Cesarean delivery is associated with celiac disease but not ...

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Sep 24, 2010 - DOI: 10.4161/gmic.2.2.15414. Correspondence to: Mathias Hornef and ... A, Gerner P, Laass M, Ney D, et al. Cesarean deliv- ery is associated ...
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ARTICLE ADDENDUM

Gut Microbes 2:2, 91-98; March/April 2011; © 2011 Landes Bioscience

Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children Evalotte Decker, Mathias Hornef and Silvia Stockinger Institute for Medical Microbiology and Hospital Epidemiology; Hannover Medical School; Hannover, Germany

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Key words: cesarean delivery, celiac disease, gut microbiota, inflammatory bowel disease, mucosal immunology, epithelial barrier Submitted: 09/24/10 Revised: 01/28/11 Accepted: 03/08/11 DOI: 10.4161/gmic.2.2.15414 Correspondence to: Mathias Hornef and Silvia Stockinger; Email: [email protected] and [email protected] Addendum to: Decker E, Engelmann G, Findeisen A, Gerner P, Laass M, Ney D, et al. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics 2010; 125:e1433-40. DOI: 10.1542/peds.2009-2260, PMID: 20478942

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he postnatal period represents a particularly dynamic phase in the establishment of the host-microbial homeostasis. The sterile protected intestinal mucosa of the fetus becomes exposed to and subsequently colonized by a complex and diverse bacterial community. Both, the exposure to microbial ligands and the bacterial colonization have been described to differ between neonates born vaginally or by cesarean delivery. These differences might influ©20 1 1L an desBi os c i enc e. ence the development of the mucosal Donotdi s t r i but e. immune system, the establishment of a stable intestinal host-microbial homeostasis, and ultimately contribute to the risk to acquire immune mediated diseases later in life. Indeed, an increased risk for atopic diseases such as allergic rhinitis and asthma was reported in children born by cesarean delivery. Our recent study described an association between cesarean delivery and celiac disease. Here we summarize the available information on postnatal microbial colonization and the influence of the mode of delivery on flora composition and host microbial homeostasis. We discuss possible consequences of the mode of delivery on epithelial barrier function and the establishment of the mucosal immune system and speculate on functional links between flora alterations and the development of inappropriate host immune responses that may contribute to enteric inflammatory diseases. The rate of cesarean delivery in western nations has risen dramatically in the last few decades, from 4.5% in 1962 to now 31.8% in the United States and 30.2%

in Germany.2,3 The world’s highest rate is reported from China approaching the 75% mark in big urban cities.4 Recent investigations have demonstrated that the mode of delivery influences the postnatal bacterial colonization of the intestinal mucosa.5 Considering new emerging concepts on the complex interplay between the bacterial microflora and the mammalian host, the present review aims to discuss the potential influence of alterations in the microbial exposure and microflora development associated with cesarean delivery on the pathogenesis of intestinal inflammatory diseases. Cesarean Delivery is Associated with an Altered Gut Flora During development in the uterus the fetus is sterile and protected from microbial exposure. With rupture of the membranes, passage through the birth canal, and contact to the microbially inhabited environment, the contact of the infant’s skin and mucosal surfaces with microbial substances and living microbes begins. Exposure to immunostimulatory microbial constituents may trigger an activation of the infant’s mucosal innate immune system as this has recently been demonstrated in the mouse model.6,7 In addition, exposure to the mother’s vaginal, intestinal and skin flora initiates colonization of the newborn’s skin and mucosal surfaces such as the gut with commensal bacteria. The first bacteria detected in the intestinal tract are Streptococci, Lactobacilli and members of the Enterobacteriaceae. By reducing oxygen as a consequence of their metabolic activity, these bacteria

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establish the milieu for subsequent colonization by obligate anaerobic bacteria like Bifidobacterium, Bacteroides, Clostridium and Ruminococcus that ultimately form the vast majority of intestinal commensal bacteria.8 The diversity of the microbiota increases gradually over time with some major shifts at weaning or changes in diet.9 For example, breast feeding influences the neonates’ intestinal flora by enhancing the growth of Bifidobacterium. By the end of the first year of life, the human microbial ecosystem shows a profile similar to the adult gastrointestinal tract.10 The adult human gastrointestinal tract harbors around 1014 bacteria, outnumbering the number of eukaryotic cells in the body by 10 times. The mature microbiota comprises around 500–1,000 species and the composition of an adult individual’s microbiome remains relatively stable throughout the whole life. More than 90% of species colonizing the large intestine belong to two different phyla, the Firmicutes and the Bacteroidetes. Most of the remaining 10% belong to the Proteobacteria (including e.g., the well known Escherichia coli), Actinobacteria, viruses, protists and fungi.11-13 The factors that direct the infants’ flora and maintain the bacterial composition during adulthood are largely unknown. The gut microbiota fulfils a variety of functions including processing of nutrients, regulation of fat storage, protection against pathogenic bacteria by occupation of niches and maturation of the mucosal immune system. The microbial flora has a profound influence on the general architecture of the gut and on the epithelial barrier function. Studies performed with gnotobiotic (germ-free) mice stress the importance of the commensal flora. For example, gnotobiotic mice need 30% more calorie input for maintaining their body weight, exhibit an enhanced susceptibility to infection with enteropathogenic bacteria, and develop an only immature immune system.14 The mode of delivery influences the postnatal development of the intestinal microflora.5,15 Children born by cesarean delivery prior to rupture of the amnion membrane are not exposed to the maternal flora in the birth canal. In addition, these infants are often confronted with

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prolonged mother-infant separation, longer hospital stays and deferred and shorter breast-feeding periods.16,17 Colonization after cesarean delivery is considerably delayed and the microbiota shows an altered bacterial diversity.15 In addition, cesarean delivery leads to an increased colonization by bacterial members derived from the skin of the mother or nursing staff and other environmental sources that particularly in a hospital setting may carry an enhanced antibiotic resistance profile.5,8,18 It has also been noted that infants born by cesarean delivery have lower numbers of Bifidobacterium and Bacteroides.19 Other studies have confirmed these findings and additionally demonstrated an increased colonization with Clostridium difficile compared to vaginally delivered infants.20,21 A recent analysis of the neonate’s microbiota by 16S ribosomal DNA pyrosequencing demonstrated that vaginally delivered infants acquired bacterial communities primarily resembling the mother’s vaginal microbiota (i.e., with large numbers of Lactobacilli). In contrast, ©2 babies born by cesarean delivery 01 1L ande sB i os c i enc e. harbored bacterial communities similar Donotdi s t r i but e. to those found on the skin surface (i.e., Staphylococci), with an enhanced transmission from non-maternal sources, consistent with earlier studies.5 Although these alterations are generally believed to be only transient and a large physiological variability of the intestinal flora in neonates has been documented, differences between the intestinal flora of cesarean and vaginally delivered children have been reported even after seven years of age.10,22 However, the neonates’ microbial exposure during and after birth is affected by additional factors. For example, cesarean delivery performed after rupture of the amnion membranes may expose the neonate to the mother’s bacterial flora similar to the situation during vaginal delivery. Also, ascending infections of the mother might lead to microbial exposure of the neonate prior to birth. Finally, the hygienic conditions or maternal diseases might influence the bacterial environment after birth. Careful consideration of these factors will be required in order to clarify the influence of the mode of delivery on the bacterial colonization and host-microbial homeostasis at the intestinal mucosa.

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Diseases Associated with an ­Altered Gut Flora Alterations of the microbial gut flora have been linked to inflammatory and autoimmune diseases.23-25 They have been noted in a variety of conditions including atopic dysorders like allergic asthma, inflammatory bowel diseases (IBD) with its two major forms Crohn disease and ulcerative colitis (UC) and celiac disease.23-25 It is, however, still unclear whether flora alterations in humans play a disease-promoting or even causative role or might merely emerge as a consequence of the pathophysiology of the diseases or associated factors such as e.g., antibiotic or immunomodulatory treatment regimens. Nevertheless, many diseases associated with an altered gut flora are characterized by a deregulated immune response towards harmless antigens in a genetically predisposed host and thus a careful evaluation of a possible disturbance in the host-microbial interaction is warranted. IBD is characterized by a chronic recurring inflammation of the intestinal mucosa, leading to diarrhea, abdominal pain and an increased risk to develop colon carcinoma. Whereas the inflammatory process in UC is restricted to the colon and rectum, any part of the gastrointestinal tract can be affected in patients with Crohn disease.26,27 Both types of IBD are multifactorial disorders and occur in genetically susceptible individuals. In recent years, several genetic risk factors have been identified that might be responsible for a deregulated immune response towards harmless antigens. The identified genes are involved in the epithelial barrier formation of the mucosal immune system. For example, multiple genes involved in the IL-23 signalling pathway like IL23R, IL12B or Stat3 are associated with both manifestations of IBD, Crohn disease and UC. On the other hand, alterations in genes of the innate immune system such as Nod2/Card15 (encoding for a pattern recognition receptor recognizing degradation products of bacterial peptidoglycan), ATG16L1 (encoding autophagy related 16-like protein 1) and IRGM (immunityrelated GTPase family, M) are specifically linked to Crohn disease but not to UC.28 The precise functional consequence

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of the respective genetic variation in the context of the clinical symptoms of IBD in humans is only beginning to be understood. The current hypothesis proposes that the genetic predisposition causes a deregulated immune response against harmless antigens derived e.g., from intestinal commensal bacteria. Indeed, next to genetic factors, changes of the intestinal flora composition have been described in patients with IBD. Several studies found an enhanced number of Proteobacteria and Actinobacteria but decreased numbers of Firmicutes (particularly the species Faecalibacterium prausnitzii) in stool samples of IBD patients as compared to healthy controls.25,29,30 In general, studies in humans have shown that IBD patients harbor an increased total number of bacteria but a reduced microbial diversity with a diminished Firmicutes/Bacteroidetes ratio in their gastrointestinal tract.30 In biopsies of pediatric IBD patients, higher numbers of mucosa-associated aerobic and facultative-anaerobic bacteria were found, whereas bacterial species of the normal anaerobic intestinal flora such as Bifidobacteria were reduced.31,32 As mentioned above, however, it is unclear, whether the described flora alterations play a causative role or represent a consequence of the genetic defects associated with IBD or the administered medical treatment. Qualitative and quantitative changes of the intestinal flora have also been reported in irritable bowel disease.33 It represents a non-inflammatory condition associated with an enhanced susceptibility of the intestinal nervous system to exogenous and endogenous stimuli. The clinical picture is quite diverse with both constipation and diarrhea as manifestation of bowel dysfunction and abnormal gut motility. The molecular basis for the enteric dysfunction in this disease, however, is largely undefined. In contrast, a rather clear picture of the pathogenesis emerges from studies on celiac disease. Celiac disease is characterized by chronic inflammation of the small intestinal mucosa. It develops in genetically susceptible individuals in reaction to dietary gluten, the storage proteins of barley, wheat and rye. The major predisposing genetic factor is in the human leukocyte antigen (HLA) complex, with

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90–95% of celiac disease patients expressing HLA-DQ2 or HLA-DQ8. Expression of this HLA molecule by antigen-presenting cells promotes the presentation of gluten peptides to CD4 + TH1 cells in the intestinal lamina propria.34 Early gluten feeding is significantly associated with the development of celiac disease later in life.35 Activation of intestinal epithelial lymphocytes (IEL) and the secretion of cytokines subsequently lead to tissue damage and malabsorption. Interestingly, HLA-DQ8 transgene mice show a TH1mediated immune response when fed with gluten but not a gluten-induced enteropathy, indicating that additional factors play a role in the loss of oral tolerance towards gluten.36 Several studies have also demonstrated an altered composition of the microbial flora in pediatric patients with celiac disease. Culture dependent and independent methods revealed elevated levels of Bacteroides, Clostridium and Staphylococcus in the fecal microbiota.37 Also, the analysis of duodenal biopsy specimens by fluorescence in situ hybridization (FISH) and flow cytometry ©201 1L andes Bi o s c i en c e. revealed higher total bacterial counts and Donotdi s t r i but e. enhanced numbers of gram-negative bacteria like Bacteroides and E. coli in celiac disease patients compared to healthy controls.38 Temporal temperature gradient analysis (TTGE) profiles of 16S rDNA derived from duodenal biopsies showed a significantly higher biodiversity and an increased detection rate of Bacteroides vulgatus and E. coli in celiac disease patients compared to controls.39 Finally, reduced levels of immunoglobulin A (IgA)-bound to the bacterial surface were noted in fecal samples of celiac disease patients compared to healthy controls. In particular, IgA-coated bacteria of the BacteroidesPrevotella group were significantly lower, whereas the relative abundance of these bacteria was higher, suggesting a possible reduced adaptive host response against these bacteria.40 Interestingly, administration of a gluten-free diet is able to reverse alterations of the microflora composition.35,41 A number of animal models has been developed to study the consequences of defined genetic defects and their functional influence on intestinal homeostasis and the pathogenesis of mucosal

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inflammation. Of note, these models not only illustrate the complex regulatory circuits that facilitate gut homeostasis but additionally highlight the important role of environmental factors such as the microbial exposure in the context of a genetic dysfunction. The observation that several genetic mouse models of intestinal inflammation do not develop clinical symptoms when rederived under germfree conditions, supports the hypothesis that the interaction between the intestinal flora and the immune system plays an important role in disease pathogenesis.25,42 On the other hand, mice carrying defined mutations in genes associated with the intestinal mucosal host defense exhibit significant alterations of the intestinal flora indicating a role of the host in the regulation of the flora composition.43-46 The first evidence for a critical and direct influence of the gut microbiota composition in the pathogenesis of intestinal inflammation was provided by the T-cell independent TRUC (T-bet-/- x RAG2-/-) mouse model. The transcription factor T-bet is an essential regulator of CD4 + TH1 cells but is also expressed by a variety of other immune cells. T-betdeficient mice develop spontaneous colitis and harbor a severely altered intestinal flora.47 Strikingly, TRUC colitis is vertically and even horizontally transmissible into cohoused wild-type animals suggesting both that genetic dysfunction can influence the microflora composition and that flora alterations harbor the potential to evoke an inflammatory reaction.47 Interestingly, a subsequent analysis identified a role of the Enterobacteriaceae Klebsiella pneumoniae and Proteus mirabilis in maternal transmission of TRUC colitis.48 A reason for the proinflammatory effect might be the synthesis of larger quantities and more potent immunostimulatory innate immune receptor ligands by these bacteria.49 It should be clearly stated, however, that the current information on the gut microbiota only represents the starting point of an ongoing effort to characterize the composition of the enteric microflora and identify possible disease-associated alterations. Also, due to sample accessibility, most results so far have been obtained from animal studies. Work in

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the near future will help to obtain a more representative picture and to better link flora changes with pathophysiological parameters and clinical symptoms also in humans. Nevertheless, the published studies identify the enteric microflora as a potential target for therapeutic interventions. Despite significant effort, however, oral administration of beneficial commensal bacteria (commonly referred to as probiotics) has not revealed convincing clinical improvement in patients with inflammatory intestinal diseases. Meta-analyzes on the effect of probiotic therapy in patients with Crohn disease concluded that there is insufficient evidence for a beneficial effect of probiotics for the induction or maintenance of remission, or prevention of relapse.50,51 Similar conclusions resulted from studies on UC indicating no improvement of remission rates and an only very modest effect on disease activity in selected patient groups.52 Probiotics, however, had a beneficial effect in the treatment and prevention of chronic pouchitis in UC colitis and a clinical benefit was observed in patients with irritable bowel syndrome.53-55 It also showed modest efficacy in children with viral gastroenteritis and antibiotic-associated diarrhea.54 A different strategy is the transfer of a complex bacterial mixture. Local application of fecal bacteria obtained from healthy donors was beneficial in UC patients with a prolonged effect on the flora composition.56,57 Thus, although new strategies might be required, reconstitution of the physiological flora remains an interesting therapeutic aim and might become part of the treatment regimen of enteric inflammatory disorders in the future. Interaction between the Gut Flora and the Immune System Around 70% of the vertebrate’s immune system is found within the gut tissue. Immune cells are situated in well-organized lymphoid structures as well as scattered throughout the lamina propria. Only separated by one layer of mucuscovered epithelial cells, an enormous number of intestinal bacteria as well as antigens derived from processed food are found within the intestinal lumen. The

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epithelial barrier hinders invasion and systemic spread of microbes and prevents an inappropriate immune response to innocuous luminal antigens. On the other hand, the bacterial flora represents an important stimulus for the maturation of the mucosal immune system illustrated by the only immature immune system in gnotobiotic mice.14 Intestinal epithelial cells (IECs) and mucosal immune cells have been shown to express pattern-recognition-receptors (PRR) like Toll-like receptors (TLR) and nucleotide-oligomerization-domain (NOD) like receptors, enabling them to respond to distinctive microbial-associated molecular patterns (MAMPs) such as for example lipopolysaccharide (LPS), peptidoglycan degradation products or unmethylated bacterial CpG DNA. In general, signalling initiated by the recognition of these non-self molecules culminates in the activation of transcription factors like NFκB and the production of proinflammatory mediators, antimicrobial substances and reactive oxygen species. This facilitates a potent host defense inL the event of infection ©201 1 a nd esBi os c i enc e.with enteropathogenic microorganisms.58 Donotdi s t r i but e. However, tight regulatory mechanisms exist that prevent an inappropriate reaction to harmless non-invasive microbes. These mechanisms include compartmentalization of pattern recognition receptor expression, a large number of regulatory circuits of the involved signal transduction cascades and enzymatic degradation of microbial immune stimuli.59-61 In addition, members of the bacterial flora dampen immune activation by inducing inhibitory regulatory circuits or by expression of pattern molecules with reduced immunostimulatory potential.14 A certain degree of innate immune stimulation by pattern recognition molecules from commensal bacteria appears to be beneficial. For example, mutations in Nod2 are associated with IBD in humans.62,63 Also, signal transduction via TLR2 and 4 triggered by commensal bacteria promotes an intact epithelial barrier after a chemicallyinduced colitis in mice.64 TLR dependent signals mediate important regenerative signals to maintain mucosal integrity in the mouse colon.65 Additionally, lack of expression of TLR5, the pattern recognition receptor responsible for recognition of

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bacterial flagellin, is associated with a significantly altered gut flora in mice, which triggers the development of a metabolic syndrome.46 Although alterations in the gut microbiota have also been observed in obese humans66 and functionally relevant mutations in human TLR5 are known, the role of TLR5 in human metabolic disorders has not been studied.67 In addition to the effect of global changes in the flora composition, also individual commensal bacteria might promote specific functions of the mucosal immune system. For example, segmented filamentous bacteria (SFB) are essential for the development of TH17 cells, a subset of T cells producing the proinflammatory cytokine IL17.68,69 SFBs are sufficient to drive autoimmune disease via the induction of TH17 cells which has been shown in mouse models for autoimmune arthritis70 and multiple sclerosis.71 Also, a single molecule produced by one specific bacterial species can have a profound impact on the gastrointestinal immune system. Polysaccharide A (PSA) produced by Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential.72 PSA can even cure established experimental colitis in animals by promoting the development of IL-10 producing regulatory T cells.73 Influence of the Mode of D ­ elivery on the Immune System and ­Enteric Disease Vaginal birth exposes the newborn to the maternal vaginal and fecal flora and thereby provides the first microbial stimulus which the neonate’s innate immune system encounters.7 A spontaneous transcriptional activation of the intestinal epithelium shortly after vaginal delivery was described in mice.7 This early epithelial stimulation strongly diminishes the expression of the essential innate immune signalling molecule interleukin-1-receptor-associated kinase 1 (IRAK1) causing a shift in the epithelial gene expression and tolerance towards toll-like receptor ligands during the neonatal period. Importantly, this adaptive process of tolerance acquisition was not detected in mice born by cesarean delivery, indicating

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that the mode of delivery and contact to microbial ligands during birth indeed might exert a significant influence on the neonate’s innate immune system.7 It is unclear whether a similar adaptive process also occurs in humans but recent studies have demonstrated that the mode of delivery influences the function of phagocytes and the expression levels of TLR2 and TLR4 on monocytes.74,75 Thus, in addition to differences in the early bacterial colonization, the mode of delivery might have a direct influence on the postnatal mucosa.5,6 Epidemiological studies revealed that children born by cesarean delivery have more respiratory problems during the postnatal period, an increased risk to develop allergic asthma and a 20% higher likelihood for type I diabetes.76-78 However, a number of important confounding factors have to be considered in the discussion of a possible association. First, many chronic inflammatory diseases enhance the mother’s risk to require cesarean delivery but also exhibit a genetic predisposition. For example, mothers with type I diabetes exhibit an enhanced rate of cesarean delivery and simultaneously pass the genetic susceptibility for diabetes to their offspring.79 Diabetes additionally harbors the risk of an adverse neonatal outcome including bronchopulmonary dysplasia. Maternal Crohn disease is a known risk factor for cesarean delivery due to prematurity or colonic fistulas and given the genetic trait in turn enhances the risk of the infant to develop this disease.80 Also mothers with rheumatoid or other autoimmune disorders exhibit an enhanced risk for cesarean delivery.81 Second, the lower gestational age at birth in many infants born by cesarean delivery predisposes to respiratory morbidity. In fact, even near term prematurity (37–38 weeks of gestation) in respect to repeat cesarean delivery was recently associated with an adverse respiratory outcome.82 Thus, future studies should carefully consider these and additional possible confounding factors in their study design. Nevertheless, we feel that the published results warrant a careful analysis and discussion. In parallel to the increasing rate of cesarean delivery during the last decades, the prevalence of TH2-mediated allergic www.landesbioscience.com

disorders like asthma and TH1-mediated autoimmune diseases like celiac diseases or Crohn disease has steadily increased in western countries. The classical ‘hygiene hypothesis’ proposed an explanation for the increase in allergic diseases claiming that the prevention of infectious diseases mainly during childhood due to improved hygiene and vaccination programs may have biased the immune system towards a more TH2-prone reactivity. A modified version of this theory later more generally considered the reduction of infections and a somewhat more restricted exposure to the microbial environment to impair the establishment of an effective immuneregulatory network (for example appropriate IL-10 expression) to control both, an inappropriate TH2- and TH1-mediated immune reactivity. This might in turn promote the incidence of allergic and autoimmune diseases.83-85 In accordance with the modified hygiene hypothesis, restriction from microbial exposure early during life by cesarean delivery might affect the individual’s susceptibility to inflammatory diseases. ©201 1L andesBi os c i enc e. We recently observed an enhanced Donotdi s t r i but e. risk for children born by cesarean delivery to acquire celiac disease.1 Similar to the above mentioned studies, this finding must be interpreted with caution and requires confirmation in additional larger studies. Nevertheless it raises some interesting questions. Alterations in the microbial exposure and a delayed establishment of the enteric microbiota might impair maturation of the mucosal immune system and the formation of an intact intestinal barrier. This might affect both the anti-infectious host defense as well as regulatory mechanisms of immune homeostasis. Several studies have illustrated the necessity of immune regulatory functions to prevent gluten-induced enteropathy. Both forms of IELs, CD8 + TCRαβ+ and TCRγ/δ+ lymphocytes are increased in tissue sections of active celiac disease, while patients on a gluten free diet only exhibit enhanced numbers of TCRγ/δ+ cells.86 The latter exert immune regulatory functions on cytotoxic CD8 + TCRαβ+ cells via TGFβ. TGFβ itself seems to be regulated by the inflammatory cytokine IL-15, which plays a crucial role in the generation of epithelial damage in active

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celiac disease.87,88 The enhanced rate of early gastrointestinal infections noted in children that later develop celiac disease might indicate an impaired anti-infectious host defense.1 Similar to this, an elevated rotavirus infection rate was found in children with celiac disease.89 Breakage of the intestinal barrier during infection and the accompanying inflammatory T H1mediated immune response might act in concert with a less developed immunoregulatory network as cumulative risk factor in celiac disease.90 In addition, the altered microflora might directly influence the establishment of the TH1/TH2 balance during the postnatal period and result in a diminished expression of protective cytokines favoring a more inflammation-prone environment. Gliadin peptide p31-43 has been proposed to directly stimulate an innate immune response with subsequent secretion of IL-15.91 The increased production of proinflammatory cytokines in turn might via a self-enhancing loop increase the intestinal permeability.92 Disturbance of the intestinal epithelial barrier might then promote contact of subepithelial immune cells to the immunostimulating gluten leading to an aberrant imprinting and exaggerated deregulated immune responses later in life (Fig. 1). Conclusions and Outlook The processes that take place at the mucosal surfaces shortly after birth and during the neonatal period may exert an important influence on the development and maturation of the mucosal immune system and the establishment of a stable enteric homeostasis. Alterations of the mucosal host-microbial interaction during the neonatal period might thus contribute to the pathogenesis of inflammatory diseases of the intestinal mucosa like for example celiac disease. We are only beginning to understand the complexity of the intestinal microbiota and its functional influence on the host’s immune system. New findings and innovative technical approaches will pave the way to a deeper understanding of the physiology of the intestinal mucosa and host-microbial interplay, including efficient nutrient absorption on the one hand and a robust but dynamic barrier formation on the other hand.

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©201 1L andesBi os c i enc e. Donotdi s t r i but e.

Figure 1. (A) Birth by cesarean delivery is associated with an altered microbial exposure and an altered microflora. This might affect the antimicrobial host defense against pathogenic microorganisms, the development of an immune regulatory network and a balanced TH1/TH2 system. A possible consequence could be a shift to a more inflammation-prone environment and an increase in intestinal permeability. (B) Later in life, contact of the mucosa-associated immune system with luminal gluten might be increased in children born by cesarean delivery resulting in stronger inflammatory immune responses in genetically predisposed individuals. At the same time, immune regulatory mechanisms might be impaired, ultimately leading to tissue damage and malabsorption.

Acknowledgements

This work was supported by an APARTfellowship of the Austrian Academy of Sciences (to S.S.) and founding by the German Research Foundation (Ho2236/5-3), the German Ministry for Science and Education (DLR 01GU0825 and 01KI0752), and the Collaborative Research Center (SFB 621 and SFB900). References 1. Decker E, Engelmann G, Findeisen A, Gerner P, Laass M, Ney D, et al. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Pediatrics 2010; 125:1433-40. 2. Federal Statistical Office B, Germany 2009. Available at: http://www.destatis.de/jetspeed/portal/cms /Sites /destatis /Internet/EN/Navigation/ Homepage__NT.psml.

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3. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for 2007. Natl Vital Stat Rep 2009; 57. Available at: http://www.cdc.gov/nchs/data/nvsr/ nvsr57/nvsr_12.pdf. 4. Qiu L, Binns C, Zhao Y, Lee A, Xie X. Breastfeeding following caesarean section in Zhejiang Province: public health implications. Asia Pac J Public Health 2008; 20:220-7. 5. Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010; 107:11971-5. 6. Chassin C, Kocur M, Pott J, Duerr CU, Gutle D, Lotz M, et al. miR-146a mediates protective innate immune tolerance in the neonate intestine. Cell Host Microbe 2010; 8:358-68. 7. Lotz M, Gutle D, Walther S, Menard S, Bogdan C, Hornef MW. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 2006; 203:973-84. 8. Adlerberth I. Factors influencing the establishment of the intestinal microbiota in infancy. Nestle Nutr Workshop Ser Pediatr Program 2008; 62:13-29.

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9. Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R, et al. Microbes and Health Sackler Colloquium: Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci USA 2010. 10. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol 2007; 5:177. 11. Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 2010; 10:159-69. 12. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora. Science 2005; 308:1635-8. 13. Ley RE, Hamady M, Lozupone C, Turnbaugh PJ, Ramey RR, Bircher JS, et al. Evolution of mammals and their gut microbes. Science 2008; 320:1647-51. 14. Hooper LV. Do symbiotic bacteria subvert host immunity? Nat Rev Microbiol 2009; 7:367-74. 15. Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr 2008; 138:1796-800.

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