Background and Aims Herein we analysed the influence of early life factors, including breast milk composition, on the development of the intestinal microbiota of infants born to mothers with and without IBD. Methods The MECONIUM [Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome] study is a prospective cohort study consisting of pregnant women with or without IBD and their infants. Longitudinal stool samples were collected from babies and analysed using 16s rRNA sequencing and faecal calprotectin. Breast milk proteomics was profiled using Olink inflammation panel. Results We analysed gut microbiota of 1034 faecal samples from 294 infants [80 born to mothers with and 214 to mothers without IBD]. Alpha diversity was driven by maternal IBD status and time point. The major influencers of the overall composition of the microbiota were mode of delivery, feeding, and maternal IBD status. Specific taxa were associated with these exposures, and maternal IBD was associated with a reduction in Bifidobacterium. In 312 breast milk samples [91 from mothers with IBD], mothers with IBD displayed lower abundance of proteins involved in immune regulation, such as thymic stromal lymphopoietin, interleukin-12 subunit beta, tumour necrosis factor-beta, and C-C motif chemokine 20, as compared with control mothers [adjusted p = 0.0016, 0.049, 0.049, and 0.049, respectively], with negative correlations with baby & PRIME;s calprotectin, and microbiome at different time points. Conclusion Maternal IBD diagnosis influences microbiota in their offspring during early life. The proteomic profile of breast milk of women with IBD differs from that of women without IBD, with distinct time-dependent associations with baby's gut microbiome and feacal calprotectin.

Abstract Background Breastmilk (BM) is a complex fluid that contributes to shaping the immune system of the offspring. BM composition depends on stage of lactation, maternal health status and diet, environment, and genetics. Limited data exists on the composition of the BM from women with IBD and its potential impact on the newborn’s microbiome composition. Methods The MECONIUM (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome) study is a prospective cohort study including pregnant women with IBD, pregnant healthy control (HC), and their offspring. BM samples were collected 2 weeks post-delivery. Stool samples from the offspring were collected throughout the first 3 years of life and used to assess faecal calprotectin (fCal) and gut microbiota composition (16S). Targeted proteomics of the BM samples was performed with the Olink inflammation panel (92 protein biomarkers). Correlations between specific proteins in the BM, fCal and 16S were assessed using non-parametric tests. Multiple testing correction was performed with false discovery rate (FDR). MaAsLin2 R package was used for multivariate testing. Results 236 BM samples were analysed: 174 from HC, 37 Crohn’s disease (CD), 25 ulcerative colitis (UC). Thymic stromal lymphopoietin (TSLP), a cytokine with an important role in the maturation of T cells, was significantly lower in BM of women with IBD vs HC (FDR p=0.0017). The levels of TSLP in the BM of the mothers correlated negatively with infant fCal at year1 (rho=-0.20, p=0.01), and with the relative abundance of Cronobacter (MaAsLin2 FDR 0.1) of the offspring at month 1. Chemokine (C-C motif) ligand 20 (CCL20), which acts in chemotaxis of dendritic cells and T-cells and B-cells, was also significantly lower in women with CD vs HC (FDR 0.013) and in women with CD vs UC (p=0.014). Matrix metalloproteinase-1 (MMP-1), a collagenase involved in the breakdown of extracellular matrix, was also lower in BM of women with CD (p=0.009) and a negative correlation was observed between the levels of MMP1 and fCal at 3 months and 1 year (rho=-0.20 and -0.18, p=0.01 and 0.02, respectively). Osteoprotegerin (OPG), higher in BM of women with UC (p=0.018), was positively correlated with Streptococcus (MaAsLin2 FDR p=0.2) and negatively correlated with Bacteroides and Parabacteroides (MaAsLin2 FDR p=0.03 and 0.1) in the offspring at month 1. Conclusion The proteomic profile of BM of women with IBD is distinct from that of women without IBD. BM composition may influence offspring’s’ gut microbiome signatures and fCal level at different timepoints. These findings suggest that BM composition may impact the offspring’s intestinal immune system maturation and microbiome development, and warrant further research.

Mother-to-child transmission of Helicobacter pylori (H. pylori) is the primary source of intrafamilial spread in early childhood in regions of high H. pylori prevalence. However, early-in-life H. pylori colonization and associated protective or risk factors have not been fully evaluated in lower prevalence regions, such as the USA. Therefore, from a well-characterized prospective US cohort, we selected women who provided fecal samples during pregnancy and had paired fecal samples from their babies up to 24 months postpartum. We evaluated maternal and baby factors associated with likelihood of H. pylori colonization in the babies. Fecal antigen testing was used to determine H. pylori status. We also evaluated the association between maternal breastmilk cytokines and H. pylori colonization in breastfed babies. Among included mother-baby pairs (n = 66), H. pylori prevalence was 31.8

Abstract Background Data on the impact of geographic location on the gut microbiota of pregnant women with and without inflammatory bowel disease (IBD) and their infants are lacking. Methods 420 pregnant women with or without IBD and 331 infants were prospectively enrolled in the MECONIUM (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome) study in Hong Kong (HK) and United States (US). Of these individuals, the fecal microbiota compositions from 105 mothers (47 from HK and 58 from US) at third trimester and 54 babies (26 from HK and 28 from US) at 1 month were surveyed using 16s rRNA sequencing. Results The birthweight of infants in HK was significantly lower compared to that of infants in the US (p-value<0.001), while other baseline characteristics were comparable (Table 1). We observed differential gut microbiome beta-diversity between pregnant women without IBD (PERMANOVA test, p-value<0.05) and their infants (p<0.05) from HK and the US (Figure 1A). At the genus level, compared to pregnant women without IBD in the US, those in HK had a higher abundance of 15 taxa including Bifidobacterium, Faecalibacterium and Bacteroides and lower abundance of 6 taxa including Blautia and Turicibacter (Figure 1B). Compared to infants born to women without IBD in the US, those in HK had higher abundance of 3 taxa including Klebstella and Escherichia/Shigella and lower abundance of Enterococcus (Figure 1B). When comparing the gut microbiome alpha-diversity of women with and without IBD (Figure 1C), and that of their infants, both were lower in HK, (p-values= 0.077, 0.13, respectively) and in the US (p-values=0.0024, 0.019, respectively). Conclusion Our results suggest the impact of geographic location on the gut microbiome diversity and composition irrespective of IBD status. Maternal IBD is associated with reduced microbiome diversity in infants in both the US and HK.

Abstract Background Preliminary evidence suggests changes in breast milk cytokines in women with inflammatory bowel disease (IBD) compared to healthy controls, with potential implications toward offspring immunological development. However, changes in breast milk cytokine profiles in consecutive pregnancies are not known. Methods In this pilot study, we prospectively enrolled 11 pregnant women with, and 10 without IBD during two consecutive pregnancies and collected clinical data during each pregnancy and post birth. We collected breast milk samples at two weeks post birth and obtained the expression levels of 92 cytokines using the Olink proteomic platform. We further analyzed the correlation of cytokine profiles within each sample, in paired breast milk samples from consecutive pregnancies, and in random two unpaired breast milk samples, of women with and without IBD. Results The baseline characteristics of women with and without IBD were comparable (Table). The cytokine profiles were significantly correlated between paired breast milk samples from consecutive pregnancies compared to unpaired breast milk samples from women with or without IBD. The overall correlations of cytokine profiles in paired IBD pregnancies were significantly higher than the controls (Figure). Conclusion Our pilot study results suggest that the breast milk cytokine signatures are more conserved in consecutive pregnancies of women with IBD compared to those without IBD. Future analysis will test if our findings have implications toward familial clustering of immune functions in offspring.

Abstract Background There are increasing data on changes in intestinal inflammation and microbiome diversity during pregnancy in women with inflammatory bowel disease (IBD) with implications towards individual and offspring immune function. However, differences in intestinal inflammation, as measured by fecal calprotectin (FC) and microbial a-diversity, in consecutive pregnancies are not known. Methods We prospectively enrolled a cohort of women, 37 with IBD and 39 without IBD, during two consecutive pregnancies, and their offspring. We collected serial stool samples and clinical data, and measured FC and bacterial abundance during each trimester of each pregnancy. We further performed correlation analysis between FC in consecutive pregnancies and between microbial a-diversity in consecutive pregnancies among women with and without IBD. Results Compared to healthy controls, IBD pregnancies had significantly lower gestational age at birth and higher frequency of Cesarean section. Mode of delivery, the status of Group B Streptococcus (GBS) infection and GBS infection prophylaxis were significantly associated with the pregnancy order in both IBD and controls (Table). Furthermore, we observed strong correlations of FC (r=0.56, p-value=0.093) and microbial alpha-diversity assessed as operational taxonomic unit (OTU) richness (r=0.88, p=0.0087) between paired consecutive pregnancies in women with IBD, but not in those without IBD (Figure). There were no differences in microbial alpha-diversity using the Shannon and Simpson indices when comparing consecutive pregnancies of women with and without IBD. Conclusion In this study, we demonstrate that intestinal inflammation and microbiome diversity are more conserved in consecutive pregnancies of women with IBD compared to healthy controls. These findings may have implications towards understanding the impact of pregnancy on host-microbiome interactions in IBD as well as the potential impact on offspring health.

Abstract Background Inflammatory bowel diseases (IBD) are associated with a dysregulation of the intestinal microbiota and some of these dysbiotic taxa may be transmitted to the offspring of pregnant patients with IBD. We analysed the influence of early life events on the development of the intestinal microbiota of infants born to mothers with and without IBD. Methods The MECONIUM (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome) study is a prospective cohort study including pregnant women with or without IBD and their infants. Stool samples were collected during pregnancy and in babies throughout the first 2 years of life. Stool microbiota composition in the baby stool was assessed using 16S rRNA sequencing. Results We analysed 1037 faecal samples from 294 infants (born to 80 mothers with and 214 without IBD). The overall composition of the microbiota at 1 month was influenced by the mode of delivery (r = 0.1224, p = 0.001), feeding (breastfeeding, formula feeding or mixed; r = 0.0366, p = 0.013), and antibiotics (r = 0.0446, p = 0.004), and this was mainly driven by α-diversity (Simpson, r = 0.0529, p = 0.012), and the relative abundance of Bacteroides (r = 0.8738, p = 0.001), Bifidobacterium (r = 0.4282, p = 0.001), and Klebsiella (r = 0.6182, p = 0.001). Univariate and multivariate analysis confirmed the influence of mode of delivery in the relative abundance of Bacteroides (increased in vaginal delivery, Wilcoxon FDR p = 2.50e−07, Maaslin FDR p = 0.0016) at month 1. At month 3, mode of delivery (r = 0.0779, p = 0.001), IBD status of the mothers (r = 0.0253, p = 0.028), and pre-term birth (r = 0.0208, p = 0.045) influenced the overall composition of the microbiota, with the main drivers being Bifidobacterium (r = 0.8844, p = 0.001), Bacteroides (r = 0.8632, p = 0.001), and Klebsiella (r = 0.4374, p = 0.001). Univariate and multivariate analysis confirmed the influence of mode of delivery in the relative abundance of Bacteroides (increased in vaginal delivery, Wilcoxon FDR p = 1.23e−06, Maaslin FDR p = 0.07). None of the evaluated variables could significantly explain the variation of the overall composition of the microbiota at 1 year of life. IBD status of the mother influences the microbiota composition of 2-year-old infants; however, this association was only significant in vector fitting analysis. Conclusion Maternal IBD status is shaping early life microbiota in their offspring, likely due to altered microbiota in mothers with IBD. Additionally, the mode of delivery, feeding, and exposure to antibiotics are important determinants of the infant′s microbiota. These influences are lost with time, probably due to increasing exposure to several sources of microbiota and to confounding factors (e.g. diet).

Abstract Background IBD often affects women during their reproductive years; however, the effect of pregnancy on disease course remains poorly understood. We aimed to assess intestinal inflammation in IBD patients compared with controls as measured by faecal calprotectin (FC). We also investigated whether maternal IBD diagnosis was associated with altered FC in the offspring and if there were particular bacterial taxa that correlated with FC levels. Methods Pregnant women with or without IBD and their infants were prospectively enrolled in the MECONIUM study during 2015–2018 years. FC levels at each trimester of pregnancy and in babies throughout the first 3 years of life were measured using a quantitative enzyme immunoassay (CALPRO AS, Norway). Multivariate regression analysis was applied to investigate FC levels. Stool microbiota composition in the maternal and baby stool was assessed using 16s rRNA sequencing. Results 617 faecal samples from 342 mothers (91 IBD, 251 control) and 1005 faecal samples from 288 infants (born to 76 mothers with and 212 without IBD) were analysed. FC levels in pregnant women with IBD were significantly higher than in control pregnant women regardless of IBD type (Crohn’s disease vs. ulcerative colitis). In IBD mothers FC levels showed a decline during pregnancy (µg/g, median (interquartile range); first trimester 130.8 (102.3–147.3) vs. third trimester 85.9 (44.5–125.4), p = 0.02) (Figure 1). Patients with flare at stool collection had the highest, while those treated with anti-TNF plus thiopurine showed the lowest FC at each trimester. Babies born to mothers with IBD presented higher FC levels than those born to control mothers at multiple time points between 2 and 36 months of age (Figure 2A); the median FC levels were the highest after 1 year up to 3 years in those babies whose mothers presented active disease during pregnancy (Figure 2B). Microbial α-diversity showed an inverse relationship with FC in both mothers (r = −0.25, p = 0.032) and babies (r = −0.31, p = 0.0035). Blautia and Streptococcus abundance were positively correlated with FC in babies. Conclusion FC levels in IBD patients decreased throughout pregnancy. Maternal IBD, lower microbiome diversity and the abundance of certain microbial genera were associated with higher FC in the offspring up to 3 years of life. These findings suggest a potential favourable impact of pregnancy on IBD activity and highlight a possible effect of IBD during pregnancy on the intestinal inflammation in offspring, which could be mediated through altered microbiome.

OBJECTIVE:This study evaluated the association between exposure to several chemicals and mortality from lymphohematopoietic cancer (LHC) among 16,579 synthetic rubber industry workers who were followed up from 1943 to 1998. METHODS:Poisson regression analyses examined LHC rates in relation to butadiene, styrene, and DMDTC exposure. Models provided maximum likelihood estimates of the relative rate for the contrast between categories of one agent, adjusting for other agents and for additional potential confounders. RESULTS:Cumulative exposure to 1,3-butadiene was associated positively with all leukemia (relative rates of 1.0, 1.4, 1.2, 2.9, and 3.7, respectively, for exposures of 0, >0 to <33.7, 33.7 to <184.7, 184.7 to <425.0, and 425.0+ ppm-years), chronic myelogenous leukemia and to a lesser extent with chronic lymphocytic leukemia. Adjusting for styrene and DMDTC attenuated these associations. After controlling for butadiene, neither styrene nor DMDTC displayed a consistent exposure-response trend with all leukemia, chronic myelogenous leukemia, or chronic lymphocytic leukemia. CONCLUSIONS:This study found a positive association between butadiene and leukemia that was not explained by exposure to other agents examined.

Crohn's disease (CD), a type of inflammatory bowel disease (IBD), is a chronic condition of the gastrointestinal tract that is caused by the loss of mucosal tolerance towards the commensal bacteria resulting in inflammatory responses. It has long been postulated that the gut microbiota, a complex and dynamic population of microorganisms, plays a key role in the pathogenesis of IBD. Maternal diagnosis of IBD has been identified as the greatest risk factor for IBD in offspring increasing the odds of developing the disease >4.5-fold. Moreover, babies born to mothers with IBD have demonstrated reduced gut bacterial diversity. There is accumulating evidence that the early life microbiota colonization is informed by maternal diet within the 3rd trimester of pregnancy. While babies born to mothers with IBD would pose an ideal cohort for intervention, no primary prevention measures are currently available. Therefore, we designed the MELODY (Modulating Early Life Microbiome through Dietary Intervention in Pregnancy) trial to test whether the IBD-AID™ dietary intervention during the last trimester of pregnancy can beneficially shift the microbiome of CD patients and their babies, thereby promoting a strong, effective immune system during a critical time of the immune system development. We will also test if favorable changes in the microbiome can lead to a reduced risk of postpartum CD relapse and lower mucosal inflammation in the offspring. This study will help create new opportunities to foster a healthy microbiome in the offspring at high risk of other immune-mediated diseases, potentially reducing their risk later in life.

Background: The development of the esophagus results from the balanced coordination of esophageal progenitor cell (EPC) proliferation and differentiation.Much remains unknown about the molecular mechanisms related to the development of the esophagus.YAP is an important regulator of proliferation in several endodermal derived organs; however, the role of YAP in esophageal development remains to be elucidated.We hypothesize that YAP is required for the proliferation and stratification of EPCs in the developing esophagus.To address this we used genetic mouse models and 3D human pluripotent stem cell (hPSC)derived esophageal organoids to evaluate the role of YAP in esophageal development.Methods: We deleted Yap using Shh-Cre; Yap loxp/loxp mutants to examine the role of Yap deletion in the developing mouse esophagus.To investigate the effect of Yap overexpression we generated Shh-Cre;Yap loxp/loxp ;R26 Yap5SA mutants in which endogenous Yap is replaced by constitutively nuclear Yap.We utilized our previously established protocol to generate EPCs from human pluripotent stem cells (hPSCs) that are able to self-renew and differentiate into a stratified squamous epithelium in 3D organoid culture.We treated hPSCs-derived EPCs with the YAP inhibitor Verteporfin to examine its effects on proliferation and differentiation of EPCs.Results: Deletion of Yap in the mouse esophagus reduces the number of epithelial layers and lumen size.Reduction of the numbers of p63 + , pHH3 + and Edu + EPCs suggests that EPC proliferation is affected by Yap loss.Deletion of Yap affects stratification, as seen in the reduction in the thickness of the Krt13 + epithelium and reduction of Krt8 + suprabasal cells.Yap overexpression causes a hyperplastic phenotype of the epithelium in which the thickness of basal cell layers (p63 + Krt5 + ) and differentiated cell layers (Krt13 + ) are increased.Additionally, the number of p63 + basal cells and pHH3 + proliferating epithelial cells are increased.YAP inhibition with Verteporfin reduces the number and size of esophageal organoids.Consistently, YAP knockdown by siRNA reduces the numbers proliferation (Ki67 + ) of EPCs and stratification of hPSC-derived esophageal organoids.Conclusions: Our results show that YAP plays a conserved role in the development of the mouse and human esophageal epithelium by regulating EPC proliferation.Notably, YAP has been shown to be increased in dysplastic esophageal epithelium and esophageal squamous cell carcinoma.Future directions include evaluating whether YAP can act as an oncogene to transform these EPCs at early stages of these malignancies.

Environmental factors are thought to play a major role in the pathogenesis of inflammatory bowel disease (IBD). Importantly, increasing epidemiological evidence suggests that exposures occurring during early life may be determinant of disease development. However, studying exposures occurring during this window of susceptibility is challenging, and very little has been elucidated about environmental exposures preceding disease onset. Teeth develop in an incremental manner, storing environmental information on compounds such as metals and organics as we age. The study of deciduous (baby) teeth-matrix biomarkers allows assessment of cumulative exposures, starting as early as the second trimester of prenatal development, and continuing into early childhood until teeth shedding. Herein, by studying deciduous teeth, we aimed to identify whether critical exposures during early development may be associated with IBD diagnosis later in life. Adult IBD patients and healthy controls from a single-centre in Portugal were asked to donate their baby teeth; it is traditional for Portuguese families to keep naturally-shed deciduous teeth for years. Thirty teeth were obtained from 14 IBD patients (8 CD, 6 UC) and 16 from unaffected controls (3 from unaffected siblings of IBD patients). Laser ablation-inductively coupled mass spectrometry analysis was used to create temporal metal exposure profiles from the second trimester of pregnancy through the first 6 months of life. Data were analysed using distributed lag models by estimating the time-lagged association of exposures with IBD diagnosis while accounting for the correlated exposures. We found divergences in metal uptake in the teeth of individuals who eventually developed IBD when compared with controls in a time-dependent manner. Lead exposure, a known inflammatory toxicant that has been shown to predispose to murine colitis, as well as alter the gut microbiome and affect metabolic functions, was significantly higher during intra-uterine and the first 6 months of life (p < 0.05). Likewise, in IBD patients, copper (Cu) levels were significantly higher up to 15 weeks postnatally, and chromium (Cr) levels were also significantly elevated from 10 to 15 weeks before birth (both p < 0.05). While elevated copper levels have been shown in patients with UC, no link between chromium and IBD in humans has been previously established. These data suggest that a deregulation in metal uptake during a critical window in early-life is a feature of IBD, prior to the emergence of any clinical symptoms.

Background and aimsPrenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring’s microbiome.MethodsWe prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines.ResultsPregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in Gammaproteobacteria and depletion in Bifidobacteria. Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon.ConclusionAberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.

IBD patients experience greater stress, anxiety and depression which impair quality of life and increase disease burden. It is not known whether women with IBD have more stress and anxiety than healthy controls (ctl) during pregnancy or how these psychosocial factors influence their experience of pregnancy. We investigated measures of stress, anxiety and depression affecting pregnant women with and without IBD participating in the MECONIUM (Exploring MEChanisms Of IBD traNsmission In Utero through the Microbiome) Study. 34 IBD women (median age = 33, 62%CD, 88%white, median parity = 2) and 145 matched ctls, all pregnant/recent delivery, completed the Perceived Stress Scale-14, Autonomic Function Questionnaire (AFQ), Brief Symptom Inventory (BSI) and the Pregnancy Experiences Scale (PES). Questions were answered based on current feelings. Women not currently pregnant answered the PES based on their most recent pregnancy. Mean scores comparison was conducted between four groups (IBD vs. ctl pregnant, IBD vs. ctl not pregnant) using one-way ANOVA with planned comparisons. We conducted a stepwise linear regression to find potential predictors of negative pregnancy experiences in IBD. We ran correlation network analysis between stress variables and pregnancy stool microbiome profiled using 16s rRNA sequencing. There were significant differences in the mean scores of the four groups of subjects across four subscales: PES frequency, intensity and total uplifts (positive feelings about pregnancy) and the BSI somatic symptoms subscale, with higher mean uplift scores in the ctl/non-pregnant groups vs. pregnant/IBD groups and higher BSI somatic scores in the pregnant groups vs. non-pregnant groups. Higher BSI somatic scale scores and parity were significant predictors of hassles (negative feelings about pregnancy) in pregnant women with IBD. There was strong crosstalk between psychological scores and maternal gut microbial genera at third trimester but not second trimester. Boxplots of statistically significant psychological variable comparisons (PES uplifts frequency, uplifts intensity, and total uplifts: p < 0.05; BSI somatic symptoms subscale: p < 0.01) by ANOVA. Correlation networks between psychological scores and maternal gut microbial genera. Left panel: second trimester; right panel: third trimester. Red line indicates positive correlation (q [adjusted p-value] < 0.05); blue line indicates negative correlation (q<0.05); grey line indicates correlation (p < 0.05, q > 0.05). A negative pregnancy experience for IBD women is predicted by somatic symptoms of psychological distress as indicated by the BSI and parity. Higher crosstalk between microbiota and psychological scores was observed in stool collected during third trimester than second trimester. Further analysis of microbiome correlation to psychological variables is on-going.

higher FC levels at 1y (median FC=502µg/g) as compared to those born to mothers in remission (median FC=141µg/g; p=0.17), or with no IBD (median FC=124µg/g; p=0.016, Figure 1).FC levels across all time points correlated with relative abundance of Gammaproteobacteria (r=0.39;p=0.0002).Conclusion Newborns had high levels of FC that decreased with age.Babies born to mothers with active IBD during pregnancy displayed higher FC levels at 1 year of life compared to babies not exposed to IBD in utero.FC levels also correlated with more pro-inflammatory bacterial profiles in early life.If confirmed in a larger sample size, these results may suggest evidence of early subclinical inflammation of which duration and consequences need to be further investigated.

Monitoring IBD activity during pregnancy is challenging because clinical and laboratory markers may be altered due to the physiological adaptation that occurs, and endoscopy use is limited. Fecal Lactoferrin (FL) is a non-invasive biomarker of gut inflammation used for the diagnostics and management of IBD; however, little is known about its use in pregnant women. Herein, we investigated FL concentrations in IBD and control women, participating in the MECONIUM (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome) study, prior to (T0) and during each trimester of pregnancy. 405 faecal samples [32 at T0; 50 at first trimester (T1); 134 at second trimester (T2) and 189 at third trimester (T3)] from 76 IBD women and 175 controls were analysed using a quantitative enzyme immunoassay (LACTOFERRIN SCANTM, TECHLAB®). Correlation analyses with clinical scores collected prospectively [physician global assessment (PGA), modified Harvey-Bradshaw index (HBI) for CD and partial Mayo score for UC] and with fecal calprotectin analysed using a quantitative enzyme immunoassay (CalproLabTM Calprotectin ELISA, Norway) were performed. Statistical analyses were conducting using R software. The median FL (µg/ml) for pregnant was not different to that of non-pregnant women in controls (1.52 at T1 vs. 1.08 at T0; p = 0.08) and in IBD group (3.58 at T1 vs. 2.64 at T0; p = 0.53). FL was significantly higher in IBD women compared with controls at each trimester of pregnancy (Figure 1) and differed by disease activity (active vs. in remission) but showed significance at only T3 (p = 0.002). At T3, FL significantly correlated with PGA (spearman r = 0.42; p = 0.001), partial Mayo score in UC patients (r = 0.41; p = 0.04) and with HBI in CD patients (r = 0.36; p = 0.05). Finally, FL correlated closest with fecal calprotectin (r = 0.63; p < 0.0001), especially in IBD women (r = 0.78; p < 0.0001, Figure 2) at T3. Fecal Lactoferrin concentrations in pregnant women with and without IBD (T0: prior to pregnancy, T1: first trimester, T2: second trimester, T3: third trimester Correlation between fecal Lactoferrin and fecal Calprotection concentrations at third trimester (T3) in pregnant women with or without IBD FL is not affected by pregnancy regardless of maternal IBD status. IBD women had higher FL levels than controls at each trimester of pregnancy. Suggesting that FL could be a reliable, non-invasive biomarker of gut inflammation to monitor IBD activity during this period.