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Review Article | DOI: https://doi.org/10.31579/2690-8816/041
1 Department of Gyne and Obstetrics, Gomal Medical College, D.I.Khan, KP, Pakistan.
2 Institute of Chemical Sciences, Gomal University, D.I. Khan, KP, Pakistan.
3 Gomal Center of Biochemistry and Biotechnology, Gomal University, D.I.Khan, KP, Pakistan.
4 Department of Health Sciences, The University of Agriculture, D.I.Khan, KP, Pakistan.
*Corresponding Author: Khurram Rehman, Department of Health Sciences, The University of Agriculture, D.I.Khan, KP, Pakistan.
Citation: Naseem Saba, Hina Ayub, Laraib Malik, Muzammil A. Khan and Khurram Rehman. (2021). Postnatal Variation in Microbiota Compositional Dynamics of Infants of Cesarean versus Vaginal mode of Delivery. J. Clinical Research Notes. 2(2). DOI: 10.31579/2690-8816/041
Copyright: © 2021 Khurram Rehman. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 02 October 2021 | Accepted: 24 November 2021 | Published: 08 November 2021
Keywords: microbiota; cesarean delivery; postnatal factors; leukemia; immunoglobin; allochthonous;; acinetobacter
Introduction: Human microbial communities’ influences human physiology but, how they attain unique taxonomical and functional signatures within each body is still underexplored. Many studies have characterized that shape and composition of infant’s microbiome is substantially dependent upon the delivery mode at birth. The epidemiological data have shown C-section delivered babies are failed to exposed to maternal vaginal microbiota so they develop altered bacterial communities or microbiome that increases the risk of metabolic disorders later in life. The microbiota composition of C-section delivered babies is quick different from the infants deliver vaginally which expose to vaginal fluid during birth. C-section delivered babies acquire different microbiota from vaginally delivered infants as they exposing to vaginal fluid during birth. Following this, various postnatal factors are involving in the modulation of infant's microbiome composition such as exposure of different environmental conditions, antibiotic intake, diet, genetics and body sites that negatively influences the infant’s immune system.
Objectives: In this review, it is intended to describe the variation in shape and composition of microbiome of vaginally and cesarean delivered babies and how microbiome's composition and immune system development is affected by various postnatal factors. In this study, homeostatic aspects of Cesarean delivered babies are also being discussed as it is also affected by the postnatal microbiome-mediated pathogen, variation in gut, oral and body sites bacterial communities.
Conclusion:
We concluded that cesarean delivered children showed significantly immune deficiencies which make them more prone to various disorders such as arthritis, asthma, allergic diseases, connective tissues diseases, leukemia and inflammatory bowel syndrome. These finding are highlighting the importance of shape and composition of microbiome in early-life.
Over the last few years’ microbiome is the major focus area of research after being a well establishing co-relationship by epidemiological studies between various factors affecting microbiota during infancy and immune conditions. These studies suggested altered immune development in childhood is caused by aberrant bacterial communities. Recent neonatal microbiome studies successfully described the assembly of microbial communities and related diseases caused by their interruption. They further explained the microbiome modifying interventions, and therapeutically outcome of microbiome imbalance. In this review, mostly we discussed gut’s microbial communities, however, we will also discuss the neonatal microbiome in multiple body sites [1]. In this review, ‘early life’ will be mentioning to the first 2 years of life, ‘neonates’ are those subjects having ages less than four weeks. Young children with the age of more than 4 weeks will be referred to as ‘infant’, while, the ‘child’ will be the subjects having age below the puberty. The factors affecting micobiota composition before and immediately after birth is mentioned and the association between development of immune and induction of diseases later in life are also highlighted in this review [2].
Microbiota is mainly dependent on the mode of delivery. The microbiota composition of vaginally delivered infants resembles to the bacterial communities of maternal vagina, whereas cesarean delivered babies are enriched in skin microbiota. The immune system is mainly dependent upon the microbial communities that colonizes the newborns body [3]. The development of healthy immune and metabolic programming is associated with the early commensal microbial interactions, whereas, impaired development of immune system and host metabolism associated with exposure to the aberrant microbial colonies in newborns [4]. Various diseases reported by epidemiological studies occurring in later life of C-section delivered babies due to weak immune system. Epidemiological study data showed C-section delivered infants are having high chance of development of asthma, allergies and several immune systems related disorders [5]. Globally, cesarean delivery rate is increasing and has been excessed by 50% of total births in some countries. Although, C-section delivery helps to protect maternal health, but rate of cesarean delivery has been substantially increased than the estimated 15% of births [6]. A study on C-section and vaginally delivered infants was conducted by exposing to C-section delivered infants to maternal vaginal fluids at birth in order to determine whether microbiota composition remain similar to vaginally delivered infants or not. The study was comprised of 18 infants and their mother samples, among them 7 were vaginally born and 11 were C-section delivered. At the birth, four C-section delivered babies exposed to the vaginal fluids of their mothers (Table 1).
Descriptive Factor | Study | Illness/findings | Cohort Characteristics |
C-Section Delivery | Stene et al., (2003). Pediatric research, 54(4), 487-490. | Transient Ischemic Dilatation | 1,863 cases were found with TID |
Stene et al., (2003). Pediatric research, 54(4), 487-490. | Transient Ischemic Dilatation | 1,863 cases were found with TID | |
Eggesbo et al., (2003). Journal of Allergy and clinicalImmunology, 112(2), 420-426. | Allergy to nuts, fish and egg | Norwegian Children 2803 cases with age from 0-2 years | |
Negele et al., (2004). Pediatric Allergy and Immunology, 15(1), 48-54. | Allergy | Cohort study enrolled 2,500 infants of Germany | |
Thavaganam et al., (2008). Clinical & Experimental Allergy, 38(4), 629-633. | Asthma | Sample size 501,947 of 23 studies meta-analysis revealed high risk of asthma in C-section infants | |
Bonifacio et al., (2011). Diabetes, 60(12), 3300-3306. | Transient Ischemic Dilatation | 1650 C-section delivered infants born with TID | |
Huh et al., (2012).Archives of disease in childhood, 97(7), 610-616. | High body mass index or Obesity | 1,255 US children with age of 3 year | |
Bager et al., (2012). Inflammatory bowel diseases, 18(5), 857-862. | Inflammatory bowel disease | Cohort study of 2.1 million Danish children born between 1973 and 2008 | |
Li et al., (2013). International journal of obesity, 37(7), 893-899. | Obesity | Nine studies meta-analysis | |
Darmasseelane et al., (2014). PloS one, 9(2), e87896. | Obesity | 35 studies meta-analysis | |
Sevelsted et al., (2015). Pediatrics, 135(1), e92-e98. | Chronic immune condition, asthma, leukemia, IBD | Denmark 1.9 million children aged between 0-15 years | |
Yuan et al., (2016). JAMA pediatrics, 170(11), 162385-89. | Obesity/overweight | Cohort study on Caesarean deliveries of 4,921 cases among 22,068 cases | |
Shao et al., (2019). Nature, 574(7776), 117-121. | Hospital acquired antimicrobial-resistance pathogens in C-section delivered babies | Metagenomic analysis of 1,679 gut microbiota samples from 596 full-term babies | |
Hurley et al., (2019). Journal of oral microbiology, 11(1), 1599652. | Infant oral microbiota infants remain unaffected to 4 weeks and continues to develop until 1 year of age | A cohort of pregnant women (n = 84) using high-throughput sequencing of V4-V5 region 16S rRNA amplicons of vaginal delivery & C-section | |
Stokholm et al., (2020). Science translational medicine, 12(569). | High asthma risk associated to C-section delivery | Gut microbiota of C-section delivered 700 children, examined by 16S rRNA gene amplicon sequencing | |
Susic et al., (2020). BMJ open, 10(9), e040189. | abnormal pregnancy physiology and development of disease | longitudinal cohort study on microbiota of 100 Australian mother-infant pairs | |
Antibiotic treatment changes Microbiota composition | Saari et al., (2011). Annals of medicine, 43(3), 235-248. | Obesity | A Finnish study enrolled 12062 children & ages between 0-2 years |
Kuppala et al., (2011). The Journal of pediatrics, 159(5), 720-725. | Antibiotic therapy associated with change in microbiota, leads to severe outcomes. | Multivariable logistic regression performed on infants with body weight (≤1500g) & gestational age (≤32weeks) to evaluate independent relationships between antibiotic therapy and study outcomes. | |
Kronman et al., (2012). Pediatrics, 130(4), e794-e803. | Inflammatory bowel disease | A study conducted in UK enrolled 9 million children | |
Hoskin-Parr et al., (2013). Pediatric Allergy and Immunology, 24(8), 762-771. | Eczema | Study in UK, cases enrolled 5780 with ages 0-2 years | |
Schwartz et al., (2016). International journal of obesity, 40(4), 615-621. | Obesity | Cohort US study enrolled 163820 children with ages 2-18 Years | |
Neuman et al., (2018). FEMS microbiology reviews, 42(4), 489-499. | Obesity, Allergies, autoimmunity diseases. | In this review, antibiotics effects on children microbiome was study to determine their correlation with long-lasting complications. | |
Eck et al., (2020). PloS one, 15(2), e0228133. | Antibiotic treatment reduces Bacteroidetes diversity which play vital role in healthy & stable gut microbiota development | This study enrolled 98 infants to examine antibiotic effects on the development of intestinal microbiota. | |
Probiotics | Braegger et al., (2010). Journal of pediatric gastroenterology and nutrition, 51(1), 110-122. | Probiotics use reduced non-specific GI infections | ESPGHAN Committee on Nutrition |
Maldonado et al., (2012). Journal of pediatric gastroenterology and nutrition, 54(1), 55-61. | Probiotics improved Respiratory tract & gastrointestinal and infections | Spanish study on 215 children having 0-6 months of ages | |
Grzeskowiak et al., Anaerobe. 2012 Feb; 18(1):7-13.
| Maternal probiotic supplementation showed significant influence on the composition of infants’ gut microbial, i.e., bifidobacteria increased significantly | Pregnant females (n=29) fed probiotic for four weeks before delivery and up to three weeks after delivery,
| |
Rutten et al., (2015). PloS one, 10(9), e0137681. | Minute and short term differences was observed in microbiota composition of probiotic and placebo group | In this double-blind, randomized, placebo-controlled study, probiotic administered to pregnant women and faecal samples of 99 children collected for bacterial profiling by IS-pro. | |
Tintore et al., (2017). Arch. Clin. Microbiol, 8(4), 56. | Probiotics supplementation modulates gastrointestinal microbiota in colicky babies which decreases relative abundance of Enterobacteria and help colic management. | This review focused on infant gut microbiota growth in infant with colic syndrome by providing probiotic formulations for infant colic management.
| |
Korpela et al., (2018). Microbiome, 6(1), 1-11. | Undesired changes in microbiota and its function improved by supplementing infants with a probiotic with breastfeeding. | Study was conducted to examine whether probiotic improve infant microbiota effected by antibiotic use or caesarean birth. | |
Dietary Supplementation | Zimmerman et al., (2010). The American journal of clinical nutrition, 92(6), 1406-1415. | Intestinal inflammation, lower frequency of colic or irritability | Study enrolled African children (n=139) with the ages of 6-14 years |
Chin et al., (2021). Nutrients, 13(3), 807. | Breastfeeding along supplementation with formula changes the microbiome composition of the gut,
| Study enrolled 24 infants, divided into two groups, first group were on breastfed while other group was on breastfeeding and also supplemented with formula. Evaluation of microbiotas was performed by 16S rRNA Sequencing and flow cytometry. | |
Dizzell et al., (2021). PloS one, 16(4), e0248924. | Significant modulation in infants microbiota | Cohort study enrolled 35 infants, who had started intake of solid food and cessation of breastfeeding. Metagenomics, 16S rRNA gene profiling & metabolomics of fecal sampling was analyzed. | |
Chen et al., (2021). New England Journal of Medicine, 384(16), 1517-1528. | Dietary supplementation findings provided significant changes in microbiota components that are linked infant’s growth. | Supplementary food administered to Bangladeshi children (123) to study microbiota composition.
|
Vaginal microbial transfer or exposure was consisting of sterile gauze incubated in the maternal vagina having pH < 4 xss=removed>5 and which were B Streptococcus negative. After birth, the gauze was used to spread or expose the maternal vaginal contents on the entire body of babies. During the first month of infant’s life, 1519 samples collected from anal, oral and skin and sequencing the V4 region of 16S rRNA gene was performed for the characterization of microbiome composition [7].
In this study, adverse events were not observed in the infants. The microbiome source tracking results revealed that four previously vaginal fluids exposed infants resemble microbiome to the vaginally delivered infants. At first day of life, microbiomes of vaginally delivered babies were similar to the C-section delivered babies which were exposed to vaginal fluids [8]. In newborn babies, microbial colonization occurs rapidly and changes continue to occur throughout the first month in all of the groups. Lactobacillus enriched anal samples were observed in both, exposed and vaginally delivered infants, that was not found in C-section delivered infants not exposed to vaginal fluids [9]. Previous studies explained a rich ecosystem of human microbiome that are important for the human health and physiology. The structure and function of microbial community in each body site is distinctive such as enteric microbes produce in the gastrointestinal tract (GIT) can modify various host metabolism supporting bio-active compounds. whereas low vaginal pH supports the growth of Lactobacillus spp. in the vagina [10]. It has been highlighted in previous studies that dysbiotic shifts in microbial communities is associated with the development of various human diseases, for instants, autoimmune disease, inflammation, obesity, inflammatory bowel disorders and GI-cancer [11]. In an animal model study, deficits in both innate and adaptive immune was confirmed in germ-free (GF) mouse models and concluded that normal growth and development is dependent on the commensal microbiota [12]. Postnatally, reintroducing microorganisms can improve these defects by immune development, however, even a short germ-free period can induce immunological changes that persist into adulthood and leads to various diseases [13]. The host immune system modulated by particularly different bacterial species, which confirms the normal pattern of host immune system depends upon the presence of specific bacteria within a given developmental window [14].
Human Microbiome Project Consortium explained dissimilarity in microbial communities populate in each body site on adults, even microbial composition is different in close proximity sites because of variations in micro-environmental conditions, such as nutrient, oxygen availability. A cohort study conducted on very low-birth-weight and pre-term babies and reported rapidly diverged microbiota of the skin, saliva and stool during first three weeks of life [15]. A large cohort study on healthy infants found on accurate determination/differentiation in microbiota of body site. Also, exogenous factors induced alteration microbiome is not cleared, like, delivery mode and breastfeeding practices. Recently, infant’s microbiota composition affected by the mode of delivery (i.e., C-section or vaginal delivery) has been subjected to evaluation of high rate cesarean deliveries and also to analyze association between microbiome structure and related autoimmune disease [16]. The cesarean delivery mode is a clinical decision made upon the basis of underlying maternal or fetal medical diagnoses. In previous studies, it is reported that composition differences in infant's gut microbiota with underlying medical indications among the cesarean deliver (emergent vs non-labored or elective) infants, rather than the surgical procedure [17]. The cesarean births are not performing on maternal request, but underlying medical conditions compels to the surgical procedures. Among these underlying medical conditions, the most important are arrest of active labor, fetal macrosomia, preeclampsia, fetal mal-presentation, increase serum levels of liver enzymes and C-section mode of delivery [18].
Mostly, cesarean deliveries are classified on the basis of active labor in mother. Also, not only cesarean deliveries but diet is one of the potent microbiota composition modifier because human milk has ability to potentially modify the infant microbiota [19]. Recently, our knowledge about the variations in the composition of human microbiome and their related disorders is expanding. There are numerous molecular techniques are using to understand and identify structure and function of the human microbiome through their proteomic, transcriptomic, metabolomics and immunomic knowledge through accurate and sophisticated DNA sequencing and the genomes analysis methods [20].
1.1 Human Microbiota
There are about more then100 trillion cells in the human body, and ten times more microorganisms in the intestines. The hundred times more genes are present in these gut flora then human genome so they perform almost same metabolic activities like an organ do [21]. Various beneficial functions are performing by gut flora like fermentation of substrates for energy, improve immunity, pathogenic bacteria growth inhibition, gut development regulation, and vitamin production (biotin and vitamin K) [22]. Now a day, pro- and prebiotics are most commonly using for therapeutic purposes to potentiate the intestinal microbiota for better health. Though, culturing of all gut species is very difficult, therefore, all gut microorganisms have not been identified yet. “Human Microbiome Project” is a newly non-cultured based technique using to describe microflora of the gut and other body sites [23]. This project also helping to characterization of human microbiome and their potential role to develop immune system for the better growth of human health. It is reported that however, microflora of human intestine and other body sites have divergent microbial populations, but playing foremost roles in health and disease [24]. In mucosal and skin environments colonizing microbial cells also have more genes than our human genome. It is estimated that about 500 to 1000 bacterial species existing in the human body at any one time, have greater orders of magnitude unique genotypes. Thousands of genes present in the genome of each bacterial strain that depicts the genetic diversity and flexibility in microbial genome than human [25].
Though, types and densities of microbes vary among individuals but it is poorly understood that what leads to variation and how they regulated. Notably, it is not yet clear that these microbial inter and intra-variation among individuals influences the overall health condition, occurrences or/and disease progression [26]. But, it is well established that immune deficiency is highly associated with the alteration in the human microbiome or microbial metabolome. Furthermore, the interaction of microbiome or their metabolome with the nervous, immune and endocrine systems are linked with the occurrences of various illnesses, such as, malignancy, inflammatory disease and nervous system disorders [27].
Previous studies reported the GIT of fetus the remain sterile but soon after delivery, microbial community come from maternal vagina, other body sites and the nearby environment for infant's gut colonization [28]. The mode of delivery has an impact on microbial exposure at birth because a huge and diverse bacterial spectrum found in mother’s amniotic fluid which is naturally 400 to 500 milliliters swallows by the baby when is in utero. In an order to confirm the promising infant’s microbiota origins, the investigators evaluated vaginal and maternal milk of the mothers, and stool samples of parents and two siblings. They found significant variations in temporal patterns and composition of microbial communities from baby to baby, but they suggested that distinctive characteristics of the microbial community depends mainly upon the incidental environmental exposures [29].
Vaginal delivery has been believed to be important for infant’s health because maternal vaginal and intestinal flora contacts with infant body which is essential for the start the colonization of the infant's body. In case of C-section delivery, infants do not contact with vaginal fluid and non-maternal environmental bacteria involved in infants’ colonization [30].
In breast feeding babies, first microbial colonization has long lasting effect upon the composition of microbiota. In a study it has been reported that infants born by cesarean delivery have disturbed primary gut flora up to first 6 months of the life [31]. In an another study it was confirmed by culture based techniques that differences in composition of intestinal microbes correlated with the mode of delivery [32]. Studies concluded the postnatal immune system development is depending primarily on intestinal bacteria and composition of the intestinal flora depending mainly upon the mode of delivery. In cesarean delivery, infants bypass the vagina and do not expose to microbes enriched vaginal fluid during birth. Variation in Differences in intestinal microbiota of new born babies is mainly linked with mode of delivery [33].
The epidemiological studies have reported that infants born by cesarean delivery most often suffer from atopic diseases because the postnatal immune system development might be different from infants of vaginally delivered [34]. There is an increasing evidence that the postnatal immune system development depends upon the intestinal microbiota, however, exact mechanisms is still unclear. It is observed that the development of neonatal immunity promoted by the production of various cytokines that are induces only by the vaginally delivery [35]. Previous studies found positive correlation between cesarean mode of delivery and disturbance in the infant's intestinal colonization. This interruption in intestinal colonization causes necrotizing enterocolitis (NEC) in preterm infants. Furthermore, they also confirmed that elective cesarean delivery infants may develop allergic diseases in upcoming life of childhood [36]. The infant’s enteric microbiota composition plays an important role in infant’s good health in the years to come. So, intestinal ecosystem of infants need more thorough identification and understanding for better health of newborns. Several epidemiological studies proved data that cesarean delivered infants are associated with a delayed onset of lactation. Therefore, the early support or stimulator needed to develop a normal physiological intestinal flora in cesarean mode delivered infants is the proper feeding of breast milk [37]. The development of improper infant's immune system and occurrence of various immune and nervous system related disorders are associated with both, non-physiological initiation of microbial colonization and poor dietary support by delayed start of lactation. Therefore, the careful identification of the intestinal ecosystem is fundamental need to assess the immune status of the newborn [38].
The immunological tolerance of new born-babies is instructed by proper induction of regulatory T lymphocytes their mother, which act as a source of first inoculum to colonized in new born babies [39]. Another current investigative study explained that initial communities’ inoculation at the early stages of life are direct source of protective microbes that are primary source of body's colonization. Vaginally born babies are colonized mostly by Lactobacillus, while in C-section delivery mode, a mixture of potentially pathogenic bacteria tends to colonize in babies such as Acinetobacter [40]. The negative effects of C-section mode of delivery appear in childhood or later age is related with immune mediated diseases, mostly they suffer from asthma and allergic rhinitis. Majority females born by cesarean found to be susceptible to asthma, while, most of C-Section delivered children are more significantly susceptible to celiac disease and they are needed to be hospitalized to properly treat gastroenteritis [41]. There is no association between cesarean delivery and ulcerative colitis or Crohn's disease has been reported up till now, however, while various other disorders such as Diabetes Mellitus (Type-I) and inflammatory bowel disease are reported to be induced by preterm birth [42].
2.1 Infant’s Microbiome
Both, culture-independent and culture-based studies examined that microbial habitat in maternal body sites that helps in infant’s body colonization. The culture-based studies reported that cultivatable bacteria such as Enterococcus, Streptococcus, Staphylococcus and Propionibacterium found up to some extent in umbilical cord and in larger quantity was observed in the meconium samples [43]. In a recent study, DNA extraction was performed from human placental samples containing bacterial species (Bifidobacterium & Lactobacillus). The analysis of intrauterine samples revealed not occurrence of cultivable bacterial cells. In animal studies, it is demonstrated that microbiota of maternal gut translocated through bloodstream to the fetus [3]. It is well established that the microbial biomass (Firmicutes, Tenericutes, Proteobacteria, Bacteroides and Fusobacteria) found in placenta have similar composition to nonpathogenic microbiota present in oral cavity and they suggested the translocation of bacterial biomass from placenta through material bloodstream to the fetus [16]. In vaginally delivered infants, Lactobacillus species enriched microbiome found in skin, gut, oral and nasopharyngeal cavities, which is similar to the vaginal microbiome of mother [44]. But this inoculum is not found in various body sites of the cesarean mode infants, though, their skin microbiome contains microbes found in environment such as Streptococcus, Staphylococcus or Propionibacteria [45].
The characterization of the maternal vaginal microbiota has been performed, because first bacterial inoculum is most important that is received by vaginally delivered newborns. The vaginal microbiota found in non-pregnant women is of almost six types, and five bacterial community state types (CSTs) have been successfully identified. Among these CSTs, four are present in white women and Asian females which are enriched in (Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners and Lactobacillus jensenii), while, fifth CST present in black and Hispanic women with significant lower Lactobacillus spp. level and highest diversity in numerous anaerobic bacteria [46]. It has been reported that pregnancy leads to alteration in the vaginal microbiome that produces distinction between pregnant and non-pregnant females. During pregnancy, vaginal microbiome shows greater stability in its composition with less microbial diversity that indicating the significance of microbiome in maintaining a healthy vaginal ecosystem [47].
2.2 The role Neonatal Microbiome in Immune Development
It is essential for a healthy immune system to have a balance correlation with the host’s microbiota because it is considered as critical factor for a host’s homeostatic response to the invasion of pathogenic bacteria and to cope with the development of inflammation in the body [48]. Many investigative studies have successfully reported that chronic pro-inflammatory states in host is associated with the dysbiosis in infants. The vaginally delivered babies have healthy immune system that induced by first bacterial inoculum that baby receives during vaginal delivery through their mother vaginal tract and contact with fecal matter. This inoculation causes significant bacterial load to the immature immune system of new born baby [49]. A TH2 phenotype is mostly observed in the neonatal innate immune system that results in the detection of helminth and parasite which ultimately leads to the induction of allergic responses in infants. Therefore, harmful pro-inflammatory responses are avoided by the neonatal innate immune system due to its biasness against TH1-cell-polarizing cytokines [50]. It is reported that immunosuppressed neonates usually have impaired immune response that make them highly susceptible towards attack by opportunistic pathogenic microorganism. With the passage of time and age, multiple pathogenic results in the conversion of TH2 phenotype toward TH1 polarization which make them resistant against the occurrence of allergy and atopy in adulthood [45]. While, in infant’s gut dysbiotic state cause the secretion of cytokines and interferon by making pro-inflammatory immune system which results in the disturbance in host’s normal immune regulating system, tissue damaging and poor infection healings. These conditions leads to longer duration pathological conditions such as autoimmune disorders [51].
2.3 Early-life Microbiome Composition and Diseases
As discussed before that abnormal composition of neonatal microbiota causes multiple diseases in adulthood. The abnormal lung function is associated with the to an abnormal microbiota that causes occurrence of asthma in pediatrics. In a comparative study, the gut microbiota of 319 children was analyzed and slightly bacterial diversity was found, but gut microbiome having both atopy and wheeze, were depleted with Fecalibacterium, Lachnospira, Rothia and Veillonella. [52]. In another study, gut microbiome composition was analyzed of 226 children with milk allergy and it was observed that usually upto the age of 8 years’ milk allergy resolves and children upto the age of 6 months’ resolve milk allergy if their gut’s microbiome enriched with Clostridia and Firmicutes, while, those children failed to resolved their milk allergy have higher Enterobacter, Trabulsiella and Salmonella levels in microbiomes. This alteration in young children microbiota was occurred due to reduced metabolism of bacterial fatty acid as results decreased branched-chain short fatty acids present in the gut of babies as compare to infants with milk allergy [53]. Many other studies explained that transitory bacterial community’s disturbances in infants commonly show clear phenotypes in adulthood [54].
2.4 Human genetics effect on infant’s microbiome
Each individual has a unique composition of the human microbiome. It is reported that even identical twins are also not similar in their microbial composition so human genome do not exert any significant effect on the assembly of the microbial community. Previous studies reported that no similarly in monozygotic twins in term of gut microbiota composition other than dizygotic twins, in contrast, large size twin cohort studies have showed that genetics have a less but statistically significant effect on human microbiome composition [55]. Host genetics involved in human diseases, such as metabolic disorders are associated with a distinctive gut microbiota composition that indicating the initiation of potential mechanism for pathogenic disorders that are linked with impaired bacterial regulation. Furthermore, it is also suggested that notoriously complexes are form upon interaction of host genetics and microbiota that may leads to genetic polymorphisms. In a study, Goodrich demonstrated that host bacterial composition is partially shaped by genetics and mostly it is environmentally determined which involved the colonization by Ruminococcaceae, Lachnospiraceae, and Bacteroidetes [56]. The complex and bidirectional relationship show by microbiome and immune system of all mammalian. In cohort studies it has been reported that the human genome is involved in inconsistency in stimulations by human immune response, whereas, 10% of this response variability is linked with interaction of human microbiome [57].
2.5 Postnatal factorsModulate Microbiome and Immune System
Human microbiome develops a specific biogeography in each site of the body during human growth. It has been reported that histrionic changes occur at different body sites in the microbiome structure and composition [58]. Microbial community composition and shape between different body’s sites is mainly dependent upon certain characteristics such as physical and topographical, which causes different shaping of microbiome among the individuals to develops a distinctive microbial signature regardless of the differences between skin sites [59]. Similarly, microbiota in adults are also unique to each person and remain relatively stable which was confirmed by the longitudinal characterization of the gut microbiome, but, in first three years of child life it undergoes extreme modifications [60]. Though, being a living ecosystem significant fluctuations have been observed in the microbiome growth rate and survival. Following are the factors which exerts profoundly impact on the microbiome composition and structure in early life [61].
2.5.1 Antibiotics: The most commonly prescribe drugs for the children is antibiotics. The neonatal microbiome is considered to be a delicate ecosystem that is disturbed by the use of postnatal antibiotics. Prolong antibiotics therapy is related with the increase risk of alternation in composition of normal microbiome composition that ultimately leads to the occurrence of several neonatal diseases such as asthma, allergies, inflammatory bowel disease, type 2 diabetes [62]. Previous studies suggesting that children expose to antibiotics in early life are more susceptible to the viral infections, and they attributed the impaired viral immunity to the increase antibiotic use in early age [63]. The antibiotics induced alteration in composition of microbiome and time require to return to baseline, is mainly dependent upon the both, type and duration of antibiotics used. Mice model studies have provided insight that how antibiotics disrupts microbiota composition, similar alternation in microbiota has also been reported in human studies. In another study, disruption in gut microbiota of mice was found followed by the increase in the total fat mass in mice [64]. After antibodies treatment, the significant flora reduction such as Allobaculum, Lactobacillus and filamentous bacteria after antibiotics treatment, which may further lead to the decrease in response of T-helper 17 cell in colon. A study on neonatal mice showed increased sensitization to food allergens after their treatment with broad-spectrum antibiotics. There were several members of Clostridia was involved in this phenotype that causes interleukin (IL)-22 production in the body, which further block food allergens to cross the intestinal epithelial layer [65]. The imbalance in the cell count of bacteria, viruses and fungi has also been observed with the antibiotic treatment. Previous studies have found that infant’s antibiotic treatment significant elevation in gastrointestinal fungal (Candida albicans) abundance that may lead to respiratory tract diseases due to the induction of mast cells, cytokines and other inflammatory mediators. In infants, prolong antibiotic use is also associated with the diminishing of the anti-viral immune response [66]. Although mouse models studies provided sufficient understanding about antibiotics induced alteration in host microbiome and their health outcomes. Though, antibiotic treatment for extended period of time in humans is unusual, so, human physiological responses can better be studied through the use of the humanized mice by prolong antibiotics use [67].
2.5.2 Diet: On human microbiome composition, impact of diet has been extensively previously studied and reported that diet modulation is related with the change the in microbiome. Thus, this study helps in producing new therapeutic strategies for treating various diseases by using gut microbiome as well as their metabolic products. The previous data suggested that gut microbiome composition is highly effected by the long term use of specific diet, while change in the diet for shorter period of time can cause similarly in the composition of gut microbiomes of different people within few days [68]. Interestingly, same dietary ingredient showed significant different effects on human blood glucose level among different people, this variation is assuming to be induced by the microbiome. The microbiome influences appetite by affecting the leptin concentration in humans [69].
The maternal breast milk is mainly nutrient source for infants during the first month of life, that has many benefits for the infants and their mothers such as lactation decreases maternal risk of hyperlipidemia, hypertension, diabetes and cardiovascular disease. However, the breast feeding positive effect on asthma is still not known, whereas, many studies collected evidence that improves lung function is associated with the prolonged breast-feeding [70]. The beneficial effects of breast-feeding to the infants are linked with secreted factors in the breast milk such as immunoglobin (Ig) A, lactoferrin and defensins. Breast-fed infants are enriched with Bifido bacterium and Lactobacillus and high acidic intestinal content found in those infants that fed entirely with formula which causes abundance of short-chain fatty acids (SCFAs) [71]. The bacterial fermentation of oligosaccharides in breast milk causes the production of SCFAs in infants, which cannot easily digest by the host and do not provide energy. Notably, milk oligosaccharides an only metabolize by Bifidobacterium strains present in children, while, certain other species found in the gut of adults such as B. longum ssp. longum species that are only responsible for the fermentation of complex carbohydrates but not to the oligosaccharides [72]. Previous studies reported that breast milk serve as a first inoculum for the newborn because it contains 107 bacterial cells per 800 ml of breast milk including Staphylococcus, Streptococcus, Lactobacillus and Bifidobacterium. In order to boost and support the beneficial microbial organism’s growth, probiotics are using now a day, which are live microorganisms provide health benefits to the host. Supplementation of pre or probiotics enriched infant formula milks are commonly using throughout the world, regardless sufficient data supporting their efficacy [73]. Several studies failed to provide probiotics supplementation beneficial effects on health in numerous pediatric diseases including obesity, GI infections and allergies [74]. Many meta-analyses reported probiotics produces positive therapeutic outcomes in the treatment of atopic dermatitis, while, others studies did not highlight any therapeutic effect of probiotics in disease treatment. The IgE reduction reported by a meta-analysis on the probiotics using infants, but they did not find directly any effect on the wheeze or asthma [75].
2.5.3 Environmental Exposure: One of the natural source of microbes to colonize in different body parts of infants is surrounding environment comprise of touching and shared objects, surfaces and indoor air generates the probability of bacterial exchange. In a study on 60 family members, it was observed that all family members have similar composition of oral, gut and skin microbiota than unrelated subjects. A study was performed on microbiota composition among 60 family members and it was found that microbiota composition of their oral, gut and skin was similar than unrelated subjects.
This similarity in microbiota composition is probability due to cohabiting [76]. Furthermore, impact of cohabiting is more highlighted by a study, which suggesting that genetically unrelated parents also share their microbiota to the larger extent with their children [77]. These finding are further confirmed by the genomes sequencing of bacterial strains present in the family members, that similar bacterial strains are shared among the family members than unrelated subjects. Remarkably, genomic sequencing analysis revealed that some of shared bacterial strains detected in mothers and their adult daughters, indicating their infant’s life exposure to specific strains that make life-long colonization [78].
In early infant’s life, pets and animal’s frequent exposure in early life help in the development of immune tolerance in infants by increasing protective effect against various diseases though divergent microbial colonization in different body parts [79]. Similarly, in another study of 3143 children showed inverse relationship with preclinical type I diabetes, which were exposing to indoor dogs during the first year of life demonstrating their healthy immune status. The significant reduction in allergy and asthma was observed in children which were exposing to pets during their early life. Previous studies attempted to understand the protective effect of pet exposure against allergies and suggested that Lactobacillus johnsonii were increased in the gut microbiota of pet exposed mice [80]. A large size of family and frequent exposure to endotoxin in house dust may leads to increase in Bifidobacterium and reduction in Bifidobacterium adolescentis, Lactobacillus and Clostridium difficile in the first 2 months of infant’s life, which is responsible for the development of allergies in later period of their life [81]. The impact of environment on microbial diversity is highlighted by a study conducted on the children living in the farms and they found microorganism on farm dwellings children were similar to those microbial organisms found in animal sheds and differ significantly than those of not farm dwellings children. These finding demonstrating that bacterial colonization in infants is highly linked with their environmental exposure during childhood [82].
2.5.4 Body Site:
Each site of the human body develops a specific biogeography all through human development, because site specific routes followed by the human microbiome. The microbiome composition and structure shows intense distinction in across different skin sites. The shape of microbial community mainly dependent upon the physical characteristics of skin [83]. A distinctive microbial signature develops between each person regardless of the variances between skin sites. Previous studies explained that composition of microbial community is highly influenced by the prolonged physical interaction between humans, while each individual maintain their unique oral microbiome composition. The gut microbiota composition remains relative stable in life, in contrast drastic changes in composition take place over the first three years of life [84]. It has been observed that the proliferation of the microbes in gut is also influence by the transit time of food in the gut. Biofilm formation or rapid cell division is also related with a rapid transit time in gut [85]. Similar to skin microbiome, vaginal microbiome also shows a higher degree of stability. But Asymptomatic women show either domination by individual species or diverse additional anaerobic taxa in the vaginal microbiota. The abundance of
Lactobacilli
in considered to be beneficial by reduction in the vaginal pH of host by fermenting end products, that ultimately leads to the reduction of chance of colonization of
allochthonous
microbial species. The normal vaginal ecosystem is easily disrupted by various diseases such as bacterial vaginosis as result microbial profile becomes similar among the women that provides investigative biomarker of disease [86].
The high impact of the caesarean delivery mode on the composition of infant’s microbiota and on their effect on the future maternal and infant’s health is highlighted by the evidence discussed in this review. The observations presented here emphasize that abnormal microbiome development in infants are related with high risk of chronic immune disease. Cesarean delivery bypasses the baby from vaginal fluid that is most important first inoculum for newborn to develop proper immunity. Cesarean delivery is associated with immune deficiency that leads to several chronic immune diseases in later life. Further studies are needed to understand and confirm the relationship between C-section mode of delivery and infant’s brain function later in life.
Conflict of Interest: The authors report no conflicts of interest.
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