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Allergic diseases are the most common chronic diseases in childrenin the Western world, but little is know about what factors influence immune maturation and allergy development. We therefore aimed to associate infant and maternal metabolomes to T- and B-cell subpopulations and allergy diagnosis. We performed liquid chromatography-mass spectrometry based untargeted metabolomics on blood plasma from mothers (third trimester, n = 605; delivery, n = 558) and from the umbilical cord (n = 366). The measured metabolomes were associated to T- and B-cell subpopulations up to 4 months after delivery and to doctor´s diagnosed eczema, food allergy and asthma at one year of age using random forest analysis. Maternal and cord plasma at delivery could predict the number of CD24 + CD38 low memory B-cells (p = 0.033, n = 26 and p = 0.009, n = 22), but future allergy status could not be distinguished from any of the three measured metabolomes. Replication of previous literature findings showed hypoxanthine to be upregulated in the umbilical cord of children with subsequent asthma. This exploratory study suggests foetal immune programming occuring during pregnancy as the metabolomic profiles of mothers and infants at delivery related to infants’ B-cell maturation.

Type 1 diabetes (T1D) is an autoimmune disease caused by T-cell mediated destruction of pancreatic beta cells. Eosinophils are found in pancreatic tissue from individuals with T1D. Eosinophilic suppression of T cells is dependent of the protein galectin-10. Little is known when it comes to the role of eosinophil granulocytes in type 1 diabetes. Here we show that individuals with long-standing T1D had lower levels of galectin-10 hi eosinophils and a subgroup of galectin-10 hi eosinophils were entirely absent in all T1D patients. In addition, 7% immature eosinophils were present in the circulation of T1D patients whereas 0.8% in healthy individuals. Furthermore, higher levels of CD4+CD8+ T cells and Th17 cells were observed in patients with T1D. Blood samples from 12 adult individuals with long-standing T1D and 12 healthy individuals were compared using cytometry by time-of-flight. Lower levels of galectin-10 hi eosinophils, which are potent T cell suppressors, in individuals with T1D could indicate that activated T cells are enabled to unrestrictedly kill the insulin producing beta cells. This is the first study showing absence of galectin-10 hi eosinophilic subgroup in individuals with T1D compared with healthy controls. This study is a first important step toward unraveling the role of the eosinophils in patients with T1D.

Introduction Uterus bioengineering offers a potential treatment option for women with uterine factor infertility and for mitigating the risk of uterine rupture associated with women with defective uterine tissue. Decellularized uterine tissue scaffolds proved promising in further in vivo experiments in rodent and domestic species animal models. Variations in the extracellular matrix composition among different species and adaptations of the decellularization protocols make it difficult to compare the results between studies. Therefore, we assessed if our earlier developed sodium deoxycholate‐based decellularization protocol for the sheep and the cow uterus could become a standardized cross‐species protocol by assessing it on the non‐human primate (baboon) uterus. Material and Methods The baboon uterus was decellularized using sodium deoxycholate, and the remaining acellular scaffold was quantitatively assessed for DNA, protein, and specific extracellular matrix components. Furthermore, electron microscopy deepened morphology examination, while the chorioallantoic membrane assay examined the scaffolds' cytotoxicity, bioactivity, and angiogenic properties. The in vitro recellularization efficiency of the scaffolds using xenogeneic (rat) bone marrow‐derived mesenchymal stem cells was also assessed. Finally, the immune potential of the scaffolds was evaluated by in vitro exposure to human peripheral blood mononuclear cells. Results We obtained a decellularized baboon uterus with preserved extracellular matrix components by adding an 8‐h sodium deoxycholate perfusion to our previously developed protocol for the sheep and cow models. This minor modification resulted in scaffolds with less than 1% of immunogenic host DNA content while preserving important uterine‐specific collagen, elastin, and glycosaminoglycan structures. The chorioallantoic membrane assay and in vitro recellularization experiments confirmed that the scaffolds were bioactive and non‐cytotoxic. As we have observed in other animal models, the enzymatic scaffold preconditioning with matrix metalloproteinases improved the recellularization efficiency further. Additionally, the preconditioning generated more immune‐privileged scaffolds, as shown in a novel in vitro co‐culture assay with human peripheral blood mononuclear cells. Conclusions For the first time, our data demonstrate the efficiency of our protocol for non‐human primate uteri and its translational potential. This standardized protocol will facilitate cross‐study comparisons and expedite clinical translation. This study establishes an interspecies sodium deoxycholate (SDC)‐based decellularization C) protocol that generates bioactive, non‐toxic uterus scaffolds. Furthermore, preconditioning with metalloproteinases (MMP) does not affect the scaffold's properties, improving recellularization potential and attenuating their immunogenicity. Graphical created with BioRender.com

Children growing up on farms or with pets have a lower risk of developing allergy, which may be linked to their gut microbiota development during infancy. Children from the FARMFLORA birth cohort (N = 65), of whom 28 (43%) lived on a dairy farm and 40 (62%) had pets, provided fecal samples at intervals from 3 days to 18 months of age. Gut microbiota composition was characterized using quantitative microbial culture of various typical anaerobic and facultatively anaerobic bacteria, with colonization rate and population counts of bacterial groups determined at the genus or species level. Allergy was diagnosed at three and eight years of age by experienced pediatricians. Generalized estimating equations were used to identify associations between farm residence or pet ownership, gut microbiota development and allergy. Adjustments were made for important potential confounders. Growing up on a farm was associated with a higher ratio of anaerobic to facultative bacteria in the first week, smaller Escherichia coli populations in colonized children in the first months of life and less frequent colonization by Clostridioides difficile at 12 months of age. Having pets in the household was associated with more frequent colonization by Bifidobacterium, Lactobacillus and Bacteroides in the first months. A higher ratio of anaerobic to facultative bacteria at one week of age, early colonization by Bifidobacterium, Lactobacillus and Bacteroides, and reduced carriage of C. difficile at 4-12 months of age all correlated negatively with subsequent allergy diagnosis. Our findings indicate that lower rates of allergy in children growing up on farms or with pets may be related to early establishment of typical anaerobic commensals in their gut microbiota. However, further studies are needed to validate our observations in this small birth cohort study.

Background The gut microbiota may influence immune maturation during infancy. While cesarean delivery is known to delay acquisition of a mature anaerobic microbiota, the influence of being firstborn on early gut colonization is less well studied. Methods Feces were collected regularly from 3 days to 18 months of age in the FARMFLORA cohort ( N  = 65) and cultured quantitatively for major anaerobic and facultative bacteria. Colonization rates and population counts of different gut bacteria were analyzed in relation to birth order, delivery mode, and antibiotic exposure during delivery. Each exposure was adjusted for the other two. Results Birth order, delivery mode and antibiotic exposure were each independently associated with gut colonization. Firstborn infants ( N  = 29) acquired Escherichia coli and bifidobacteria later than infants with older sibings ( N  = 36) and had signs of microbiota immaturity, including higher levels of facultative bacteria and increased carriage of opportunistic colonizers such as Clostridioides difficile and Staphylococcus aureus . Cesarean-delivered infants ( N  = 10) showed delayed E. coli acquisition and increased colonization by other enterobacteria, while antibiotic exposure during delivery ( N  = 10) delayed colonization by Bacteroides . Conclusions Delayed colonization by typical fecal bacteria in firstborn infants suggests reduced maternal bacterial transfer during delivery. This might contribute to the predilection of firstborn children to develop allergy.

Amniotic fluid is clinically accessible via amniocentesis and its protein composition may correspond to birth timing. Early changes in the amniotic fluid proteome could therefore be associated with the subsequent development of spontaneous preterm delivery. The main objective of this study was to perform unbiased proteomics analysis of the association between mid-trimester amniotic fluid proteome and spontaneous preterm delivery and gestational duration, respectively. A secondary objective was to validate and replicate the findings by enzyme-linked immunosorbent assay using a second independent cohort. Women undergoing a mid-trimester genetic amniocentesis at Sahlgrenska University Hospital/Östra between September 2008 and September 2011 were enrolled in this study, designed in three analytical stages; 1) an unbiased proteomic discovery phase using LC-MS analysis of 22 women with subsequent spontaneous preterm delivery (cases) and 37 women who delivered at term (controls), 2) a validation phase of proteins of interest identified in stage 1, and 3) a replication phase of the proteins that passed validation using a second independent cohort consisting of 20 cases and 40 matched controls. Nine proteins were nominally significantly associated with both spontaneous preterm delivery and gestational duration, after adjustment for gestational age at sampling, but none of the proteins were significant after correction for multiple testing. Several of these proteins have previously been described as being associated with spontaneous PTD etiology and six of them were thus validated using enzyme linked immunosorbent assay. Two of the proteins passed validation; Neutrophil gelatinase-associated lipocalin and plasminogen activator inhibitor 1, but the results could not be replicated in a second cohort. Neutrophil gelatinase-associated lipocalin and Plasminogen activator inhibitor 1 are potential biomarkers of spontaneous preterm delivery and gestational duration but the findings could not be replicated. The negative findings are supported by the fact that none of the nine proteins from the exploratory phase were significant after correction for multiple testing.

Children growing up on farms or with pets have a lower risk of developing allergy, which may be linked to their gut microbiota development during infancy. Children from the FARMFLORA birth cohort (N = 65), of whom 28 (43%) lived on a dairy farm and 40 (62%) had pets, provided fecal samples at intervals from 3 days to 18 months of age. Gut microbiota composition was characterized using quantitative microbial culture of various typical anaerobic and facultatively anaerobic bacteria, with colonization rate and population counts of bacterial groups determined at the genus or species level. Allergy was diagnosed at three and eight years of age by experienced pediatricians. Generalized estimating equations were used to identify associations between farm residence or pet ownership, gut microbiota development and allergy. Adjustments were made for important potential confounders. Growing up on a farm was associated with a higher ratio of anaerobic to facultative bacteria in the first week, smaller Escherichia coli populations in colonized children in the first months of life and less frequent colonization by Clostridioides difficile at 12 months of age. Having pets in the household was associated with more frequent colonization by Bifidobacterium, Lactobacillus and Bacteroides in the first months. A higher ratio of anaerobic to facultative bacteria at one week of age, early colonization by Bifidobacterium, Lactobacillus and Bacteroides, and reduced carriage of C. difficile at 4-12 months of age all correlated negatively with subsequent allergy diagnosis. Our findings indicate that lower rates of allergy in children growing up on farms or with pets may be related to early establishment of typical anaerobic commensals in their gut microbiota. However, further studies are needed to validate our observations in this small birth cohort study.

Children growing up on farms or with pets have a lower risk of developing allergy, which may be linked to their gut microbiota development during infancy. Children from the FARMFLORA birth cohort (N = 65), of whom 28 (43%) lived on a dairy farm and 40 (62%) had pets, provided fecal samples at intervals from 3 days to 18 months of age. Gut microbiota composition was characterized using quantitative microbial culture of various typical anaerobic and facultatively anaerobic bacteria, with colonization rate and population counts of bacterial groups determined at the genus or species level. Allergy was diagnosed at three and eight years of age by experienced pediatricians. Generalized estimating equations were used to identify associations between farm residence or pet ownership, gut microbiota development and allergy. Adjustments were made for important potential confounders. Growing up on a farm was associated with a higher ratio of anaerobic to facultative bacteria in the first week, smaller Escherichia coli populations in colonized children in the first months of life and less frequent colonization by Clostridioides difficile at 12 months of age. Having pets in the household was associated with more frequent colonization by Bifidobacterium, Lactobacillus and Bacteroides in the first months. A higher ratio of anaerobic to facultative bacteria at one week of age, early colonization by Bifidobacterium, Lactobacillus and Bacteroides, and reduced carriage of C. difficile at 4-12 months of age all correlated negatively with subsequent allergy diagnosis. Our findings indicate that lower rates of allergy in children growing up on farms or with pets may be related to early establishment of typical anaerobic commensals in their gut microbiota. However, further studies are needed to validate our observations in this small birth cohort study.

ABSTRACT Cystic fibrosis (CF) is a genetic disease leading to chronic bacterial airway infection and inflammation. T helper 17 (Th17) cells are identified by their production of interleukin (IL)-17A, which recruit neutrophils to the site of airway infection. IL-23 is an important inducer of IL-17 and IL-22 production. The aim of this study was to study the role of Th17 cells in CF airway infection by measuring the levels of Th17 associated cytokines in sputum from CF patients with or without airway infection and by comparison with non-CF-controls. In a cross-sectional screening study, cytokine levels were measured with a Th17 multiplex cytokine ELISA. Significantly lower levels of IL-17A and IL-23 were found in sputa from infected CF patients. The lowest levels of IL-17A were found in patients chronically infected with P. aeruginosa, which also had the lowest IL-17/IL-22 ratio, while children had a higher ratio. Children also had higher IL-23 levels than adults. IL-1ß and IL-10 were significantly lower in CF sputum compared to controls. Thus, in our study CF patients with chronic infections had a lower production of Th17 associated cytokines in sputum compared with non-infected CF patients and infected patient without CF. In this study cystic fibrosis (CF)-patients with chronic infections had a lower production, in sputum, of substances needed for host defense compared with non-infected CF-patients and infected patient without CF.

Allergic diseases are the most common chronic diseases in childrenin the Western world, but little is know about what factors influence immune maturation and allergy development. We therefore aimed to associate infant and maternal metabolomes to T- and B-cell subpopulations and allergy diagnosis. We performed liquid chromatography-mass spectrometry based untargeted metabolomics on blood plasma from mothers (third trimester, n = 605; delivery, n = 558) and from the umbilical cord (n = 366). The measured metabolomes were associated to T- and B-cell subpopulations up to 4months after delivery and to doctor´s diagnosed eczema, food allergy and asthma at one year of age using random forest analysis. Maternal and cord plasma at delivery could predict the number of CD24+CD38low memory B-cells (p = 0.033, n = 26 and p = 0.009, n = 22), but future allergy status could not be distinguished from any of the three measured metabolomes. Replication of previous literature findings showed hypoxanthine to be upregulated in the umbilical cord of children with subsequent asthma. This exploratory study suggests foetal immune programming occuring during pregnancy as the metabolomic profiles of mothers and infants at delivery related to infants’ B-cell maturation.