Table 1.
Human studies exploring the relationship between early life gut microbiota and neurodevelopment outcomes in preterm infants.
| Author, year (Reference) | Study details | Study population | Intervention | Gut microbiota assessment timing method | Neurodevelopment assessment timing method | Results |
|---|---|---|---|---|---|---|
| Beghetti et al. (2021) Italy (6) | O P M |
Preterm infants <32 weeks GA [n = 27, median GA 30.6 (IQR 28.6–33.6) weeks] | NA | 1, 4, 7, and 30 days of life 16S rRNA Illumina sequencing | 24-month CA Griffiths Mental Development Scale (GMDS-R) and General Development Quotient (GQ) performed by psychologist | Early-life GM of infants with normal vs. impaired neurodevelopment followed distinct temporal trajectories with peculiar compositional rearrangements. Early Bifidobacterium deficiency appeared to be a negative biomarker f adverse neurological outcomes. |
| Oliphant et al. (2021) USA (8) | O P M |
Preterm infants <34 weeks GA (n = 58) | NA | Weekly during NICU hospitalization until discharge or 36 weeks PMA 16S rRNA Illumina sequencing | Head Circumference Growth (HCG) weekly during NICU hospitalization until discharge or 36 weeks PMA | Preterm infants with suboptimal HCG trajectories had a depletion in the abundance/prevalence of Bacteroidota and Lachnospiraceae, independent of morbidity and caloric restriction. |
| Rozé et al. (2020) France (5) | C P Multic. |
Preterm newborns born at 24 to 31 weeks GA [n = 577, mean GA 28.3 (SD 2.0) weeks] | NA | Week 4 after birth 16S rRNA Illumina sequencing | 2 years CA Survey assessing cerebral palsy completed by the referring physician and parent assessed 24-month Ages and Stages questionnaire (ASQ) | GM cluster driven by Enterococcus and cluster driven by Staphyloccoccus, were significantly associated with 2-year non optimal outcome. |
| Sarkar et al. (2022) United States (7) | O P M |
Preterm infants with birth weight < 1,500 g [n = 24, mean GA 27.95 (SD 1.81) weeks] | NA | Weekly for 6 weeks after NICU admission and at 2 and 4 years of age | 2 and 4 years of age Battelle Development Inventory-2Screening Test (BDI-2ST) administered by researcher team scored by psychologist | Both NICU infant stool diversity and particular microbial ASVs were associated with BDI-2 ST cognition, adaptive, and communication subscales. Network analysis of the NICU infant stool microbial ecology showed differences in children needing neurodevelopmental referral. |
| Seki et al. (2021) Austria (9) | O P M |
Extremely preterm infants [n = 60, mean GA 25.5 (SD 1.2) weeks] | NA | Days 3, 7, and 14, followed by biweekly sampling until discharge | Brain injuries identification by cUS and neurophysiological development assessment by aEEG (days 3, 7, and 14, then biweekly until discharge); cMRI at term-equivalent age | Klebsiella overgrowth in the gut was highly predictive for brain damage and was associated with a pro-inflammatory immunological tone. |
| Sun et al. (2020) United States (10) | O P M |
Preterm infants [n = 34, mean BW 1451. (SD 479.3) g] | NA | Daily from 5 to 28 days of life 16S rRNA Illumina sequencing | 36–38 weeks of post-menstrual age or prior to hospital discharge NICU Network Neurobehavioral Scale (NNNS) | A functional log-contrast regression model identified microbiota components at order (Clostridiales, Lactobacillales, Enterobacteriales) and genus level (Veillonella, Enteroccoccus, Shigella) that were associated with the neurobehavioral outcome of infant assessed by Stress/Abstinence subscale (NSTRESS) |
| Van den Berg et al. (2016) Netherlands (11) | RCT DB M |
Very preterm infants GA < 32 weeks and/or BW < 1,500 g [n = 77 mean GA 29.9 (SD 1.7) weeks] | scGOS/lcFOS/pAOS or placebo supplemented to breast milk or to preterm formula days 3–30 of life | days 1, 7, 14 and 30 fluorescent in situ hybridisation (FISH) analysis | 24 months CA Bayley Scales of Infant and Toddler Development (BSID) administered by blinded psychologist | Lower percentages of bifidobacteria at days 7 and 14 were associated with lower mental developmental index. Total bacterial count did not influence mental and psychological developmental index scores. |
RCT, randomized controlled trial; P, prospective; B, blinded; DB, double-blinded; C, cohort; O, observational; M, monocentric; Multic, multicentric. BW, birth weight; GA, gestational age; PMA, postmenstrual age; GM, gut microbiota; ASVs, amplicon sequence variants. cUS, cranial ultrasound; aEEG, amplitude-integrated electroencephalography; cMRI, cranial magnetic resonance imaging. NA, not applicable.