Content uploaded by Carsten Posovszky
Author content
All content in this area was uploaded by Carsten Posovszky
Content may be subject to copyright.
A preview of the PDF is not available
Cesarean Delivery Is Associated With Celiac Disease but Not Inflammatory Bowel Disease in Children
Abstract and Figures
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.
Figures - uploaded by Carsten Posovszky
Author content
All figure content in this area was uploaded by Carsten Posovszky
Content may be subject to copyright.
... 13 Of note, one of the items was the representativeness of the exposed cohort, with the inclusion of only at-risk populations. The results from at-risk total score for case-control studies (Table S7) ranged from five (one study) 42 to nine (maximum score). 13 The weakest item was definition of controls (nine studies did not achieve a star). ...
... 13 The weakest item was definition of controls (nine studies did not achieve a star). 39,42,[44][45][46][49][50][51]53 The main reason was not reporting a history of CD in the control group. ...
... Assessment of exposure was done using other than recommended methods (i.e., secure records) in seven studies. 39,40,42,46,48,50,53 Five studies did not make any adjustment of effect measures for any confounding factors. 40,41,43,47,48 The same method of ascertainment for cases and controls was used in all studies. ...
Background
The effects of early feeding practices on the risk of coeliac disease (CD) remain debated.
Aims
To update evidence on these practices on the risk of CD and/or CD‐related autoimmunity (CDA), defined as anti‐transglutaminase or anti‐endomysial antibody positivity
Methods
We searched MEDLINE, EMBASE and the Cochrane Library to May 2022 for randomised controlled trials (RCTs) and observational studies.
Results
We included 36 publications (30 studies). In the population at genetic risk of developing CD (HLA DQ2/DQ8‐positive), exclusive or any breastfeeding and longer breastfeeding duration did not reduce the risk of developing CD/CDA during childhood. While a meta‐analysis of four case–control studies showed a decreased risk for CD when gluten was introduced during breastfeeding, this was not shown in RCTs and cohort studies. Age at gluten introduction was not associated with cumulative CD/CDA risk, although two RCTs suggested that earlier gluten introduction was associated with earlier CDA appearance. Evidence from six observational studies suggests that consumption of a higher amount of gluten at weaning and/or thereafter may increase CD risk. There is insufficient evidence to determine the amount of gluten associated with an increased CD/CDA risk. Regarding whether infant feeding practices modulate the risk conferred by different HLA genotypes results were inconsistent.
Conclusions
For the population at genetic risk of CD, breastfeeding and age at gluten introduction have no effect on its cumulative incidence during childhood. There is some evidence for an effect of the amount of gluten consumed at weaning and/or thereafter on CD/CDA risk.
... There is increasing evidence of the role of the gut microbiota in the pathogenesis of CD, which can be explained in part as follows: first, the prevalence of CD has increased rapidly over the past two decades, and this cannot be attributed solely to a genetic basis [7]; only few genetically predisposed individuals develop an active disease [8], again highlighting the role of external factors; moreover, delivery by cesarean section, that highly affects the microbial composition of the intestine of newborns [9], has been associated with increased susceptibility to CD [10]. Finally, a positive correlation between early antibiotic use and the development of CD was found [11], even though with conflicting results so far. ...
... It has been reported that cesarean section may be associated with an increased risk of developing CD [10], however with inconsistent results so far [45]. Of note, infants born via cesarean section showed an increased amount of Enterococcus faecalis and a lower amount of Bacteroides and Parabacteroides compared to infants born vaginally [44], which might be relevant as Parabacteroides seem to decreasethe severity of intestinal inflammation [46]. ...
Celiac disease (CD) is a common systemic disorder that results from an abnormal response of human immunity to gluten intake, affecting the small intestine. In individuals who carry a genetic susceptibility, CD is triggered by environmental factors, including viral infections and dysbiosis of the gut microbiota. The gut microbiome is essential in controlling the immune system, and recent findings indicate that changes in the gut microbiome may contribute to various chronic immune disorders, such as CD through mechanisms that still require further exploration. Some bacteria exhibit epitopes that mimic gliadin and may enhance an immune response in the host. Other bacteria, including Pseudomonas aeruginosa, may work in conjunction with gluten to trigger and escalate intestinal inflammation. The microbiota may also directly influence antigen development through the production of immunogenic or tolerogenic gluten peptides or directly influence intestinal permeability through the release of zonulin. Finally, the gut microbiome can impact intestinal inflammation by generating proinflammatory or anti-inflammatory cytokines and metabolites. It is crucial to consider the impact of genetic factors (specifically, HLA-DQ haplotypes), perinatal elements such as birth mode, type of infant feeding, and antibiotic and infection exposure on the composition of the early intestinal microbiome. According to the available studies, the gut microbiome alterations associated with CD tend to exhibit a decreased presence of beneficial bacteria, including some anti-inflammatory Bifidobacterium species. However, some controversy remains as some reports have found no significant differences between the gut microbiomes of individuals with and without CD. A better understanding of the gut microbiome’s role in the development of CD would greatly benefit both prevention and treatment efforts, especially in complicated or treatment-resistant cases. Here, we have attempted to summarize the available evidence on the relationship between the gut microbiota and CD, with a particular focus on potential therapeutic targets.
... В случае латентного течения целиакии отмечено повышение риска повторных выкидышей и преждевременных родов, ухудшает рост плода с пониженной массой тела при рождении. В недавнем исследовании, проведенном в Германии отмечена повышение частоты неблагоприятных осложнений и кесарева сечения у рожениц с целиакией, по сравнению с частотой контрольной группы заболеваний пищеварительной системы и глаз или стоматологических амбулаторных пациентов клиники [13]. ...
The article presents a review of retrospective cohort studies of fertility and pregnancy outcomes in women with celiac disease. The article presents the results of our own observations of obstetric and gynecological anamnesis 17 women with celiac disease for the period from 2016 to 2020. Materials and methods. Information collected from patients was analyzed in retrospective cohort studies. Patients with celiac disease and healthy women of reproductive age were included in these studies. Result. The ability of IgA and IgG class antibodies to tissue transglutaminase to disrupt trophoblast invasiveness and endometrial endothelial cell differentiation underlies the failure of early placentation in celiac disease. In the case of the latent course of celiac disease there is an increased risk of recurrent miscarriages and preterm births, impaired growth of the fetus with low birth weight. Conclusion. Given the high percentage of unidentified diagnoses, it is extremely important to identify risk groups for timely treatment and prevention of complications.
... Moreover, Koletzko et al. reported a lack of association between cesarean delivery and the risk of CD or CD autoimmunity in 6,087 genetically predisposed children (85). On the other hand, a multicentre, case-control study showed, that the type of delivery may affect gut microbiota and enhance the risk of CD (86). Finally, in 2022 Yang et al. performed a meta-analysis of 11 observational studies and found that C-section is not associated with CD in offspring (87). ...
The prevalence of celiac disease increased in recent years. In addition to the genetic and immunological factors, it appears that environmental determinants are also involved in the pathophysiology of celiac disease. Gastrointestinal infections impact the development of celiac disease. Current research does not directly confirm the protective effect of natural childbirth and breastfeeding on celiac disease. However, it seems that in genetically predisposed children, the amount of gluten introduced into the diet may have an impact on celiac disease development. Also western lifestyle, including western dietary patterns high in fat, sugar, and gliadin, potentially may increase the risk of celiac disease due to changes in intestinal microbiota, intestinal permeability, or mucosal inflammation. Further research is needed to expand the knowledge of the relationship between environmental factors and the development of celiac disease to define evidence-based preventive interventions against the development of celiac disease. The manuscript summarizes current knowledge on factors predisposing to the development of celiac disease including factors associated with the western lifestyle.
Context:
Overweight/obesity is one of the most important health problems. Birth by cesarean section has been shown to influence long-term health outcomes including obesity.
Objective:
The aim of this systematic review-meta-analysis is to update acknowledgment of the increased risk of cesarean section on offspring's overweight/obesity.
Methods:
This study follows the PRISMA guidelines. A systematic literature search was conducted on Scopus, PubMed, and Web of Science; we have selected all the articles published until January 2, 2022. For inclusion, studies must have reported either (i) both birth by cesarean section and adult (≥18 years) offspring's body mass index; (ii) cohort or case-control study design; and (iii) a risk estimate. Heterogeneity testing was performed using Cochran's Q and I2 statistics. Publication bias was assessed by the Egger test and the Begg test. Meta-analysis was performed through a random-effects model.
Results:
Twelve studies with a combined population of 180 065 subjects were included in the meta-analysis. The overall analysis (N = 19) yielded a combined risk estimate for overweight/obesity of 1.19 (95% CI, 1.08-1.30) and the test of heterogeneity resulted into Q = 57.44 ( I2 = 68.67%, P ≤ .001). The risk of offspring obesity is 1.23 (95% CI, 1.09-1.39) and the test of heterogeneity resulted into Q = 39.55 ( I2 = 69.66%, P ≤ .001). Children born by cesarean section have an increased risk of obesity in adulthood.
Aim:
To evaluate whether pregnancy and birth-related factors are associated with celiac disease (CD) in a large, United States (US)-based mother-child cohort.
Methods:
We analyzed data gathering from the Massachusetts General Hospital Maternal Child Cohort (MMCC) of children born between 1998 and 2016. Data included the mode of delivery, maternal pregnancy and their offspring characteristics. We searched for CD cases by using diagnosis billing codes. Cox proportional hazard regression models were created to identify variables associated with CD.
Results:
We identified 44,539 mother-child pairs who had at least one encounter by 5 years old and identified 173 children (0.4%) with CD diagnosis; median age at the diagnosis was 6 years. Overall, the adjusted hazard ratio (aHR) of caesarean delivery for CD was 1.39 (95% CI: 0.99, 1.96, P=.06) when compared to children born vaginally. After stratifying for the presence of labor, children born by Cesarean delivery without labor had a higher risk of CD (aHR 1.56; 95%CI: 1.01, 2.41; P =.046) while infants born by Cesarean delivery with labor did not (aHR 1.26; 95% CI: 0.83, 1.93; P= .28).
Conclusion:
Being born by Cesarean delivery without labor may be associated with an increased risk for CD in the US children.
Context
The continuous rise in urbanisation and its associated factors have been reflected in the structure of the human gut ecosystem.
Objective
The main focus of the review is to discuss and summarise the major risk factors associated with urbanisation that affects human gut microbiota thus affecting human health.
Methods
Multiple medical literature databases, namely PubMed, Google, Google Scholar, and Web of Science were used to find relevant materials for urbanization and its major factors affecting human gut microbiota/microbiome. Both layman and Medical Subject Headings (MeSH) terms were used in the search. Due to the scarcity of the data, no limitation was set on the publication date. Relevant material in the English language which includes case reports, chapters of books, journal articles, online news reports and medical records was included in this review.
Results
Based on the data discussed in the review, it is quite clear that urbanisation and its associated factors have long-standing effects on the human gut microbiota that result in alterations of gut microbial diversity and composition. This is a matter of serious concern as chronic inflammatory diseases are on the rise in urbanised societies.
Conclusion
A better understanding of the factors associated with urbanisation will help us to identify and implement new biological and social approaches to prevent and treat diseases and improve health globally by deepening our understanding of these relationships and increasing studies across urbanisation gradients.
• HIGHLIGHTS
• Human gut microbiota has been linked to almost every important function, including metabolism, intestinal homeostasis, immune system, biosynthesis of vitamins, brain processes, and its behaviour.
• However, dysbiosis i.e., alteration in the composition and diversity of gut microbiota is associated with the pathogenesis of many chronic conditions.
• In the 21st century, urbanisation represents a major demographic shift in developed and developing countries.
• During this period of urbanisation, humans have been exposed to many environmental exposures, all of which have led to the dysbiosis of human gut microbiota.
• The main focus of the review is to discuss and summarize the major risk factors associated with urbanisation and how it affects the diversity and composition of gut microbiota which ultimately affects human health.
Cesarean birth has increased substantially in many parts of the world over recent decades and concerns have been raised about the propriety of this change in obstetric practice. Sometimes, a cesarean is necessary to preserve fetal and maternal health. But in balancing the risks of surgical intervention the implicit assumption has been that cesarean birth is an equivalent alternative to vaginal birth from the standpoint of the immediate and long-term health of the fetus and neonate. Increasingly, we realize this is not necessarily so. Delivery mode per se may influence short-term and abiding problems with homeostasis in offspring, quite independent of the indications for the delivery and other potentially confounding factors. The probability of developing various disorders, including respiratory compromise, obesity, immune dysfunction, and neurobehavioral disorders has been shown in some studies to be higher among individuals born by cesarean. Moreover, many of these adverse effects are not confined to the neonatal period and may develop over many years. Although the associations between delivery mode and long-term health are persuasive, their pathogenesis and causality remain uncertain. Full exploration and a clear understanding of these relationships is of great importance to the health of offspring.
Objective:
To investigate why certain at-risk individuals develop celiac disease, we examined the association of proton pump inhibitors (PPI), histamine-2 receptor antagonist (H2RA), and antibiotic prescriptions in the first six months of life with an early childhood diagnosis of celiac disease.
Study design:
A retrospective cohort study was performed using the Military Healthcare System (MHS) database. Children with a birth record from October 1, 2001- September 30, 2013, were identified. Outpatient prescription records were queried for antibiotic, PPI, and H2RA prescriptions in the first 6 months of life. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of developing CD based on medication exposure. ICD-9 codes identified children with an outpatient visit for celiac disease.
Results:
968,524 children met inclusion criteria with 1,704 cases of celiac in this group. Median follow up for the cohort was about 4.5 years. PPI's (HR, 2.23; 95% CI, 1.76-2.83), H2RA's (HR, 1.94 95% CI, 1.67-2.26) and antibiotics (HR 1.14 95%CI 1.02-1.28) were all associated with an increased hazard of celiac disease.
Conclusion:
There is an increased risk of developing celiac disease if antibiotics, PPI's and H2RA's are prescribed in the first 6 months of life. Our study highlights modifiable factors such as medication stewardship that may change the childhood risk of CD.
The human gut microbiome is a complex and dynamic microbial entity that interacts with the environment and other parts of the body including the brain, heart, liver, and immune system. These multisystem interactions are highly conserved from invertebrates to humans, however the complexity and diversity of human microbiota compositions often yield a context that is unique to each individual. Yet commonalities remain across species, where a healthy gut microbiome will be rich in symbiotic commensal biota while an unhealthy gut microbiota will be experiencing abnormal blooms of pathobiont bacteria. In this review we discuss how omics technologies can be applied in a personalized approach to understand the microbial crosstalk and microbial-host interactions that affect the delicate balance between eubiosis and dysbiosis in an individual gut microbiome. We further highlight the strengths of model organisms in identifying and characterizing these conserved synergistic and/or pathogenic host-microbe interactions. And finally, we touch upon the growing area of personalized therapeutic interventions targeting gut microbiome.
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 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][1][Abstract/FREE Full Text][2]
[1]: {openurl}?query=rft.jtitle%253DJ.%2BExp.%2BMed.%26rft_id%253Dinfo%253Adoi%252F10.1084%252Fjem.20050625%26rft_id%253Dinfo%253Apmid%252F16606665%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi
Background and aim: The colonic microflora is involved in the pathogenesis of Crohn's disease (CD) but less than 30% of the microflora can be cultured. We investigated potential differences in the faecal microflora between patients with colonic CD in remission (n=9), patients with active colonic CD (n=8), and healthy volunteers (n=16) using culture independent techniques. Methods: Quantitative dot blot hybridisation with six radiolabelled 16S ribosomal ribonucleic acid (rRNA) targeting oligonucleotide probes was used to measure the proportions of rRNA corresponding to each phylogenetic group. Temporal temperature gradient gel electrophoresis (TTGE) of 16S rDNA was used to evaluate dominant species diversity. Results: Enterobacteria were significantly increased in active and quiescent CD. Probe additivity was significantly lower in patients (65 (11)% and 69 (6)% in active CD and quiescent CD) than in healthy controls (99 (7)%). TTGE profiles varied markedly between active and quiescent CD but were stable in healthy conditions. Conclusion: The biodiversity of the microflora remains high in patients with CD. Enterobacteria were observed significantly more frequently in CD than in health, and more than 30% of the dominant flora belonged to yet undefined phylogenetic groups.
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.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Background:
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.
Objectives:
To determine if there is any evidence for the efficacy of probiotics for the induction of remission in Crohn's disease.
Search strategy:
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.
Selection criteria:
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.
Main results:
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).
Authors' conclusions:
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.