Background: The process of early gut colonization is extremely variable among individuals and is influenced by numerous factors. Among these, the mode of birth will strongly shape the early microbial exposure and immune environment of the neonate. Summary: Here, I review how the concomitant processes of microbiota and immune system development are altered by C-section delivery and the effects of such alterations on long-term health. Key messages: C-section delivery impinges on microbiota and immune system development through various means: (i) if labor is lacking, intrauterine immune responses dependent on this process will not occur, affecting the immune environment of the neonate; (ii) the lack of exposure to the vaginal and fecal microbes of the mother will alter the type and diversity of the microbes that colonize the gut at birth; (iii) the different starting points in terms of microbial exposure and immune environment will mark the course of microbiota and immune system development during the first months of life, generating multiple feedbacks between these 2 processes. Given that the first months of life represent a crucial time window in the ontogenesis of the immune system and the establishment of tolerance, C-section delivery will impact on the lifelong risk of developing immune disease.

1.
Thornton CA, Capristo CC, Power LL, et al: The effect of labor on neonatal T-cell phenotype and function. Pediatr Res 2003; 54: 120–124.
2.
Opsjln SL, Wathen NC, Tingulstad S, et al: Tumor necrosis factor, interleukin-1, and interleukin-6 in normal human pregnancy. Am J Obstet Gynecol 1993; 169: 397–404.
3.
Steinborn A, Gunes H, Halberstadt E: Signal for term parturition is of trophoblast and therefore of fetal origin. Prostaglandins 1995; 50: 237–252.
4.
Steinborn A, Kuhnert M, Halberstadt E: Immunmodulating cytokines induce term and preterm parturition. J Perinat Med 1996; 24: 381–390.
5.
Romero R, Brody DT, Oyarzun E, et al: Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol 1989; 160: 1117–1123.
6.
Thilaganathan B, Meher-Homji N, Nicolaides KH: Labor: an immunologically beneficial process for the neonate. Am J Obstet Gynecol 1994; 171: 1271–1272.
7.
Pittard WB 3rd, Schleich DM, Geddes KM, Sorensen RU: Newborn lymphocyte subpopulations: the influence of labor. Am J Obstet Gynecol 1989; 160: 151–154.
8.
Samelson R, Larkey DM, Amankwah KS, McConnachie P: Effect of labor on lymphocyte subsets in full-term neonates. Am J Reprod Immunol 1992; 28: 71–73.
9.
Ruth V, Hallman M, Laatikainen T: Corticotropin-releasing hormone and cortisol in cord plasma in relation to gestational age, ­labor, and fetal distress. Am J Perinatol 1993; 10: 115–118.
10.
Steinborn A, Sohn C, Sayehli C, et al: Spontaneous labour at term is associated with fetal monocyte activation. Clin Exp Immunol 1999; 117: 147–152.
11.
Ly NP, Ruiz-Perez B, Onderdonk AB, et al: Mode of delivery and cord blood cytokines: a  birth cohort study. Clin Mol Allergy 2006; 4: 13.
12.
Rowe J, Heaton T, Kusel M, et al: High IFN-gamma production by CD8+ T cells and early sensitization among infants at high risk of atopy. J Allergy Clin Immunol 2004; 113: 710–716.
13.
Malamitsi-Puchner A, Protonotariou E, Boutsikou T, et al: The influence of the mode of delivery on circulating cytokine concentrations in the perinatal period. Early Hum Dev 2005; 81: 387–392.
14.
Dominguez-Bello MG, Costello EK, Contreras M, et al: Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 2010; 107: 11971–11975.
15.
Rutayisire E, Huang K, Liu Y, Tao F: The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants’ life: a systematic review. BMC Gastroenterol 2016; 16: 86.
16.
Gronlund MM, Lehtonen OP, Eerola E, Kero P: Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J Pediatr Gastroenterol Nutr 1999; 28: 19–25.
17.
Penders J, Thijs C, Vink C, et al: Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 2006; 118: 511–521.
18.
Biasucci G, Benenati B, Morelli L: et al; Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr 2008; 138: 1796S–1800S.
19.
Hesla HM, Stenius F, Jaderlund L, et al: Impact of lifestyle on the gut microbiota of healthy infants and their mothers – the ALADDIN birth cohort. FEMS Microbiol Ecol 2014; 90: 791–801.
20.
Huurre A, Kalliomaki M, Rautava S, et al: Mode of delivery – effects on gut microbiota and humoral immunity. Neonatology 2008; 93: 236–240.
21.
Azad MB, Konya T, Maughan H, et al: Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ 2013; 185: 385–394.
22.
Jakobsson HE, Abrahamsson TR, Jenmalm MC, et al: Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut 2014; 63: 559–566.
23.
Kabeerdoss J, Ferdous S, Balamurugan R, et al: Development of the gut microbiota in southern Indian infants from birth to 6 months: a molecular analysis. J Nutr Sci 2013; 2:e18.
24.
Bokulich NA, Chung J, Battaglia T, et al: Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Transl Med 2016; 8: 343ra382.
25.
Salminen S, Gibson GR, McCartney AL, Isolauri E: Influence of mode of delivery on gut microbiota composition in seven year old children. Gut 2004; 53: 1388–1389.
26.
Maynard CL, Elson CO, Hatton RD, Weaver CT: Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012; 489: 231–241.
27.
Romagnani S: Regulation of the T cell response. Clin Exp Allergy 2006; 36: 1357–1366.
28.
Hansen CH, Nielsen DS, Kverka M, et al: Patterns of early gut colonization shape future immune responses of the host. PLoS One 2012; 7:e34043.
29.
Olszak T, An D, Zeissig S, et al: Microbial exposure during early life has persistent effects on natural killer T cell function. Science 2012; 336: 489–493.
30.
Francino MP: Early development of the gut microbiota and immune health. Pathogens 2014; 3: 769–790.
31.
Brugman S, Perdijk O, van Neerven RJ, Savelkoul HF: Mucosal immune development in early life: setting the stage. Arch Immunol Ther Exp (Warsz) 2015; 63: 251–268.
32.
Round JL, Mazmanian SK: Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A 2010; 107: 12204–12209.
33.
Hansen CH, Andersen LS, Krych L, et al: Mode of delivery shapes gut colonization pattern and modulates regulatory immunity in mice. J Immunol 2014; 193: 1213–1222.
34.
Lotz M, Gutle D, Walther S, et al: Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 2006; 203: 973–984.
35.
Fusunyan RD, Nanthakumar NN, Baldeon ME, Walker WA: Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr Res 2001; 49: 589–593.
36.
Neu J, Rushing J: Cesarean versus vaginal delivery: long-term infant outcomes and the hygiene hypothesis. Clin Perinatol 2011; 38: 321–331.
37.
Cardwell CR, Stene LC, Joner G, et al: Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia 2008; 51: 726–735.
38.
Bager P, Wohlfahrt J, Westergaard T: Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin Exp Allergy 2008; 38: 634–642.
39.
Keag OE, Norman JE, Stock SJ: Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: systematic review and meta-analysis. PLoS Med 2018; 15:e1002494.
40.
Renz-Polster H, David MR, Buist AS, et al: Caesarean section delivery and the risk of allergic disorders in childhood. Clin Exp Allergy 2005; 35: 1466–1472.
41.
Eggesbo M, Botten G, Stigum H, et al: Is delivery by cesarean section a risk factor for food allergy? J Allergy Clin Immunol 2003; 112: 420–426.
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