were born vaginally or by caesarean section. This observation is consistent with previous studies demonstrating the capacity of this subspecies to utilize human milk glycans as a nutrient and underscores the importance of pairing a probiotic organism with a specific substrate. Colonization by B. infantis EVC001 resulted in significant changes to fecal microbiome composition and was associated with improvements in fecal biochemistry. The combination of human milk and an infant-associated Bifidobacterium sp. shows, for the first time, that durable changes to the human gut microbiome are possible and are associated with improved gut function.

Project description:BackgroundHistorically, bifidobacteria were the dominant intestinal bacteria in breastfed infants. Still abundant in infants in developing nations, levels of intestinal bifidobacteria are low among infants in developed nations. Recent studies have described an intimate relationship between human milk and a specific subspecies of Bifidobacterium, B. longum subsp. infantis (B. infantis), yet supplementation of breastfed, healthy, term infants with this organism, has not been reported. The IMPRINT Study, a Phase I clinical trial, was initiated to determine the safety and tolerability of supplementing breastfed infants with B. infantis (EVC001).MethodsEighty mother-infant dyads were enrolled in either lactation support plus B. infantis supplementation (BiLS) or lactation support alone (LS). Starting with Day 7 postnatal, BiLS infants were fed 1.8-2.8 × 1010 CFU B. infantis EVC001 daily in breast milk for 21 days. Mothers collected fecal samples, filled out health questionnaires, and kept daily logs about their infants' feeding and gastrointestinal symptoms from birth until Day 61 postnatal. Safety and tolerability were determined from maternal reports.ResultsThere were no differences in the mean gestational age at birth, weight 1 and 2 months postnatal, and breast milk intake between groups. The mean Log10 change in fecal Bifidobacterium from Day 6 to Day 28 was higher (p = 0.0002) for BiLS (6.6 ± 2.8 SD) than for LS infants (3.5 ± 3.5 SD). Daily stool number was higher (p < 0.005) for LS and lower (p < 0.05) for BiLS infants during supplementation than at Baseline. During supplementation, watery stools decreased and soft stools increased by 36% over baseline in BiLS infants (p < 0.05) with no significant changes in stool consistency for the LS infants. None of the safety and tolerability endpoints, including flatulence, bloody stool, body temperature, ratings of gastrointestinal symptoms, use of antibiotics or gas-relieving medications, infant colic, jaundice, number of illnesses, sick doctor visits, or diagnoses of eczema were different for the groups at any point.ConclusionsThe B. infantis EVC001 supplement was safely consumed and well-tolerated. Stools were fewer and better formed in infants in the BiLS group compared with LS group. Adverse events were those expected in healthy infants and not different between groups.Trial registrationClinicalTrials.gov NCT02457338 . Registered May 27, 2015.

Project description:Not all infants carry specialized gut microbes, meaning they cannot digest human milk oligosaccharides and therefore do not receive complete benefits from human milk. B. infantis EVC001 is equipped to convert the full array of complex oligosaccharides into compounds usable by the infant, making it an ideal candidate to stabilize gut function and improve nutrition in preterm infants. A prospective, open-label study design was used to evaluate the tolerability of B. infantis EVC001 and its effects on the fecal microbiota in preterm infants in a Neonatal Intensive Care Unit. Thirty preterm infants <1,500 g and/or <33 weeks gestation at birth were divided into two matched groups, and control infants were enrolled and discharged prior to enrolling EVC001 infants to prevent cross-colonization of B. infantis: (1) fifteen control infants received no EVC001, and (2) fifteen infants received once-daily feedings of B. infantis EVC001 (8.0 x 109 CFU) in MCT oil. Clinical information regarding medications, growth, nutrition, gastrointestinal events, diagnoses, and procedures was collected throughout admission. Infant stool samples were collected at baseline, Study Days 14 and 28, and 34-, 36-, and 38-weeks of gestation. Taxonomic composition of the fecal microbiota, functional microbiota analysis, B. infantis, and human milk oligosaccharides (HMOs) in the stool were determined or quantified using 16S rRNA gene sequencing, metagenomic sequencing, qPCR, and mass spectrometry, respectively. No adverse events or tolerability issues related to EVC001 were reported. Control infants had no detectable levels of B. infantis. EVC001 infants achieved high levels of B. infantis (mean = 9.7 Log10 CFU/μg fecal DNA) by Study Day 14, correlating with less fecal HMOs (ρ = -0.83, P < 0.0001), indicating better HMO utilization in the gut. In this study, B. infantis EVC001 was shown to be safe, well-tolerated, and efficient in colonizing the preterm infant gut and able to increase the abundance of bifidobacteria capable of metabolizing HMOs, resulting in significantly improved utilization of human milk. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03939546, identifier: NCT03939546.

Project description:BackgroundRecent studies have reported a dysfunctional gut microbiome in breastfed infants. Probiotics have been used in an attempt to restore the gut microbiome; however, colonization has been transient, inconsistent among individuals, or has not positively impacted the host's gut.MethodsThis is a 2-year follow-up study to a randomized controlled trial wherein 7-day-old infants received 1.8 × 1010 colony-forming unit Bifidobacterium longum subsp. infantis (B. infantis) EVC001 (EVC) daily for 21 days or breast milk alone (unsupplemented (UNS)). In the follow-up study, mothers (n = 48) collected infant stool at 4, 6, 8, 10, and 12 months postnatal and completed the health-diet questionnaires.ResultsFecal B. infantis was 2.5-3.5 log units higher at 6-12 months in the EVC group compared with the UNS group (P < 0.01) and this relationship strengthened with the exclusion of infants who consumed infant formula and antibiotics. Infants in the EVC group had significantly higher Bifidobacteriaceae and lower Bacteroidaceae and Lachnospiraceae (P < 0.05). There were no differences in any health conditions between the two groups.ConclusionsProbiotic supplementation with B. infantis within the first month postnatal, in combination with breast milk, resulted in stable colonization that persisted until at least 1 year postnatal.ImpactA dysfunctional gut microbiome in breastfed infants is common in resource-rich nations and associated with an increased risk of immune diseases. Probiotics only transiently exist in the gut without persistent colonization or altering the gut microbiome. This is the first study to show that early probiotic supplementation with B. infantis with breast milk results in stable colonization of B. infantis and improvements to the gut microbiome 1 year postnatal. This study addresses a key gap in the literature whereby probiotics can restore the gut microbiome if biologically selected microorganisms are matched with their specific food in an open ecological niche.

Dataset Information

Impact of Probiotic B. infantis EVC001 Feeding in Premature Infants on the Gut Microbiome, Nosocomially Acquired Antibiotic Resistance, and Enteric Inflammation.

Publications

Impact of Probiotic <i>B. infantis</i> EVC001 Feeding in Premature Infants on the Gut Microbiome, Nosocomially Acquired Antibiotic Resistance, and Enteric Inflammation.

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