The aim of this study was to analyze a possible association between cesarean delivery and enteric inflammatory diseases in children.
A retrospective, multicenter, case-control study that included 1950 children was performed in cooperation with 26 university and 16 nonacademic children's hospitals. Information on intestinal disease manifestation, together with mode of delivery and gestational age at birth, postnatal complications, and breastfeeding, was collected by the attending physician from children and their parents who were visiting a gastrointestinal outpatient clinic for Crohn disease (CD; 516 cases), ulcerative colitis (250 cases), celiac disease (157 cases), and other gastrointestinal diseases (165 cases) and control subjects who were visiting ophthalmologic, orthodontic, and dental outpatient clinics (862 cases).
Whereas the rate of cesarean delivery of children with Crohn disease or ulcerative colitis was similar to that of control subjects, a significantly enhanced likelihood of being born by cesarean delivery was found in children with celiac disease compared with control subjects (odds ratio: 1.8 [95% confidence interval: 1.13-2.88]; P = .014).
The mode of delivery and associated alterations in the development of the enteric homeostasis during the neonatal period might influence the incidence of celiac disease.
All content in this area was uploaded by Carsten Posovszky
Content may be subject to copyright.
A preview of the PDF is not available
... Several studies [21,71,75,77] have described a protective effect of breastfeeding on the development of CD, although most of the studies published to date have not been able to corroborate this protective effect. Other prospective studies [45,66,67,72,80, have not been able to demonstrate a beneficial effect of breastfeeding with respect to the development of the disease. ...
... Regarding the duration of breastfeeding, four prospective studies [45,67,72,86] analyzed the influence of the duration of breastfeeding on the risk of developing CD, and five case-control studies [21,133] also investigated whether breastfeeding for a longer time had an advantage over a shorter time of breastfeeding. Of all of them, only two studies [75,77] found statistically significant differences between breastfed infants and infants fed with artificial formulas. ...
Experimental and epidemiological evidence has shown that modifications of the intrauterine environment can have deleterious consequences for individuals, expressed as an increased risk of suffering non-communicable pathologies in adult life, which is known as the hypothesis of the early origin of diseases or programming fetal. On the other hand, changes in gene expression patterns through epigenetic modifications can be the basis for long-term maintenance of the effects of fetal programming. In this sense, epigenetics comprises the study of intrauterine disturbances, which develop diseases in the adult, including Celiac Disease (CD). In addition, early feeding practices could influence the risk of CD development, such as breastfeeding timing and duration and age at gluten introduction in the diet. Gluten acts as a trigger for CD in genetically predisposed subjects, although approximately 30% of the world population has HLA DQ2 or DQ8, the prevalence of the disease is only 1-3%. It is not known what factors act to modify the risk of disease in genetically at risk subjects. Taking into account all these considerations, the aim of the current review is to elucidate the role of early programming and the effect of early nutrition on the development and progression of CD.
... Mode of delivery, infant feeding type, timing of gluten introduction into the diet, occurrence of viral infections, and early exposure to antibiotics are just a few of the many environmental factors suggested to influence the development of chronic inflammatory diseases such as CD . When evaluating these factors independently, case-control studies and meta-analyses have found that cesarean section delivery [14,15], lack of breast-feeding [16,17], timing of gluten introduction [17,18], and exposure to antibiotics  increase the risk of developing CD. However, two independent double blind placebo controlled prospective studies in Europe involving infants with compatible HLA genetics and a first-degree relative with CD (who are therefore at high risk of developing CD) found that vaginal delivery, breast-feeding, and timing of gluten introduction were not protective against developing CD [20,21]. ...
... Several studies have linked exposure to a variety of genetic and environmental risk factors with the onset of non-infective chronic inflammatory diseases . This link has been typically based on the results obtained from either clinical case-control studies [14,15,19,67] or metanalyses  in which cause-effect relationship cannot always conclusively be determined. Since host genetics and environmental factors are known to influence the gut microbiota composition and function, researchers have started to explore alterations in the gut microbiota of infants at risk of autoimmune conditions such as IBD  or T1D . ...
Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery and exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD.
Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at birth, 3 months and 6 months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function, and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways, and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time, while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects.
Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects. Video Abstract.
... Mode of delivery, infant feeding type, timing of gluten introduction into the diet, occurrence of viral infections and early exposure to antibiotics are just a few of the many environmental factors suggested to in uence the development of chronic in ammatory diseases such as CD . When evaluating these factors independently, case-control studies and meta-analyses have found that cesarean section delivery [14,15], lack of breast-feeding [16,17], timing of gluten introduction [17,18] and exposure to antibiotics  increase the risk of developing CD. However, two independent double blind placebo controlled prospective studies in Europe involving infants with compatible HLA genetics and a rst-degree relative with CD (who are therefore at high risk of developing CD) found that vaginal delivery, breast-feeding, and timing of gluten introduction were not protective against developing CD [20,21]. ...
... Several studies have linked exposure to a variety of genetic and environmental risk factors with the onset of non-infective chronic in ammatory diseases . This link has been typically based on the results obtained from either clinical case-control studies [14,15,19,68] or metanalyses  in which causeeffect relationship cannot always conclusively be determined. Since host genetics and environmental factors are known to in uence the gut microbiota composition and function, researchers have started to explore alterations in the gut microbiota of infants at risk of autoimmune conditions such as IBD  or T1D . ...
Background: Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery, exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD.
Results: Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional and longitudinal analyses using metagenomic and metabolomic data collected at birth, three months and six months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway, and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects.
Conclusions: Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects.
... In New Zealand (NZ), approximately one in four babies are born by CS . However, birth by CS has also been associated with increased risk of adverse health outcomes in the long-term, including asthma , type 1 diabetes , coeliac disease , and childhood obesity . The microbiome of infants born by caesarean section differs from those of infants born vaginally [7,8]. ...
Vaginal seeding is the administration of maternal vaginal bacteria to babies following birth by caesarean section (CS), intended to mimic the microbial exposure that occurs during vaginal birth. Appropriate development of the infant gut microbiome assists early immune development and might help reduce the risk of certain health conditions later in life, such as obesity and asthma. We aimed to explore the views of pregnant women on this practice.
We conducted a sequential mixed-methods study on the views of pregnant women in New Zealand (NZ) on vaginal seeding. Phase one: brief semi-structured interviews with pregnant women participating in a clinical trial of vaginal seeding ( n = 15); and phase two: online questionnaire of pregnant women throughout NZ (not in the trial) ( n = 264). Reflexive thematic analysis was applied to interview and open-ended questionnaire data. Closed-ended questionnaire responses were analysed using descriptive statistics.
Six themes were produced through analysis of the open-ended data: “seeding replicates a natural process”, “microbiome is in the media”, “seeding may have potential benefits”, “seeking validation by a maternity caregiver”, “seeding could help reduce CS guilt”, and “the unknowns of seeding”. The idea that vaginal seeding replicates a natural process was suggested by some as an explanation to help overcome any initial negative perceptions of it. Many considered vaginal seeding to have potential benefit for the gut microbiome, while comparatively fewer considered it to be potentially beneficial for specific conditions such as obesity. Just under 30% of questionnaire respondents ( n = 78; 29.5%) had prior knowledge of vaginal seeding, while most ( n = 133; 82.6%) had an initially positive or neutral reaction to it. Few respondents changed their initial views on the practice after reading provided evidence-based information ( n = 60; 22.7%), but of those who did, most became more positive ( n = 51; 86.4%).
Given its apparent acceptability, and if shown to be safe and effective for the prevention of early childhood obesity, vaginal seeding could be a non-stigmatising approach to prevention of this condition among children born by CS. Our findings also highlight the importance of lead maternity carers in NZ remaining current in their knowledge of vaginal seeding research.
... For many years, comparative studies have been conducted on the effect of the mode of delivery on the early and distant consequences for children's psychosomatic traits. The increased risk of disease associated with immune function in the offspring , sensitisation allergens, and asthma and respiratory complications , metabolic and hormonal disorders  and the effect on colonisation of the gut flora correlated with gastrointestinal symptoms  has been repeatedly evaluated, and the results of these studies are consistent. However, no current reports regarding the comparison of the thermal ...
Newborns, regardless of the method of termination of pregnancy, are exposed to the first exogenous stress factors during delivery. The purpose of the study was to evaluate the differences in newborns’ thermal response to vaginal (VD) vs caesarean section (CS) delivery. The temperature was measured during the first minutes of life within 122 healthy full-term newborns, on the forehead, chest and upper-back by infrared camera (FLIR T1030sc HD). The lowest temperatures were recorded in the forehead of VD newborns (significantly difference with CS; p < 0.001), the warmest was the chest. A significant correlation was found between the duration of the second stage of natural childbirth and surface temperature and pO2 in the newborn blood. The temperatures of selected body surface areas correlate highly positively, regardless of the mode of delivery. In the case of healthy neonates, with normal birth weight and full-term, VD creates more favourable conditions stimulating the mechanisms of adaptation for a newborn than CS.
... According to an increasing number of epidemiologic studies, children delivered by cesarean section more commonly developed respiratory and neurological disorders (e.g., autism spectrum disorders , schizophrenia ) and immune-related diseases, such as asthma [13,14], skin atopy , juvenile arthritis, coeliac disease , type 1 diabetes (T1D)  or obesity [1,. It is worth noting differences between the occurrence of the above-mentioned conditions in cases when the surgical procedure was performed after delivery had started. ...
Cesarean section is a surgical procedure, which is the most frequently performed in gynecology and obstetrics. It is commonly believed that an operative delivery is a less painful and safer mode of delivery, which translates into an increasing number of the procedures performed without medical indications. The maternal sequelae of cesarean sections are well elucidated and widely discussed in the literature, while long-term neonatal consequences still remain the issue of research and scientific dispute. The aim of the present paper was to perform a systematic review of current literature regarding pediatrics consequences of cesarean section.
We reviewed available data from PubMed, Science Direct as well as Google Scholar bases concerning early and long-term neonatal sequelae of operative deliveries. The following key words were used: "cesarean section", "caesarean section", "neonatal outcomes", "respiratory disorders", "asthma", "obesity", "overweight", and "neurological disorders". A total of 1636 papers were retrieved out of which 27 were selected for the final systematic review whereas 16 articles provided data for meta-analysis. Statistical analyses were performed using RevMan 5.4. To determine the strength of association between the caesarean section and respiratory tract infections, asthma, diabetes type 1 as well as obesity the pooled odds ratios (OR) with the 95% confidence intervals (CI) were calculated.
Conducted meta-analyses revealed that caesarean section is a risk factor for respiratory tract infections (pooled OR = 1.30 95%CI 1.06-1.60, p = 0.001), asthma (pooled OR = 1.23 95%CI 1.14-1.33, p < 0.00001) as well as obesity (pooled OR = 1.35 95%CI 1.29-1.41, p < 0.00001) in offspring.
The results of the studies included indicated that children delivered by cesarean section more commonly developed respiratory tract infections, obesity and the manifestations of asthma than children delivered vaginally. The risk of developing diabetes mellitus type 1 or neurological disorders in offspring after caesarean section is still under discussion.
... One study detected accelerated weight gain among infants born by CS as soon as 3 months,  while another reported higher mean body mass index (BMI) at 6 months, although this difference was not observed in later childhood.  Aside from obesity, there is also inconsistent evidence for an association between birth by CS and increased risk of asthma,  eczema/atopic dermatitis, [16,18] coeliac disease,  and type 1 diabetes.  Altered colonization of the gut microbiota in babies born by CS may partially account for the increased risk of obesity and other health conditions. ...
There is evidence that caesarean section (CS) is associated with increased risk of childhood obesity, asthma, and coeliac disease. The gut microbiota of CS-born babies differs to those born vaginally, possibly due to reduced exposure to maternal vaginal bacteria during birth. Vaginal seeding is a currently unproven practice intended to reduce such differences, so that the gut microbiota of CS-born babies is similar to that of babies born vaginally. Our pilot study, which uses oral administration as a novel form of vaginal seeding, will assess the degree of maternal strain transfer and overall efficacy of the procedure for establishing normal gut microbiota development.
Methods and analysis:
Protocol for a single-blinded, randomized, placebo-controlled pilot study of a previously untested method of vaginal seeding (oral administration) in 30 CS-born babies. A sample of maternal vaginal bacteria is obtained prior to CS, and mixed with 5 ml sterile water to obtain a supernatant. Healthy babies are randomized at 1:1 to receive active treatment (3 ml supernatant) or placebo (3 ml sterile water). A reference group of 15 non-randomized vaginal-born babies are also being recruited. Babies' stool samples will undergo whole metagenomic shotgun sequencing to identify potential differences in community structure between CS babies receiving active treatment compared to those receiving placebo at age 1 month (primary outcome). Secondary outcomes include differences in overall gut community between CS groups (24 hours, 3 months); similarity of CS-seeded and placebo gut profiles to vaginally-born babies (24 hours, 1 and 3 months); degree of maternal vaginal strain transfer in CS-born babies (24 hours, 1 and 3 months); anthropometry (1 and 3 months) and body composition (3 months).
Ethics and dissemination:
Ethics approval by the Northern A Health and Disability Ethics Committee (18/NTA/49). Results will be published in peer-reviewed journals and presented at international conferences.
Australian New Zealand Clinical Trials Registry (ACTRN12618000339257).
... The Cesarean section commonly thought to have a permanent impact on the intestinal microbiota of infants, due to the lack of exposure to the maternal vaginal and gut microbiota . Studies have indicated that there is an association between cesarean section and an increased risk of coeliac disease . Differences in elective cesarean section where babies are not exposed to the maternal microbiota have been observed . ...
PurposeAlthough genetic predisposition and exposure to dietary gluten are considered necessary triggers for the development of coeliac disease, alterations in the gut microbial composition may also contribute towards the pathogenesis of coeliac disease. This review aims to provide an overview of the available data on the potential mechanisms through which the gut microbiota plays a role in the causation of coeliac disease and to discuss the potential therapeutic strategies that could diminish the consequences of microbial dysbiosis.MethodA search of the literature was performed using the PubMed, Embase, and JSTOR databases; relevant articles were included.ResultsRecent studies in patients with coeliac disease have reported an increase in the relative amounts of gram negative bacterial genera such as Bacteroides, Prevotella, and Escherichia, and reduced amounts of protective anti-inflammatory bacteria such as Bifidobacteria and Lactobacilli. Dysbiotic microbiota may lead to a dysregulated immune response that may contribute to the pathogenesis of coeliac disease. In infancy, antibiotic use and certain infant feeding practices may lead to alterations in the developing gut microbiota to influence the immune maturation process and predispose to coeliac disease.Conclusion
The induction of the intestinal immune system and gluten intolerance may be influenced by the relative abundance of certain microbiota. Factors such as infant feeding practices, diet, antibiotics, and infections, may be involved in the development of coeliac disease due to their influence on gut microbial composition. The efficacy of potential modulators of the gut microbiota such as probiotics, prebiotics, and fecal microbial transplant as adjunctive treatments to gluten-free diet in coeliac disease is unproven and requires further investigation.
... Data available so far have also proved that many factors could contribute to CD onset in genetically high-risk individuals, including method of infant feeding , of birth (vaginal vs. caesarean section) , a chronic inflammatory immune response to gliadin  and its deficient suppression by Treg cells , time of gluten introduction into the diet , infections occurrence and also the presence of several non-HLA genes . In addition, the risk of developing CD is higher in the presence of other autoimmune diseases or other pathologies, including Down syndrome, Williams syndrome, Turner syndrome and also cystic fibrosis [28,. ...
Celiac Disease (CD) is an immune-mediated disease triggered by the ingestion of wheat gliadin and related prolamins from other cereals, such as barley and rye. Immunity against these cereal-derived proteins is mediated by pro-inflammatory cytokines produced by both innate and adaptive system response in individuals unable to adequately digest them. Peptides generated in this condition are absorbed across the gut barrier, which in these patients is characterized by the deregulation of its permeability. Here, we discuss a possible correlation between CD and Autistic Spectrum Disorder (ASD) pathogenesis. ASD can be induced by an excessive and inappropriate brain opioid activity during the neonatal period. Cereal-derived peptides produced in celiac patients cross the blood–brain barrier and bind to endogenous opioid receptors interfering with neurotransmission and generating deleterious effects on brain maturation, learning and social relations. Moreover, an increase in oxidative stress and a decrease in the antioxidant capacity, as well as an extended mitochondrial impairment in the brain, could represent a possible connection between ASD and CD. Therefore, we critically discuss the proposed relationship between ASD and CD and the possible usefulness of a gluten-free diet in ASD patients.
Current evidence supports a vital role of the microbiota on human health outcomes, with alterations in an otherwise healthy balance linked to chronic medical conditions such as celiac disease (CD). Recent advances in microbiome analysis allow for unparalleled profiling of the microbes and metabolites. With the growing volume of data available, trends are emerging that support a role for the gut microbiota in CD pathogenesis.
In this article, the authors review the relationship between factors such as genes and antibiotic exposure on CD onset and the intestinal microbiota. The authors also review other microbiota within the human body (such as the oral microbiota) that may play a role in CD pathogenesis. Finally, the authors discuss implications for disease modification and the ultimate goal of prevention. The authors reviewed literature from PubMed, EMBASE, and Web of Science.
CD serves as a unique opportunity to explore the role of the intestinal microbiota on the development of chronic autoimmune disease. While research to date provides a solid foundation, most studies have been case-control and thus do not have capacity to explore the mechanistic role of the microbiota in CD onset. Further longitudinal studies and integrated multi-omics are necessary for investigating CD pathogenesis.
Qualitative and quantitative anaerobic cultures were performed on faecal samples from 27 normal full-term newborn infants; from 32 preterm infants during intensive or intermediate care, not treated with antibiotics; and from 106 mostly preterm newborns, treated with antibiotics for various reasons. There were no major differences between the children in the first two groups. In these, Caesarean section led to a lower isolation rate of bifidobacteria and a much lower incidence ofBacteroides spp. During antibiotic treatment anaerobic bacteria were isolated from only 10% of the infants. After treatment, there was a slow regrowth of bifidobacteria, butBacteroides spp. were not usually re-established. There was a colonisation of infants delivered by Caesarean section with newLactobacillus spp. after treatment. In particularBacteroides colonisation may be facilitated and more stable if it occurs during passage through the birth canal.
The 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 influence the development of the mucosal 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 adaptive immune system is central to the development of coeliac disease. Adaptive immune responses are, however, controlled by a preceding activation of the innate immune system. We investigated whether gliadin, a protein present in wheat flour, could activate an innate as well as an adaptive immune response in patients with coeliac disease.
Methods: duodenal biopsy samples from 42 patients with untreated coeliac disease, 37 treated patients, and 18 controls, were cultured in vitro for 3 h or 24 h, in the presence of either immunodominant gliadin epitopes (pα-2 and pα-9) or a non-immunodominant peptide (p31–43) known to induce small intestine damage in coeliac disease. We also incubated biopsy samples from nine untreated and six treated patients with a non-immunodominant peptide for 3 h, before incubation with immunodominant gliadin epitopes. Different combinations of interleukin-15 or signal transduction inhibitors were added to selected incubations.
Findings: only the non-immunodominant peptide induced rapid expression of interleukin-15, cd83, cyclo-oxygenase (COX)-2, and CD25 by CD3– cells (p=O005 vs medium alone) and enterocyte apoptosis (p<0·0001). Only the non-immunodominant peptide induced p38 MAP kinase activation in CD3– cells. Pre-incubation with the non-immunodominant peptide enabled immunodominant epitopes to induce T-cell activation (p=0·001) and enterocyte apoptosis. Inhibition of interleukin-15 or of p38 MAP kinase controlled such activity.
Interpretation: a gliadin fragment can activate the innate immune system, affecting the in situ T-cell recognition of dominant gliadin epitopes. Although our findings emphasise the key role of gliadin-specific T cells, they suggest a complex pathogenic situation, and show that inhibition of interleukin-15 or p38 MAP kinase might have the potential to control coeliac disease.
Lotz et al. 2006. J. Exp. Med. doi:10.1084/jem.20050625[OpenUrl][Abstract/FREE Full Text]
The intestinal microbiota is a complex ecosystem harbouring about 1014 micro-organisms composed of nearly 400 hundred species. It plays various important functions in the gut, including metabolic, flora, barrier and stimulation of the intestinal immune system. Most studies have been based on culture, but more recent molecular biology techniques have provided complementary information. The formation of this ecosystem begins rapidly in the newborn; it is sterile at birth and is based on contact with the maternal flora and the surrounding environment. Although little is known about the factors leading to the development of bacteria, numerous external factors will affect the microbial succession: mode of delivery, environmental conditions, type of feeding, gestational age, and antibiotics. Recent data report a delay in intestinal colonization especially of enteric maternal bacteria. Which may be due to strict hygiene measures during birth. The clinical impact of these variations is not known but they could lead to lack of barrier flora or poor immune system stimulation in the gut. Modulation of gut microbiota in neonates with infant formulas containing either probiotics, prebiotics or non viable bacterias and their metabolites, or nucleotides is discussed.
The incidence of Crohn's disease (CD) with onset before age 16 has increased. Several perinatal characteristics have been associated with CD. Our objective was to examine the temporal change in CD incidence by period of birth and the extent that this could be attributed to perinatal characteristics associated with higher CD risk.
A record linkage study was conducted utilizing the perinatal records of Victorian births 1983-1998 inclusive and a state-based CD registry. Proportional hazards models were used to investigate the perinatal factors in relation to the onset of CD by age 16. Further, a nested case control study was conducted to examine the association between sibling exposure and CD risk.
The CD incidence rate for births 1983-1998 was 2.01 (95% confidence interval [CI] 1.79, 2.27) per 100,000 child-years. A birth cohort effect was demonstrated, with higher CD risk for 1992-1998 versus 1983-1991 births (hazard ratio [HR] 1.56; 95% CI 1.18, 2.06). Perinatal characteristics associated with higher CD risk included urban location, higher socioeconomic status, married mother, a congenital abnormality and delivery by elective cesarean section. Sibling exposure during the first 6 years of life was not associated with CD risk. The increased CD incidence among more recent births was not accounted for by changes in these measured perinatal factors.
The temporal increase in CD incidence documented for births up to 1990 has continued for children born after 1991 and was not accounted for by temporal changes in the measured perinatal factors.
Crohn's disease has a high morbidity and there is no known cure. Current treatments have multiple side effects and an effective treatment with minimal side effects is desired. Probiotics have been proposed as such a treatment but their efficacy is undetermined. There is some evidence that probiotics are effective in other conditions affecting the gastrointestinal tract and they are popular with patients. They are thought to work through competitive action with commensal and pathogenic flora, influencing the immune response.
To determine if there is any evidence for the efficacy of probiotics for the induction of remission in Crohn's disease.
The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2007), MEDLINE (1966 to 2007), Excerpta Medica/EMBASE (1974 to 2007), CINAHL (1982-2007) and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialised Trial Register were searched. Manufacturers of probiotics were also contacted to identify any unpublished trials. References of trials were also searched for any additional trials.
Randomised controlled trials (RCTs) that compared probiotics against placebo or any other intervention for the induction of remission in Crohn's disease were eligible for inclusion.
Data collection and analysis:
Data extraction and assessment of methodological quality of included studies were independently performed by two authors. The main outcome measure was the occurrence of clinical remission. Odds ratios and 95% confidence intervals were calculated for dichotomous outcomes.
One small study (n = 11) met the inclusion criteria and was included in the review. There were some methodological concerns with this study. Four of 5 patients in the probiotic group achieved remission compared to 5 of 6 in the placebo group (OR 0.80; 95% CI 0.04 to 17.20).
There is insufficient evidence to make any conclusions about the efficacy of probiotics for induction of remission in Crohn's disease. There is a lack of well designed RCTs in this area and further research is needed.
Toll-like receptor (TLR) signaling is subjected to crosstalk from other signals, with a resulting positive or negative effect. There is complex crosstalk between the NLR family of immune-regulatory molecules and TLRs, and C-type lectin receptors such as Dectin-1 synergize with TLR2 via the tyrosine kinase Syk. Bruton's tyrosine kinase plays an important positive role in TLR signaling, whereas the TAM family of receptor tyrosine kinases is inhibitory. The tyrosine phosphatase SHP1 has been shown to positively regulate induction of interferon-beta, whereas SHP2 inhibits the kinase TBK1, limiting this response. K63-linked polyubiquination has also been shown to be critical for the initiation of TLR signaling. Finally, glucocorticoids affect TLR signaling by inducing the phosphatase MKP1 and inhibiting TBK1 activation. These recent findings emphasize the importance of considering TLR signaling in the context of other signaling pathways, as is likely to occur in vivo during infection and inflammation.