Early-life formula feeding is associated with infant gut microbiota alterations and an increased antibiotic resistance load
Open accessAbstract
BACKGROUND: Infants are at a high risk of acquiring fatal infections, and their treatment relies on functioning antibiotics. Antibiotic resistance genes (ARGs) are present in high numbers in antibiotic-naive infants' gut microbiomes, and infant mortality caused by resistant infections is high. The role of antibiotics in shaping the infant resistome has been studied, but there is limited knowledge on other factors that affect the antibiotic resistance burden of the infant gut. OBJECTIVES: Our objectives were to determine the impact of early exposure to formula on the ARG load in neonates and infants born either preterm or full term. Our hypotheses were that diet causes a selective pressure that influences the microbial community of the infant gut, and formula exposure would increase the abundance of taxa that carry ARGs. METHODS: Cross-sectionally sampled gut metagenomes of 46 neonates were used to build a generalized linear model to determine the impact of diet on ARG loads in neonates. The model was cross-validated using neonate metagenomes gathered from public databases using our custom statistical pipeline for cross-validation. RESULTS: Formula-fed neonates had higher relative abundances of opportunistic pathogens such as Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, Klebsiella oxytoca, and Clostridioides difficile. The relative abundance of ARGs carried by gut bacteria was 69% higher in the formula-receiving group (fold change, 1.69; 95% CI: 1.12-2.55; P = 0.013; n = 180) compared to exclusively human milk-fed infants. The formula-fed infants also had significantly less typical infant bacteria, such as Bifidobacteria, that have potential health benefits. CONCLUSIONS: The novel finding that formula exposure is correlated with a higher neonatal ARG burden lays the foundation that clinicians should consider feeding mode in addition to antibiotic use during the first months of life to minimize the proliferation of antibiotic-resistant gut bacteria in infants.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Bifidobacterium supplementation has been associated with lower ARG abundance in the infant gut microbiome, likely due to the competitive exclusion of ARG-rich pathobionts.
“Bifidobacterium, and Bifidobacterium supplementation has been associated with lower ARG abundance in the infant gut microbiome, likely due to the competitive exclusion of ARG-rich pathobionts56–59.”
From Impact of early life antibiotic and probiotic treatment on gut microbiome and resistome of very-low-birth-weight preterm infants. (2025) · cites this paper as [58]
The Results section ('Formula-fed infants have more potential pathogens possessing ARGs'; page unavailable) reports fewer bifidobacteria and more potentially pathogenic species in formula-fed infants. The Discussion (page unavailable) links formula-associated microbial communities to higher ARG abundance. Neither passage tests Bifidobacterium supplementation or establishes competitive exclusion as the mechanism. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · see citing works
The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041 · see citing works
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
Cutadapt removes adapter sequences from high-throughput sequencing reads
Martin, M. (2011) · EMBnet.journal · doi:10.14806/ej.17.1.200 · Cited by 33,889 · see citing works
phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data
McMurdie, P. J., & Holmes, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061217 · Cited by 21,013 · see citing works
Schloss, P. D., Westcott, S. L., Ryabin, T., Hall, J. R., Hartmann, M., Hollister, E. B., Lesniewski, R. A., Oakley, B. B., Parks, D. H., Robinson, C. J., et al. (2009) · Applied and Environmental Microbiology · doi:10.1128/aem.01541-09 · Cited by 20,966 · see citing works
MultiQC: summarize analysis results for multiple tools and samples in a single report
Ewels, P., Magnusson, M., Lundin, S., & Käller, M. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw354 · Cited by 10,143 · see citing works
Building Predictive Models in R Using the caret Package
Kühn, M. (2008) · Journal of Statistical Software · doi:10.18637/jss.v028.i05 · Cited by 9,986 · see citing works
Generalized linear mixed models: a practical guide for ecology and evolution
Bolker, B. M., Brooks, M. E., Clark, C. J., Geange, S. W., Poulsen, J. R., Stevens, M. H. H., & White, J.-S. S. (2009) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2008.10.008 · Cited by 8,910 · see citing works
Accelerated Profile HMM Searches
Eddy, S. R. (2011) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002195 · Cited by 6,975 · see citing works
Pruesse, E., Quast, C., Knittel, K., Fuchs, B. M., Ludwig, W., Peplies, J., & Glöckner, F. O. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm864 · Cited by 6,682 · see citing works
Identification of acquired antimicrobial resistance genes
Zankari, E., Hasman, H., Cosentino, S., Vestergaard, M., Rasmussen, S., Lund, O., Aarestrup, F. M., & Larsen, M. V. (2012) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dks261 · Cited by 4,980 · see citing works
Carattoli, A., Zankari, E., García-Fernández, A., Voldby Larsen, M., Lund, O., Villa, L., Møller Aarestrup, F., & Hasman, H. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02412-14 · Cited by 4,877 · see citing works
The Pfam protein families database in 2019
El-Gebali, S., Mistry, J., Bateman, A., Eddy, S. R., Luciani, A., Potter, S. C., Qureshi, M., Richardson, L. J., Salazar, G. A., Smart, A., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky995 · Cited by 4,602 · see citing works
Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life
Bäckhed, F., Roswall, J., Peng, Y., Feng, Q., Jia, H., Kovatcheva-Datchary, P., Li, Y., Xia, Y., Xie, H., Zhong, H., et al. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.04.004 · Cited by 3,315 · see citing works
Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment
Morgan, X. C., Tickle, T. L., Sokol, H., Gevers, D., Devaney, K. L., Ward, D. V., Reyes, J. A., Shah, S. A., LeLeiko, N., Snapper, S. B., et al. (2012) · Genome Biology · doi:10.1186/gb-2012-13-9-r79 · Cited by 2,713 · see citing works
Tackling antibiotic resistance: the environmental framework
Berendonk, T. U., Manaia, C. M., Merlin, C., Fatta‐Kassinos, D., Cytryn, E. J., Walsh, F., Bürgmann, H., Sørum, H. R., Norström, M., Pons, M., et al. (2015) · Nature Reviews Microbiology · doi:10.1038/nrmicro3439 · Cited by 2,365 · see citing works
Temporal development of the gut microbiome in early childhood from the TEDDY study
Stewart, C. J., Ajami, N. J., O’Brien, J. L., Hutchinson, D. S., Smith, D. P., Wong, M. C., Ross, M. C., Lloyd, R. E., Doddapaneni, H., Metcalf, G., et al. (2018) · Nature · doi:10.1038/s41586-018-0617-x · Cited by 1,996 · see citing works
Mobile genetic elements: the agents of open source evolution
Frost, L. S., Leplae, R., Summers, A. O., & Toussaint, A. (2005) · Nature Reviews Microbiology · doi:10.1038/nrmicro1235 · Cited by 1,859 · see citing works
Human milk oligosaccharides: Every baby needs a sugar mama
Bode, L. (2012) · Glycobiology · doi:10.1093/glycob/cws074 · Cited by 1,809 · see citing works
Metagenomic microbial community profiling using unique clade-specific marker genes
Segata, N., Waldron, L., Ballarini, A., Narasimhan, V., Jousson, O., & Huttenhower, C. (2012) · Nature Methods · doi:10.1038/nmeth.2066 · Cited by 1,776 · see citing works
Species-level functional profiling of metagenomes and metatranscriptomes
Franzosa, E. A., McIver, L. J., Rahnavard, G., Thompson, L. R., Schirmer, M., Weingart, G., Lipson, K. S., Knight, R., Caporaso, J. G., Segata, N., et al. (2018) · Nature Methods · doi:10.1038/s41592-018-0176-y · Cited by 1,693 · see citing works
Measurement of "Overlap" in Comparative Ecological Studies
Horn, H. S. (1966) · The American Naturalist · doi:10.1086/282436 · Cited by 1,646 · see citing works
Breast milk and neonatal necrotising enterocolitis
Lucas, A., & Cole, T. J. (1990) · The Lancet · doi:10.1016/0140-6736(90)93304-8 · Cited by 1,601 · see citing works
Antibiotics, birth mode, and diet shape microbiome maturation during early life
Bokulich, N. A., Chung, J., Battaglia, T., Henderson, N., Jay, M., Li, H., D. Lieber, A., Wu, F., Perez-Perez, G. I., Chen, Y., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad7121 · Cited by 1,469 · see citing works
Access to effective antimicrobials: a worldwide challenge
Laxminarayan, R., Matsoso, P., Pant, S., Brower, C., Røttingen, J.-A., Klugman, K., & Davies, S. (2016) · The Lancet · doi:10.1016/s0140-6736(15)00474-2 · Cited by 1,465 · see citing works
Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth
Shao, Y., Forster, S. C., Tsaliki, E., Vervier, K., Strang, A., Simpson, N., Kumar, N., Stares, M. D., Rodger, A., Brocklehurst, P., et al. (2019) · Nature · doi:10.1038/s41586-019-1560-1 · Cited by 1,088 · see citing works
The human gut microbiome in early-onset type 1 diabetes from the TEDDY study
Vatanen, T., Franzosa, E. A., Schwager, R., Tripathi, S. M., Arthur, T. D., Vehik, K., Lernmark, Å., Hagopian, W., Rewers, M., She, J., et al. (2018) · Nature · doi:10.1038/s41586-018-0620-2 · Cited by 897 · see citing works
Collignon, P., Beggs, J. J., Walsh, T. R., Gandra, S., & Laxminarayan, R. (2018) · The Lancet Planetary Health · doi:10.1016/s2542-5196(18)30186-4 · Cited by 750 · see citing works
Pärnänen, K. M. M., Karkman, A., Hultman, J., Lyra, C., Bengtsson‐Palme, J., Larsson, D. G. J., Rautava, S., Isolauri, E., Salminen, S., Kumar, H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06393-w · Cited by 682 · see citing works
Self-citationNecrotizing enterocolitis: new insights into pathogenesis and mechanisms
Niño, D. F., Sodhi, C. P., & Hackam, D. J. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.119 · Cited by 621 · see citing works
Azad, M. B., Konya, T., Persaud, R. R., Guttman, D. S., Chari, R., Field, C. J., Sears, M., Mandhane, P., Turvey, S., Subbarao, P., et al. (2015) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/1471-0528.13601 · Cited by 619 · see citing works
Microbes in the neonatal intensive care unit resemble those found in the gut of premature infants
Brooks, B., Firek, B., Miller, C. S., Sharon, I., Thomas, B. C., Baker, R. W., Morowitz, M. J., & Banfield, J. F. (2014) · Microbiome · doi:10.1186/2049-2618-2-1 · Cited by 613 · see citing works
Fecal Microbiota in Premature Infants Prior to Necrotizing Enterocolitis
Mai, V., Young, C., Ukhanova, M., Wang, X., Sun, Y., Casella, G., Theriaque, D. W., Li, N., Sharma, R. R., Hudak, M. L., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020647 · Cited by 503 · see citing works
The Evolution of Class 1 Integrons and the Rise of Antibiotic Resistance
Gillings, M. R., Boucher, Y., Labbate, M., et al. (2008) · Journal of Bacteriology · doi:10.1128/jb.00152-08 · Cited by 498 · see citing works
Bengtsson‐Palme, J., Hartmann, M., Eriksson, K. M., Pal, C., Thorell, K., Larsson, D. G. J., & Nilsson, R. H. (2015) · Molecular Ecology Resources · doi:10.1111/1755-0998.12399 · Cited by 461 · see citing works
Developmental dynamics of the preterm infant gut microbiota and antibiotic resistome
Gibson, M. K., Wang, B., Ahmadi, S., Burnham, C.-A. D., Tarr, P. I., Warner, B. B., & Dantas, G. (2016) · Nature Microbiology · doi:10.1038/nmicrobiol.2016.24 · Cited by 457 · see citing works
Unconstrained bacterial promiscuity: the Tn916–Tn1545 family of conjugative transposons
Clewell, D. B., Flannagan, S. E., Jaworski, D. D., & Clewell, D. B. (1995) · Trends in Microbiology · doi:10.1016/s0966-842x(00)88930-1 · Cited by 391 · see citing works
Gasparrini, A. J., Wang, B., Sun, X., Kennedy, E. A., Hernandez-Leyva, A. J., Ndao, I. M., Tarr, P. I., Warner, B. B., & Dantas, G. A. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0550-2 · Cited by 305 · see citing works
Hall, M. A. L., Blok, H. E. M., Donders, A. R. T., et al. (2003) · The Journal of Infectious Diseases · doi:10.1086/345880 · Cited by 282 · see citing works
Brooks, B., Olm, M. R., Firek, B. A., Baker, R., Thomas, B. C., Morowitz, M. J., & Banfield, J. F. (2017) · Nature Communications · doi:10.1038/s41467-017-02018-w · Cited by 226 · see citing works
Baumann-Dudenhoeffer, A. M., D’Souza, A. W., Tarr, P. I., Warner, B. B., & Dantas, G. A. (2018) · Nature Medicine · doi:10.1038/s41591-018-0216-2 · Cited by 203 · see citing works
Pediatric Fecal Microbiota Harbor Diverse and Novel Antibiotic Resistance Genes
Moore, A. M., Patel, S., Forsberg, K. J., Wang, B., Bentley, G. J., Razia, Y., Qin, X. G., Tarr, P. I., & Dantas, G. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078822 · Cited by 185 · see citing works
Patel, S., & Saiman, L. M. (2010) · Clinics in Perinatology · doi:10.1016/j.clp.2010.06.004 · Cited by 151 · see citing works
Using metagenomics to investigate human and environmental resistomes
Bengtsson‐Palme, J., Larsson, D. G. J., & Kristiansson, E. (2017) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkx199 · Cited by 135 · see citing works
Infectious Causes of Necrotizing Enterocolitis
Coggins, S. A., Wynn, J. L., & Weitkamp, J.-H. (2014) · Clinics in Perinatology · doi:10.1016/j.clp.2014.10.012 · Cited by 129 · see citing works
Influence of Feeding Type on Gut Microbiome Development in Hospitalized Preterm Infants
Cong, X. S., Judge, M. P., Xu, W., Diallo, A. F., Janton, S., Brownell, E., Maas, K. R., & Graf, J. (2017) · Nursing Research · doi:10.1097/nnr.0000000000000208 · Cited by 123 · see citing works
Raveh-Sadka, T., Thomas, B. C., Singh, A., Firek, B., Brooks, B., Castelle, C. J., Sharon, I., Baker, R. W., Good, M. L., Morowitz, M. J., et al. (2015) · eLife · doi:10.7554/elife.05477 · Cited by 122 · see citing works
Rahman, S. F., Olm, M. R., Morowitz, M. J., & Banfield, J. F. (2018) · mSystems · doi:10.1128/msystems.00123-17 · Cited by 104 · see citing works
Casaburi, G., Duar, R. M., Brown, H. K., Mitchell, R. D., Kazi, S., Chew, S., Cagney, O., Flannery, R. L., Sylvester, K. G., Frese, S. A., et al. (2021) · Scientific Reports · doi:10.1038/s41598-020-80583-9 · Cited by 75 · see citing works
Acquisition of nonmaternal Enterobacteriaceae by infants delivered in hospitals
Murono, K., Fuiita, K., Yoshikawa, M., Saijo, M., INYAKU, F., Kakehashi, H., & Tsukamoto, T. (1993) · The Journal of Pediatrics · doi:10.1016/s0022-3476(05)83504-8 · Cited by 27 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [36]Wickham H. ggplot2: elegant graphics for data analysis. [ Internet]. New York (NY): Springer-Verlag; 2009. Available from: http://ggplot2.org
Cited by
Sorted by citations
The resistance within: antibiotic disruption of the gut microbiome and resistome dynamics in infancy
Thänert, R., Sawhney, S. S., Schwartz, D. J., & Dantas, G. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.03.013 · Cited by 76 · see citing works
Fu, Y., Dou, Q., Smalla, K., Wang, Y., Johnson, T. A., Brandt, K. K., Mei, Z., Liao, M., Hashsham, S. A., Schäffer, A., et al. (2023) · mLife · doi:10.1002/mlf2.12101 · Cited by 65 · see citing works
Self-citationBargheet, A., Klingenberg, C., Esaiassen, E., Hjerde, E., Cavanagh, J. P., Bengtsson-Palme, J., & Pettersen, V. K. (2023) · eBioMedicine · doi:10.1016/j.ebiom.2023.104613 · Cited by 52 · see citing works
Kiu, R., Darby, E. M., Alcon-Giner, C., Acuna-Gonzalez, A., Camargo, A., Lamberte, L. E., Phillips, S., Sim, K., Shaw, A. G., Clarke, P., et al. (2025) · Nature communications · doi:10.1038/s41467-025-62584-2 · Cited by 36 · see citing works
Breastfeeding and early Bifidobacterium-driven microbial colonization shape the infant gut resistome
Samarra, A., Alcañiz, A. J., Martínez-Costa, C., Marina, A., Comas, I., Segata, N., Quijada, N. M., & Collado, M. C. (2025) · Nature Communications · doi:10.1038/s41467-025-61154-w · Cited by 32 · see citing works
- Authors
- Pärnänen, K. M., Hultman, J., Markkanen, M., Satokari, R., Rautava, S., Lamendella, R., Wright, J., McLimans, C. J., Kelleher, S. L., & Virta, M. P.
- Affiliations
- University of Helsinki (FI)
- Juniata College (US)
- Pennsylvania State University (US)
- Corresponding author
- Pärnänen, Katariina MM
- ORCID
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 115
- Issue
- 2
- Pages
- 407-421
- ISSN
- 0002-9165 (ISSN-L)
- PMC
- PMC8827105
- OpenAlex
- W3205610405
- Cited by
- 99
- References
- 51
- Citations by year
- 2026: 24 · 2025: 25 · 2024: 23 · 2023: 23 · 2022: 4
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-02-01)
- Open access
- hybrid
- doi.org
- Locations
- American Journal of Clinical Nutrition (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Academy of Finland
- University of Helsinki
- The Gerber Foundation
- Sigrid Juselius Foundation
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Keywords
- bottle feeding, infant gut microbiota, antibiotic resistance genes, human milk feeding, preterm infants, opportunistic pathogens, Staphylococcus aureus, Klebsiella pneumoniae, Clostridium difficile, Bifidobacterium, infant nutrition
- MeSH terms
- Gastrointestinal Microbiome, Bacterial Proteins, Cross-Sectional Studies, Drug Resistance, Microbial, Feces, Female, Humans, Infant Nutritional Physiological Phenomena, Infant, Newborn, Infant, Premature, Male, Linear Models, Infant Formula
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
