Karen Harris

Karen Harris is a professional writer and editor with more than two decades of experience in research-driven nonfiction writing. With a background in journalism and a Master's degree in English, she brings a meticulous approach to fact-finding, source evaluation, and clear communication of complex topics. Her work spans health, lifestyle, and consumer education, always with a focus on accuracy and readability.

Context

The first months of life represent a critical window during which the gut microbiome and the nervous system develop in parallel. Evidence from animal models and observational studies suggests a bidirectional microbiota–gut–brain axis. This raises the question of whether infant formula enriched with bioactive compounds - specifically MFGM, synbiotics, and LC-PUFA - can steer gut microbial maturation and neurodevelopment closer to the breastfed pattern. The COGNIS trial was the first interventional study to address this question with a combined multi-ingredient formula over a 4-year follow-up.

Study Overview

Design: Prospective, double-blind, randomized controlled trial with long-term follow-up (COGNIS study; ClinicalTrials.gov: NCT02094547)


Population: 170 healthy term infants (≥37 weeks) in formula-fed groups + 50 breastfed reference infants; recruited 2010–2014, University of Granada, Spain


Follow-up: Gut microbiota: 1, 6, 12, 18 months; Neurodevelopment: 12 months (BSID-III) and 4 years (PLON-R language test)


Funding: Mixed: CDTI/FEDER public funds, Ordesa Laboratories S.L. (formula provider); three authors are Ordesa employees


Evidence Certainty (GRADE): Not formally assessed; exploratory secondary outcomes; single trial; microbiota–neurodevelopment associations are observational within the RCT


Comparison:

  • SF (Standard Formula): Unsupplemented control formula (n=85)
  • EF (Experimental Formula): SF + bovine MFGM (10% of total protein), LC-PUFA (ARA + DHA), synbiotics (FOS:inulin + sialic acid, B. infantis IM1, L. rhamnosus LCS-742) (n=85)
  • BF (Breastfed Reference): Exclusively breastfed ≥2 months (n=50, non-randomized)

Key Findings

Gut Microbiota Maturation:

  • Age was the dominant driver of microbiota composition (56.5% variance); type of feeding explained an additional 3.2%
  • Four infant enterotypes were identified: Mixed (early), U_Lach (6 months), Bact and Firm (12–18 months) - progressively maturing toward an adult-like profile
  • Breastfed infants showed the most stable, slowest-maturing trajectories, predominantly staying in Mixed and U_Lach enterotypes through 18 months
  • SF infants predominantly followed a "fast" maturation trajectory (transition to Bact/Firm by 6 months)
  • EF infants showed a bimodal split: approximately half followed a "fast" trajectory similar to SF, while the other half followed a "slow" trajectory comparable to breastfed infants - with transitions to mature enterotypes delayed to 12 or 18 months
  • Diarrhoea episodes were associated with trajectory regressions (reversals); antibiotic use was not

Who Benefits from the Slow (Breastfed-Like) Trajectory in EF?

  • "Slow" trajectory in EF infants was strongly predicted by: vaginal delivery, maternal pre-pregnancy lean BMI, and home rearing (no daycare) - not by the formula itself in isolation
  • C-section delivery, higher maternal pre-pregnancy BMI, and daycare attendance were associated with the "fast" trajectory, even in EF-fed infants (AUC = 0.84)

Microbial Composition:

  • EF promoted growth of Lactobacillus species (including the supplemented L. rhamnosus LCS-742) and selected Bifidobacterium phylotypes (including B. infantis IM1) more strongly than SF
  • EF reduced overall microbial richness at 12 months compared to SF (no difference vs. BF at this timepoint)
  • Shannon diversity did not differ significantly between EF and BF at any timepoint

Neurodevelopment:

  • At 12 months: language and expressive language scores were significantly higher in EF "fast" trajectory infants than in BF (after covariate adjustment) - but this reflects the narrow score distribution in "fast" infants, not a clinically meaningful advantage
  • EF "slow" trajectory infants showed neurodevelopmental scores similar to BF across all domains (cognitive, motor, language) at 12 months
  • At 4 years: no significant language differences between EF trajectory subgroups and BF

Limitations

  • The experimental formula combined four active components simultaneously (MFGM, LC-PUFA, two probiotics, prebiotics) - the contribution of each individual ingredient to microbiota or neurodevelopmental outcomes cannot be isolated
  • Breastfed reference group was not randomized, had higher parental education and maternal IQ - potential confounding of neurodevelopmental comparisons
  • Microbiota–neurodevelopment associations are observational correlations within the RCT, not causal claims
  • BF group was underpowered (n=50, non-randomized), limiting the validity of formula-vs-breastfeeding comparisons
  • 16S rRNA V1–V2 sequencing does not resolve species-level differences
  • Dropout rate was substantial; baseline differences in birth weight and length were observed among dropouts
  • Maternal educational level and IQ were significantly higher in BF group - a major confounder for neurodevelopmental comparisons
  • Partial industry funding (Ordesa Laboratories); three authors are company employees

Neutral Interpretation

The COGNIS trial provides the first evidence that a formula combining synbiotics, LC-PUFA, and bovine MFGM can slow gut microbiota maturation in a subset of formula-fed infants toward a trajectory resembling that of breastfed infants, with associated neurodevelopmental scores at 12 months and 4 years comparable to the breastfed reference group. However, this effect was not universal: it appeared specifically in home-reared infants born vaginally to mothers with lean pre-pregnancy BMI, suggesting that perinatal and environmental context substantially modulates formula efficacy. Because the experimental formula contained multiple active ingredients and the breastfed reference group was non-randomized with higher parental education, causal conclusions regarding any single ingredient - or regarding formula-vs-breastfeeding neurodevelopmental equivalence - are not supported by this data.

Full Citation

Cerdó T, Ruíz A, Acuña I, et al. A synbiotics, long chain polyunsaturated fatty acids, and milk fat globule membranes supplemented formula modulates microbiota maturation and neurodevelopment. Clinical Nutrition. 2022;41(8). doi: 10.1016/j.clnu.2022.06.031. 

PMID: 35777109.

Available at: https://pubmed.ncbi.nlm.nih.gov/35777109/

Disclosure

This summary is based on the published study. It is provided for informational purposes only and does not constitute medical advice. Funding sources and conflicts of interest are disclosed as reported by the authors.