Multi-population cohort meta-analysis of human intestinal microbiota in early life reveals the existence of infant community state types (ICSTs)
Open accessAbstract
Appropriate development of the intestinal microbiota during infancy is known to be important for human health. In fact, aberrant alterations of the microbial composition during childhood may cause short- and/or long-term negative health effects. Many factors influence the initial assembly and subsequent progression of the gut microbiota of a neonate, such as feeding type, delivery mode, gestational age, maternal metabolic status and antibiotic exposure. In the current study, the composition of the infant gut core-microbiota was explored, revealing particular variations of this core-microbiota during the first three years as influenced by delivery mode and feeding type. A multi-population cohort meta-analysis was performed by selecting 15 publicly available datasets pertaining to taxonomic profiles of 1035 fecal samples of healthy infants, as obtained by means of a 16S rRNA gene-based profiling approach. Interestingly, this multi-population cohort meta-analysis revealed great microbial complexity and specific taxonomic shifts in children older than six months, suggesting a major impact by the introduction of solid foods which prompts progression of infant gut microbiota towards that typical of adults. The taxonomic data sets employed in this multi-population cohort meta-analysis possess the statistical robustness to allow the identification of infant community state types (ICSTs). Our analysis therefore reveals the existence of specific taxonomic patterns that correspond to particular nutritional and developmental stages of early life, and that had previously been obscured by the high variability typical of such infant gut microbiota.
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In healthy newborns, E. coli can account on average for 15% of the entire gut microbiota and up to 40% in some subjects.
“In healthy newborns, E. coli can account, on average, for 15% of the entire gut microbiota and up to 40% in some subjects [135].”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [135]
The Results and discussion section (‘Influence of feeding on the infant microbiota’; page unavailable) reports an average Escherichia-Shigella abundance of 13.38% in breastfed infants aged 0–1 month and 35.25% in formula-fed infants of that age. These are genus-level, feeding-specific averages; the passage does not establish a 15% average for E. coli across healthy newborns or an abundance of up to 40% in individual subjects. (LLM, conf=0.83)
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“…or HMOs) cannot be digested by the infant itself and are metabolized by certain bacteria present in the infant gut, as these bacteria possess and express the necessary genetic repertoire to allow HMO metabolism, thus facilitating the selection of specific intestinal bacterial species [56].”
BackgroundSelf-citationDeciphering the Bifidobacterial Populations within the Canine and Feline Gut Microbiota
Alessandri, G., Milani, C., Mancabelli, L., Longhi, G., Anzalone, R., Lugli, G. A., Duranti, S., Turroni, F., Ossiprandi, M. C., van Sinderen, D., et al. (2020) · Applied and Environmental Microbiology · doi:10.1128/aem.02875-19 · Cited by 43 · cited 1× · see citing works
“The cut-off values were chosen based on previous publications [50,51] and adapted to the high variability of the infant microbiota.”
MethodSelf-citationThe impact of human-facilitated selection on the gut microbiota of domesticated mammals
Alessandri, G., Milani, C., Mancabelli, L., Mangifesta, M., Lugli, G. A., Viappiani, A., Duranti, S., Turroni, F., Ossiprandi, M. C., van Sinderen, D., et al. (2019) · FEMS Microbiology Ecology · doi:10.1093/femsec/fiz121 · Cited by 39 · cited 1× · see citing works
“Evaluation of the Good’s coverage index resulted in an average value of 0.99 ± 0.006, thereby indicating that sequencing depth of the assessed samples is adequate for a thorough analysis of the gut microbiota [44] (Table S5).”
BackgroundInfluentialSelf-citationMancabelli, L., Milani, C., Lugli, G. A., Fontana, F., Turroni, F., van Sinderen, D., & Ventura, M. (2020) · Microorganisms · doi:10.3390/microorganisms8010131 · Cited by 36 · see citing works
Self-citationGreathouse, K. L., White, J. R., Padgett, R. N., Perrotta, B. G., Jenkins, G. D., Chia, N., & Chen, J. (2019) · BMJ Open Gastroenterology · doi:10.1136/bmjgast-2018-000247 · Cited by 35 · cited 1× · see citing works
“These 16S rRNA profiling datasets were selected so as to obtain a high sample number and reach corresponding robust statistical power, in accordance to previous studies [28,29,39].”
ResultMortensen, M. S., Jensen, B. H., Williams, J. V. A., Brejnrod, A., Andersen, L. O., Röser, D., Andreassen, B. U., Petersen, A. M., Stensvold, C. R., Sørensen, S. J., et al. (2018) · BMC Microbiology · doi:10.1186/s12866-018-1367-5 · Cited by 30 · cited 1× · see citing works
“For this purpose, we selected 15 public datasets [12–26] obtained through 16S rRNA gene-based microbiota profiling, encompassing infants of an age that ranged between a few days to 3 years.”
MethodMilani, C., Alessandri, G., Mangifesta, M., Mancabelli, L., Lugli, G. A., Fontana, F., Longhi, G., Anzalone, R., Viappiani, A., Duranti, S., et al. (2020) · mSystems · doi:10.1128/msystems.00404-20 · Cited by 15 · cited 1× · see citing works
“In order to confirm this result, we generated artificial communities constituted by genomes of species representative of the bacterial communities typically found in adult and infant feces (Table S3 and Table S4) [43].”
Self-citationHealth benefits conferred by the human gut microbiota during infancy
Ventura, M., Milani, C., Lugli, G. A., & van Sinderen, D. (2018) · Microbial Biotechnology · doi:10.1111/1751-7915.13334 · Cited by 12 · cited 1× · see citing works
“Consequently, initial gut colonization events and associated development of the gut microbiota in early (human) life is believed to elicit both temporary as well as long-lasting health effects, and to play a key role in defining host health status [2].”
BackgroundSelf-citationDrewes, J. L., White, J. R., Dejea, C. M., Fathi, P., Iyadorai, T., Vadivelu, J., Roslani, A. C., Wick, E. C., Mongodin, E. F., Loke, M. F., et al. (2019) · npj Biofilms and Microbiomes · doi:10.1038/s41522-018-0078-x · Cited by 5 · see citing works
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Lordan, C., Roche, A. K., Delsing, D. J. M., Nauta, A., Groeneveld, A., MacSharry, J. A., Cotter, P. D., & van Sinderen, D. (2024) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00094-23 · Cited by 109 · see citing works
“The infant microbial composition can be dominated by particular taxa and is much more amenable to change than that of adults, which appears to be crucial, although the true extent remains elusive, in this early stage of microbiota establishment (39).”
BackgroundTarracchini, C., Milani, C., Longhi, G., Fontana, F., Mancabelli, L., Pintus, R., Lugli, G. A., Alessandri, G., Anzalone, R., Viappiani, A., et al. (2021) · Microbiology Spectrum · doi:10.1128/spectrum.01176-21 · Cited by 85 · see citing works
Self-citationThe human gut microbiota during the initial stages of life: insights from bifidobacteria
Turroni, F., Milani, C., Ventura, M., & van Sinderen, D. (2021) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2021.07.012 · Cited by 69 · see citing works
Self-citationMancabelli, L., Milani, C., Biase, R. D., Bocchio, F., Fontana, F., Lugli, G. A., Alessandri, G., Tarracchini, C., Viappiani, A., Conto, F. D., et al. (2024) · mSystems · doi:10.1128/msystems.01294-23 · Cited by 61 · see citing works
“…by species belonging to the Bifidobacterium genus, such as Bifidobacterium breve , B. longum , Bifidobacterium bifidum , and Bifidobacterium pseudocatenulatum , along with species characteristic of the infant microbiota, such as Veillonella parvula , Ruminococcus gnavus , and E. coli (11, 12, 38).”
BackgroundSelf-citationVaginotypes of the human vaginal microbiome
Mancabelli, L., Tarracchini, C., Milani, C., Lugli, G. A., Fontana, F., Turroni, F., van Sinderen, D., & Ventura, M. (2021) · Environmental Microbiology · doi:10.1111/1462-2920.15441 · Cited by 57 · see citing works
Self-citationKassai, S., & de Vos, P. (2023) · Comprehensive Reviews in Food Science and Food Safety · doi:10.1111/1541-4337.13271 · Cited by 38 · see citing works
Lugli, G. A., Mancabelli, L., Milani, C., Fontana, F., Tarracchini, C., Alessandri, G., van Sinderen, D., Turroni, F., & Ventura, M. (2023) · npj Biofilms and Microbiomes · doi:10.1038/s41522-023-00392-6 · Cited by 35 · see citing works
Self-citationDomestic Environment and Gut Microbiota: Lessons from Pet Dogs
Hernandez, J. L., Rhimi, S., Kriaa, A., Mariaule, V., Boudaya, H., Drut, A., Jablaoui, A., Mkaouar, H., Saidi, A., Biourge, V. C., et al. (2022) · Microorganisms · doi:10.3390/microorganisms10050949 · Cited by 40 · see citing works
“Firmicutes, Fusobacteria, Bacteroidetes and Proteobacteria were the predominant phyla from the four sites, and there was a gradual increase in bacterial diversity along the gastrointestinal tract from the duodenum to the colon [30].”
BackgroundInfluentialAlessandri, G., Fontana, F., Mancabelli, L., Lugli, G. A., Tarracchini, C., Argentini, C., Longhi, G., Viappiani, A., Milani, C., Turroni, F., et al. (2022) · npj Biofilms and Microbiomes · doi:10.1038/s41522-022-00349-1 · Cited by 31 · see citing works
Self-citationYap, P. S. X., Chong, C. W., Kamar, A. A., Yap, I. K. S., Choo, Y. M., Lai, N. M., & Teh, C. S. J. (2021) · Scientific Reports · doi:10.1038/s41598-020-80278-1 · Cited by 29 · see citing works
Phylogenomic disentangling of the Bifidobacterium longum subsp. infantis taxon
Tarracchini, C., Milani, C., Lugli, G. A., Mancabelli, L., Fontana, F., Alessandri, G., Longhi, G., Anzalone, R., Viappiani, A., Turroni, F., et al. (2021) · Microbial Genomics · doi:10.1099/mgen.0.000609 · Cited by 29 · see citing works
“…these donor genera, including the bifidobacterial ones, are known to share the human (infant) gut environment with members of B. longum species [7, 91], thus providing the opportunity for genetic transfer events, which can act as the driver of niche adaptation in members of the B. longum…”
InfluentialSelf-citationFirst encounters of the microbial kind: perinatal factors direct infant gut microbiome establishment
Linehan, K., Dempsey, E. M., Ryan, C. A., Ross, R. P., & Stanton, C. (2022) · Microbiome Research Reports · doi:10.20517/mrr.2021.09 · Cited by 25 · see citing works
Lugli, G. A., Calvete-Torre, I., Alessandri, G., Milani, C., Turroni, F., Laiolo, P., Ossiprandi, M. C., Margolles, A., Ruiz, L., & Ventura, M. (2021) · Systematic and Applied Microbiology · doi:10.1016/j.syapm.2021.126273 · Cited by 21 · see citing works
Self-citationMapping bacterial diversity and metabolic functionality of the human respiratory tract microbiome
Mancabelli, L., Milani, C., Fontana, F., Lugli, G. A., Tarracchini, C., Turroni, F., van Sinderen, D., & Ventura, M. (2022) · Journal of Oral Microbiology · doi:10.1080/20002297.2022.2051336 · Cited by 14 · see citing works
Self-citationComplementary Feeding and Infant Gut Microbiota: A Narrative Review
Noles, D. L., Matzeller, K. L., Frank, D. N., Krebs, N. F., & Tang, M. (2025) · Nutrients · doi:10.3390/nu17050743 · Cited by 13 · see citing works
“Alpha-diversity tended to be lower in infants preceding solid food introduction and increased throughout infancy until 2 years of age [42,49,50,52] with only one study reporting that beta-diversity of the infant gut microbial community increased during the first 6 months of life when measured…”
Lugli, G. A., Alessandri, G., Milani, C., Viappiani, A., Fontana, F., Tarracchini, C., Mancabelli, L., Argentini, C., Ruíz, L., Margollés, A., et al. (2021) · Environmental Microbiology · doi:10.1111/1462-2920.15559 · Cited by 12 · see citing works
“These isolates were genotypically characterized by the amplification and sequencing of their ITS sequences (Milani et al., 2014), which were then compared to a previously described ITS bifidobacterial database (Lugli et al., 2020a) updated with all bifidobacterial species classified to date in…”
BackgroundResultSelf-citationGut microbe metabolism of small molecules supports human development across the early stages of life
Tarracchini, C., Fontana, F., Mancabelli, L., Lugli, G. A., Alessandri, G., Turroni, F., Ventura, M., & Milani, C. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1006721 · Cited by 10 · see citing works
“Specifically, similar to what has been performed previously (Mancabelli et al., 2020), infant age groups were named A (n = 732, 0–1 month of age), B (n = 1,209, 1–6 months of age), C (n = 788, 6–12 months of age), D (n = 922, 12–24 months of age), and E (n = 411, 24–48 months of age).”
Self-citationPlaza‐Díaz, J., Ruiz‐Ojeda, F. J., Morales, J., Martín‐Masot, R., Climent, E., Silva, Á., Martínez-Blanch, J. F., Enrique, M., Tortajada, M., Ramón, D., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087392 · Cited by 10 · see citing works
“However, its relative abundance decreases after weaning [37], with the Actinobacteriota and Bacillota phyla representing more than 90% of the relative abundance afterward.”
BackgroundA reconceptualized framework for human microbiome transmission in early life
Rakoff-Nahoum, S., Debelius, J. W., Valles‐Colomer, M., Noordzij, H. T., Esteban-Torres, M., Zhernakova, A., Brusselaers, N., & Pettersen, V. K. (2025) · Nature Communications · doi:10.1038/s41467-025-61998-2 · Cited by 7 · see citing works
Decoding the HMO‒microbiome axis: bridging maternal milk to infant health outcomes
Song, J. M., Ding, M., Joyce, P. W. S., Pi, X., Zhang, B., & Li, B. (2026) · Gut Microbes · doi:10.1080/19490976.2026.2649456 · Cited by 6 · see citing works
Di Pierro, F., Sagheddu, V., Galletti, S., Casaroli, A., Labrini, E., Soldi, S., Cazzaniga, M., Bertuccioli, A., Matera, M., Cavecchia, I., et al. (2026) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-025-10522-5 · Cited by 5 · see citing works
“Another average, for 15% of the entire gut microbiota and up to 40% in some subjects [135].”
Compiling an early life human gut microbiome atlas and identification of key microbial drivers
Tarracchini, C., Longhi, G., Gennaioli, E., Muscò, A., Rizzo, S. M., Viappiani, A., Vitale, S. G., Mancabelli, L., Lugli, G., Angioni, S., et al. (2025) · npj Biofilms and Microbiomes · doi:10.1038/s41522-025-00868-7 · Cited by 5 · see citing works
“Based on the related metadata and consistent with previously published methodologies 18,19 , data sets were stra-ti fi ed according to corresponding infant age into three distinct categories, encompassing the neonatal ( n = 974; 0-1 month), pre-weaning ( n = 1784; 1 – 6 months), and post-weaning ( n…”
Self-citationda Silva, V. G., Roy, N. C., Smith, N. W., Wall, C. R., Mullaney, J. A., & McNabb, W. C. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1591341 · Cited by 5 · see citing works
The infant gut microbiota as the cornerstone for future gastrointestinal health
Tarracchini, C., Milani, C., Lugli, G. A., Mancabelli, L., Turroni, F., van Sinderen, D., & Ventura, M. (2024) · Advances in applied microbiology · doi:10.1016/bs.aambs.2024.02.001 · Cited by 5 · see citing works
Self-citationFontana, F., Mancabelli, L., Lugli, G. A., Tarracchini, C., Alessandri, G., Longhi, G., Anzalone, R., Viappiani, A., Famo, R., Brognan, M., et al. (2021) · Environmental Microbiology Reports · doi:10.1111/1758-2229.12960 · Cited by 5 · see citing works
Self-citationMancabelli, L., Milani, C., Fontana, F., Liotto, N., Tabasso, C., Perrone, M., Lugli, G. A., Tarracchini, C., Alessandri, G., Viappiani, A., et al. (2023) · Microbiome Research Reports · doi:10.20517/mrr.2023.11 · Cited by 4 · see citing works
Self-citationMuscò, A., Tarracchini, C., Rizzo, S. M., Viappiani, A., Ventura, M., & Turroni, F. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1725887 · Cited by 4 · see citing works
“…communities can be categorized into five Community State Types (CSTs), four of which are dominated by a single Lactobacillus species: Lactobacillus crispatus (CST I), Lactobacillus gasseri (CST II), Lactobacillus iners (CST III), and Lactobacillus jensenii (CST V) (Mancabelli et al., 2020, 2021).”
Self-citationThe Association of Neonatal Gut Microbiota Community State Types with Birth Weight
Chen, W.-L., Guo, K., Huang, X., Zhang, X., Li, X., Chen, Z., Wang, Y., Wang, Z., Liu, R., Qiu, H., et al. (2024) · Children · doi:10.3390/children11070770 · Cited by 3 · see citing works
“In healthy infants under 6 months old, the gut microbiota CSTs are mainly characterized by a higher abundance of Bifidobacterium , while in infants aged 12 to 36 months typical adult bacterial genera such as Bacteroides and Faecalibacterium predominate [26].”
BackgroundIn harmony? A scoping review of methods to combine multiple 16S amplicon datasets
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“Bifidobacterium was among the most abundant genus with little variation throughout the time points, and weaning did not seem to affect this pattern as it was reported previously (Mancabelli et al., 2020).”
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“This pattern points to a persistent foundational phage community whose relative contribution decreases as emerging phages accumulate over time, paralleling the concept of a ‘‘core bacteriome’’ 33,34 that co-develops with the (legend continued on next page) host.”
- Authors
- Mancabelli, L., Tarracchini, C., Milani, C., Lugli, G. A., Fontana, F., Turroni, F., van Sinderen, D., & Ventura, M.
- Affiliations
- University of Parma (IT)
- APC Microbiome Institute and School of Microbiology, Bioscience Institute, National University of Ireland, Cork, Ireland
- Corresponding author
- Ventura, Marco
- ORCID
- Venue
- Computational and Structural Biotechnology Journal
- Published
- 2020-01
- Volume
- 18
- Pages
- 2480-2493
- ISSN
- 2001-0370 (ISSN-L)
- PMC
- PMC7516180
- OpenAlex
- W3086115526
- Cited by
- 39
- References
- 66
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 8
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Computational and Structural Biotechnology Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Cork Open Research Archive (University College Cork, Ireland) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università degli Studi di Parma
- European Commission (15/JP/HDHL/3280)
- Science Foundation Ireland (SFI/12/RC/2273-P1, SFI/12/RC/2273-P2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Nursing › Nutrition and Dietetics › Infant Nutrition and Health
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- infant gut microbiota, community state types, core microbiome, mode of delivery, infant feeding type, solid food introduction, 16S rRNA gene profiling, fecal microbiota
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