Hashemi, A., Villa, C. R. & Comelli, E. M. Probiotics in early life: a preventative and treatment approach. Food Funct. 7, 1752–1768 (2016).
Renz, H. & Skevaki, C. Early life microbial exposures and allergy risks: opportunities for prevention. Nat. Rev. Immunol. 21, 177–191 (2021).
Houghteling, P. D. & Walker, W. A. Why is initial bacterial colonization of the intestine important to infants’ and children’s health? J. Pediatr. Gastroenterol. Nutr. 60, 294–307 (2015).
Walker, W. A. The importance of appropriate initial bacterial colonization of the intestine in newborn, child, and adult health. Pediatr. Res. 82, 387–395 (2017).
Inchingolo, F. et al. The Impact of Cesarean Section Delivery on Intestinal Microbiota: Mechanisms, Consequences, and Perspectives-a Systematic Review. Int. J. Mol. Sci. 25 (2024).
Tanaka, M. & Nakayama, J. Development of the gut microbiota in infancy and its impact on health in later life. Allergol. Int. 66, 515–522 (2017).
Hill, C. et al. The International Scientific Association for Probiotics and Prebiotics Consensus Statement on the Scope and Appropriate Use of the Term Probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).
Mazziotta, C., Tognon, M., Martini, F., Torreggiani, E. & Rotondo, J. C. Probiotics mechanism of action on immune cells and beneficial effects on human health. Cells 12 (2023).
Kim, S. H. et al. Lactic Acid Bacteria Improves Peyer’s patch cell-mediated immunoglobulin a and tight-junction expression in a destructed gut microbial environment. J. Microbiol. Biotechnol. 26, 1035–1045 (2016).
Dedobbeleer, O., Stockis, J., van der Woning, B., Coulie, P. G. & Lucas, S. Cutting Edge: Active Tgf-Β1 Released from Garp/Tgf-Β1 Complexes on the Surface of Stimulated Human B Lymphocytes Increases Class-Switch Recombination and Production of Iga. J. Immunol. 199, 391–396 (2017).
Lin, S. et al. Mucosal immunity–mediated modulation of the gut microbiome by oral delivery of probiotics into peyer’s patches. Sci. Adv. 7, eabf0677 (2021).
Kaur, H. & Ali, S. A. Probiotics and gut microbiota: mechanistic insights into gut immune homeostasis through Tlr Pathway Regulation. Food Funct. 13, 7423–7447 (2022).
Cristofori, F. et al. Anti-inflammatory and immunomodulatory effects of probiotics in gut inflammation: a door to the body. Front. Immunol. 12, 578386 (2021).
Liu, H.-Y. et al. Probiotic Lactobacillus Johnsonii Reduces Intestinal Inflammation and Rebalances Splenic Treg/Th17 Responses in Dextran Sulfate Sodium-Induced Colitis. Antioxidants 14, 433 (2025).
Javanmardi, Z. et al. Tolerogenic probiotics lactobacillus delbrueckii and lactobacillus rhamnosus promote anti-inflammatory profile of macrophages-derived monocytes of newly diagnosed patients with systemic lupus erythematosus. Cell Biochem. Funct. 42, e3981 (2024).
di Vito, R., Conte, C. & Traina, G. A multi-strain probiotic formulation improves intestinal barrier function by the modulation of tight and adherent junction proteins. Cells 11, 2617 (2022).
Iemoli, E. et al. Probiotics reduce gut microbial translocation and improve adult atopic dermatitis. J. Clin. Gastroenterol. 46, S33–S40 (2012).
Hornef, M. W. & Torow, N. ‘Layered Immunity’and the ‘Neonatal Window of Opportunity’–timed succession of non-redundant phases to establish mucosal host–microbial homeostasis after birth. Immunology 159, 15–25 (2020).
Zenner, C. et al. Noninvasive fecal cytokine and microbiota profiles predict commencement of necrotizing enterocolitis in a proof-of-concept study. Gastro Hep. Adv. 2, 666–675 (2023).
Holscher, H. D. et al. Bifidobacterium Lactis Bb12 Enhances Intestinal Antibody Response in Formula-Fed Infants: A Randomized, Double-Blind, Controlled Trial. J. Parenter. Enter. Nutr. 36, 106S–117S (2012).
Hiraku, A. et al. Early Probiotic Supplementation of Healthy Term Infants with Bifidobacterium Longum Subsp. Infantis M-63 Is Safe and Leads to the Development of Bifidobacterium-Predominant Gut Microbiota: A Double-Blind, Placebo-Controlled Trial. Nutrients 15, 1402 (2023).
Freedman, S. B. et al. Probiotic Stool Secretory Immunoglobulin a Modulation in Children with Gastroenteritis: A Randomized Clinical Trial. Am. J. Clin. Nutr. 113, 905–914 (2021).
Wanke, M. & Szajewska, H. Probiotics for Preventing Healthcare-Associated Diarrhea in Children: A Meta-Analysis of Randomized Controlled Trials. Pediatr. Pol. 89, 8–16 (2014).
Page, M. J. et al. The Prisma 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. bmj 372 (2021).
A, R. Vol. version (v5) (2018).
Deeks J. J., H. J. in Cochrane Handbook for Systematic Reviews of Interventions (DG, A. ed.) Ch. 10, (Cochrane, 2023).
Sterne, J. A. C. et al. Rob 2: A Revised Tool for Assessing Risk of Bias in Randomised Trials. Bmj 366, l4898 (2019).
McGrath, S. et al. Metamedian: An R Package for Meta-Analyzing Studies Reporting Medians. Res. Synth. Methods 15, 332–346 (2024).
Baglatzi, L. et al. Effect of Infant Formula Containing a Low Dose of the Probiotic Bifidobacterium Lactis Cncm I-3446 on Immune and Gut Functions in C-Section Delivered Babies: A Pilot Study. Clin. Med. Insights Pediatr. 10, 11–19 (2016).
Castanet, M. et al. Early Effect of Supplemented Infant Formulae on Intestinal Biomarkers and Microbiota: A Randomized Clinical Trial. Nutrients 12 (2020).
Kusumo, P. D., Bela, B., Wibowo, H., Munasir, Z. & Surono, I. Lactobacillus Plantarum Is-10506 Supplementation Increases Faecal Siga and Immune Response in Children Younger Than Two Years. Beneficial microbes 10, 245–252 (2019).
Li, X. et al. Serum Cytokine Patterns Are Modulated in Infants Fed Formula with Probiotics or Milk Fat Globule Membranes: A Randomized Controlled Trial. PLoS One 16, e0251293 (2021).
Radke, M. et al. Starter Formula Enriched in Prebiotics and Probiotics Ensures Normal Growth of Infants and Promotes Gut Health: A Randomized Clinical Trial. Pediatr. Res. 81, 622–631 (2017).
Roggero, P. et al. Analysis of Immune, Microbiota and Metabolome Maturation in Infants in a Clinical Trial of Lactobacillus Paracasei Cba L74-Fermented Formula. Nat. Commun. 11, 2703 (2020).
Kukkonen, K. et al. High Intestinal Iga Associates with Reduced Risk of Ige-Associated Allergic Diseases. Pediatr. allergy Immunol. 21, 67–73 (2010).
Xuan, N. N. et al. Effect of a Growing-up Milk Containing Synbiotics on Immune Function and Growth in Children: A Cluster Randomized, Multicenter, Double-Blind, Placebo Controlled Study. Clin. Med. Insights: Pediatrics 7, S13073 (2013). CMPed.
Marschan, E. et al. Probiotics in Infancy Induce Protective Immune Profiles That Are Characteristic for Chronic Low-Grade Inflammation. Clin. Exp. Allergy 38, 611–618 (2008).
Rinne, M., Kalliomaki, M., Arvilommi, H., Salminen, S. & Isolauri, E. Effect of Probiotics and Breastfeeding on the Bifidobacterium and Lactobacillus/Enterococcus Microbiota and Humoral Immune Responses. J. pediatrics 147, 186–191 (2005).
DI Pierro, F. et al. Use of a Probiotic Mixture Containing Bifidobacterium Animalis Subsp. Lactis Bb-12 and Enterococcus Faecium L3 as Prophylaxis to Reduce the Incidence of Acute Gastroenteritis and Upper Respiratory Tract Infections in Children. Minerva Pediatr. (Torino) 73, 222–229 (2021).
Escribano, J. et al. Bifidobacterium Longum Subsp Infantis Cect7210-Supplemented Formula Reduces Diarrhea in Healthy Infants: A Randomized Controlled Trial. Pediatr. Res 83, 1120–1128 (2018).
Dzidic, M. et al. Aberrant Iga Responses to the Gut Microbiota During Infancy Precede Asthma and Allergy Development. J. Allergy Clin. Immunol. 139, 1017–1025. e1014 (2017).
De Andrés, J. et al. Modulatory Effect of Three Probiotic Strains on Infants’ Gut Microbial Composition and Immunological Parameters on a Placebo-Controlled, Double-Blind, Randomised Study. Benef. Microbes 9, 573–584 (2018).
Wu, B.-B., Yang, Y., Xu, X. & Wang, W.-P. Effects of Bifidobacterium Supplementation on Intestinal Microbiota Composition and the Immune Response in Healthy Infants. World J. Pediatrics 12, 177–182 (2016).
Viljanen, M. et al. Induction of Inflammation as a Possible Mechanism of Probiotic Effect in Atopic Eczema–Dermatitis Syndrome. J. allergy Clin. Immunol. 115, 1254–1259 (2005).
Mageswary, M. U. et al. Probiotic Bifidobacterium Lactis Probio-M8 Treated and Prevented Acute Rti, Reduced Antibiotic Use and Hospital Stay in Hospitalized Young Children: A Randomized, Double-Blind, Placebo-Controlled Study. Eur. J. Nutr. 61, 1679–1691 (2022).
Indrio, F. et al. Probiotic Supplementation in Preterm: Feeding Intolerance and Hospital Cost. Nutrients 9, 965 (2017).
Capeding, M. R. Z. et al. Safety, Efficacy, and Impact on Gut Microbial Ecology of a Bifidobacterium Longum Subspecies Infantis Lmg11588 Supplementation in Healthy Term Infants: A Randomized, Double-Blind, Controlled Trial in the Philippines. Front Nutr. 10, 1319873 (2023).
Savino, F. et al. Lactobacillus Reuteri Dsm 17938 Probiotics May Increase Cc-Chemokine Receptor 7 Expression in Infants Treated with for Colic. Front. pediatrics 7, 292 (2019).
Farid, R., Ahanchian, H., Jabbari, F. & Moghiman, T. Effect of a New Synbiotic Mixture on Atopic Dermatitis in Children: A Randomized-Controlled Trial. Iran. J. Pediatr. 21, 225–230 (2011).
Torow, N., Hand, T. W. & Hornef, M. W. Programmed and Environmental Determinants Driving Neonatal Mucosal Immune Development. Immunity 56, 485–499 (2023).
Dzidic, M., Boix-Amorós, A., Selma-Royo, M., Mira, A. & Collado, M. C. Gut Microbiota and Mucosal Immunity in the Neonate. Med. Sci. 6, 56 (2018).
Battersby, A. J. & Gibbons, D. L. The Gut Mucosal Immune System in the Neonatal Period. Pediatr. Allergy Immunol. 24, 414–421 (2013).
Abokor, A. A. et al. Immunoglobulin a, an Active Liaison for Host-Microbiota Homeostasis. Microorganisms 9, 2117 (2021).
Guo, J. et al. Role of Iga in the Early-Life Establishment of the Gut Microbiota and Immunity: Implications for Constructing a Healthy Start. Gut microbes 13, 1908101 (2021).
Wichmann, C., Wirthgen, E., Nowosad, C. R. & Däbritz, J. B cell academy of the gut: an update on gut associated germinal centre B Cell Dynamics. Mol. Cell. Pediatrics 11, 7 (2024).
Bemark, M., Pitcher, M. J., Dionisi, C. & Spencer, J. Gut-associated lymphoid tissue: a microbiota-driven hub of B Cell Immunity. Trends Immunol. 45, 211–223 (2024).
de Groen, P., Gouw, S. C., Hanssen, N. M., Nieuwdorp, M. & Rampanelli, E. Early-life gut microbiota: education of the immune system and links to autoimmune diseases. Microorganisms 14, 210 (2026).
Ardeshir, A., Gensollen, T., Zeng, M., Al Nabhani, Z. & Blumberg, R. Vol. 15 1417060 (Frontiers Media SA, 2024).
Henrick, B. M. et al. Bifidobacteria-mediated immune system imprinting early in life. Cell 184, 3884–3898. e3811 (2021).
Lin, C. et al. Intestinal ‘Infant-Type’ bifidobacteria mediate immune system development in the first 1000 days of life. Nutrients 14, 1498 (2022).
Rigo-Adrover, M.dM., Franch, A., Castell, M. & Pérez-Cano, F. J. Preclinical immunomodulation by the probiotic bifidobacterium breve M-16v in Early Life. PLoS One 11, e0166082 (2016).
Chen, Y. Y. et al. Impact of cesarean delivery and breastfeeding on secretory immunoglobulin A in the infant gut is mediated by gut microbiota and metabolites. Metabolites 13, 148 (2023).
Stervbo, U. et al. Stability of 12 T-helper cell-associated cytokines in human serum under different pre-analytical conditions. Cytokine 129, 155044 (2020).
Semmes, E. C. et al. Understanding early-life adaptive immunity to guide interventions for pediatric health. Front. Immunol. 11, 595297 (2021).
Smolen, K. K. et al. Ontogeny of plasma cytokine and chemokine concentrations across the first week of human life. Cytokine 148, 155704 (2021).
Garcia-Serna, A. M. et al. Cytokine production by newborns: influence of sex and season of birth. Pediatr. Res. 93, 526–534 (2023).
DuPont, H. L., Jiang, Z.-D., Alexander, A. S., DuPont, A. W. & Brown, E. L. Intestinal Iga-Coated Bacteria in Healthy-and Altered-Microbiomes (Dysbiosis) and Predictive Value in Successful Fecal Microbiota Transplantation. Microorganisms 11, 93 (2022).
León, E. D. & Francino, M. P. Roles of secretory immunoglobulin a in host-microbiota interactions in the gut ecosystem. Front. Microbiol. 13, 880484 (2022).
Shapiro, J. M. et al. Immunoglobulin a targets a unique subset of the microbiota in inflammatory bowel disease. Cell host microbe 29, 83–93. e83 (2021).
Bakker-Zierikzee, A. M. et al. Faecal siga secretion in infants fed on pre- or probiotic infant formula. Pediatr. Allergy Immunol. 17, 134–140 (2006).
Dang, H. T. et al. Promising clinical and immunological efficacy of Bacillus Clausii Spore Probiotics for Supportive Treatment of Persistent Diarrhea in Children. Sci. Rep. 14, 6422 (2024).
Ellis, C. L. et al. Probiotic administration in congenital heart disease: a pilot study. J. Perinatol. 33, 691–697 (2013).
Eor, J. Y. et al. Effect of probiotic-fortified infant formula on infant gut health and microbiota modulation. Food Sci. Anim. Resour. 43, 659 (2023).
Fatheree, N. Y. et al. Lactobacillus Reuteri for infants with colic: a double-blind, placebo-controlled, randomized clinical trial. J. Pediatr. 191, 170–178.e172 (2017).
Gøbel, R., Larsen, N., Mølgaard, C., Jakobsen, M. & Michaelsen, K. Probiotics to young children with atopic dermatitis: a randomized placebo-controlled trial. Int. J. Probiotics Prebiotics 5, 53 (2010).
Lagkouvardos, I. et al. Early life gut microbiota profiles linked to synbiotic formula effects: a randomized clinical trial in European Infants. Am. J. Clin. Nutr. 117, 326–339 (2023).
Li, P. et al. Effect of Lacticaseibacillus Paracasei N1115 on Immunomodulatory and Gut Microbial Composition in Young Children: A Randomized, Placebo-Controlled Study. Nutrients 15 (2023).
Lodinová-Žádníková, R., Prokešová, L., Kocourková, I., Hrdý, J. & Žižka, J. Prevention of allergy in infants of allergic mothers by probiotic Escherichia coli. Int. Arch. Allergy Immunol. 153, 201–206 (2010).
Maldonado, J. et al. Human Milk Probiotic Lactobacillus Fermentum Cect5716 Reduces the Incidence of Gastrointestinal and Upper Respiratory Tract Infections in Infants. J. Pediatr. Gastroenterol. Nutr. 54, 55–61 (2012).
Maldonado-Lobón, J. et al. Long-Term Safety of Early Consumption of Lactobacillus Fermentum Cect5716: A 3-Year Follow-up of a Randomized Controlled Trial. Pharmacol. Res. 95, 12–19 (2015).
Piloquet, H. et al. Efficacy and safety of a synbiotic infant formula for the prevention of respiratory and gastrointestinal infections: a randomized controlled trial. Am. J. Clin. Nutr. 119, 1259–1269 (2024).
Rozé, J.-C. et al. An α-lactalbumin-enriched and symbiotic-supplemented V. A standard infant formula: a multicentre, double-blind, randomised trial. Br. J. Nutr. 107, 1616–1622 (2012).
Pehlevan, Ö. et al. Cytokine Responses to Symbiotic and Lactoferrin Combination in Very Low Birth Weight Neonates: A Randomized Control Trial. Archivos argentinos de pediatria 118 (2020).
Wang, H. et al. Bifidobacterium Regulates Premature Infant Gut Metabolites, Reducing Serum Inflammatory Factors: A Randomised Controlled Trial. Pediatric Research, 1-12 (2024).
Xiao, L. et al. Probiotics maintain intestinal secretory immunoglobulin a levels in healthy formula-fed infants: a randomised, double-blind, placebo-controlled study. Beneficial microbes 10, 729–740 (2019).