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Coeliac disease: what can we learn from prospective studies about disease risk?
Stahl, M, Koletzko, S, Andrén Aronsson, C, Lindfors, K, Liu, E, Agardh, D, ,
The Lancet. Child & adolescent health. 2024;(1):63-74
Abstract
Paediatric prospective studies of coeliac disease with longitudinal collection of biological samples and clinical data offer a unique perspective on disease risk. This Review highlights the information now available from international paediatric prospective studies on genetic and environmental risk factors for coeliac disease. In addition, recent omics studies have made it possible to study complex interactions between genetic and environmental factors and thereby further our insight into the causes of the disease. In the future, paediatric prospective studies will be able to provide more detailed risk prediction models combining genes, the environment, and biological corroboration from multiomics. Such studies could also contribute to biomarker development and an improved understanding of disease pathogenesis.
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Effects of Lactiplantibacillus plantarum and Lacticaseibacillus paracasei supplementation on the single-cell fecal parasitome in children with celiac disease autoimmunity: a randomized, double-blind placebo-controlled clinical trial.
Hurych, J, Oscarsson, E, Håkanson, Å, Jirků-Pomajbíková, K, Jirků, M, Aronson, CA, Cinek, O, Agardh, D, ,
Parasites & vectors. 2023;(1):411
Abstract
BACKGROUND Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700:2 positively affect the fecal bacteriome in children with celiac disease autoimmunity after 6 months of supplementation. The aim of the present investigation was to study the effects of Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700:2 on the single-cell parasitome, with a primary focus on Blastocystis. METHODS Stool samples were collected from 78 Swedish children with celiac disease autoimmunity participating in a randomized, double-blind, placebo-controlled clinical trial to either receive a mixture of supplementation with L. plantarum HEAL9 and L. paracasei 8700:2 (n = 38) or placebo (n = 40). A total of 227 stool samples collected at baseline and after 3 and 6 months of intervention, respectively, were retrospectively analyzed for Blastocystis by quantitative real-time PCR and subtyped by massively parallel amplicon sequencing. Other single-cell parasites were detected by untargeted 18S rDNA amplicon sequencing and verified by real-time PCR. The relation between the parasites and the bacteriome community was characterized by using 16S rDNA profiling of the V3-V4 region. RESULTS Three different single-cell protists were identified, of which the highest prevalence was found for Dientamoeba fragilis (23.1%, 18/78 children), followed by Blastocystis (15.4%, 12/78) and Entamoeba spp. (2.6%, 2/78). The quantity of the protists was stable over time and not affected by probiotic intervention (P = 0.14 for Blastocystis, P = 0.10 for D. fragilis). The positivity of the protists was associated with increased bacteriome diversity (measured by multiple indices, P < 0.03). Bacterial composition was influenced by the presence of the protists: positivity of Blastocystis was inversely associated with Akkermansia (at the levels of the genus as well as its family, order, class and phylum); P < 0.002), Faecalibacterium (P = 0.003) and Romboutsia (P = 0.029); positivity of D. fragilis was inversely associated with families Enterobacteriaceae (P = 0.016) and Coriobacteriaceae (P = 0.022) and genera Flavonifractor (P < 0.001), Faecalibacterium (P = 0.009), Lachnoclostridium (P = 0.029), Ruminococcus (P < 0.001) and Granulicatella (P = 0.018). CONCLUSIONS The prevalence of single-cell protists is low in children with celiac disease autoimmunity. The colonization was stable regardless of the probiotic intervention and associated with increased diversity of the fecal bacteriome but inversely associated with some beneficial bacteria.
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Intervention strategies in early childhood to prevent celiac disease-a mini-review.
Andrén Aronsson, C, Agardh, D
Frontiers in immunology. 2023;:1106564
Abstract
A higher intake of gluten during childhood is associated with increased risk of celiac disease, and the incidence of celiac disease peaks shortly after the time point when associations with higher gluten intake during the second and third year of life occur. Additional environmental factors are most likely necessary for celiac disease to develop. It is hypothesized that gastrointestinal infections increase gut permeability and exposure to gluten. Alternatively, infections may lead to gut dysbiosis and chronic inflammation, with leakage of self-antigens that mimic gluten peptides that leads to an autoimmune-like response. Different gluten interventions to prevent celiac disease have been proposed. Early clinical studies suggested an optimal time point introducing gluten between 4 and 6 months of age while the infant is being breastfed. However, later clinical trials on reduced gluten intake given to infants have shown no protection from celiac disease if gluten introduction was delayed or if gluten was introduced in small amounts during the child's first year of life. Still, more randomized clinical trials (RCTs) are warranted to answer the question if a reduced amount of gluten, not only at the time of introduction during infancy but also in a longer time frame, will prevent children at genetic risk from having lifelong celiac disease. It needs to be clarified whether dietary interventions are effective strategies to be proposed as future prevention of celiac disease in the general population. The present mini-review provides an overview of ongoing or completed RCTs that have focused on interventions during early childhood with the aim of preventing celiac disease.
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Effects of Lactiplantibacillus plantarum and Lacticaseibacillus paracasei supplementation on the faecal metabolome in children with coeliac disease autoimmunity: a randomised, double-blinded placebo-controlled clinical trial.
Jenickova, E, Andrén Aronsson, C, Mascellani Bergo, A, Cinek, O, Havlik, J, Agardh, D
Frontiers in nutrition. 2023;:1183963
Abstract
INTRODUCTION Coeliac disease is a lifelong immune-mediated enteropathy manifested as gluten intolerance in individuals carrying specific human leukocyte antigen (HLA) molecules. Other factors than genetics and gluten intake, however, may play a role in triggering the disease. The gut internal environment is thought to be one of these potential contributing factors, and it can be influenced throughout life. METHODS We examine the impact of Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700:2 supplementation on the faecal metabolome in genetically predisposed children having tissue transglutaminase autoantibodies, i.e., coeliac disease autoimmunity. Probiotic strains were selected based on their beneficial properties, including mucosal permeability and immune modulation effects. The intervention group (n = 40) and control group (n = 38) took the probiotics or placebo daily for 6 months in a double-blinded randomised trial. Faecal samples were collected at baseline and after 3 and 6 months and analysed using the 1H NMR for metabolome. The incorporation of 16S rRNA sequencing as a supportive dataset complemented the analysis of the metabolome data. RESULTS During the 6 months of intervention, the stool concentrations of 4-hydroxyphenylacetate increased in the intervention group as compared to controls, whereas concentrations of threonine, valine, leucine, isoleucine, methionine, phenylalanine, aspartate, and fumarate decreased. Additionally, a noteworthy effect on the glycine, serine, and threonine metabolic pathway has been observed. CONCLUSION The findings suggest a modest yet significant impact of the probiotics on the faecal metabolome, primarily influencing proteolytic processes in the gut. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT03176095.
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Review article: exposure to microbes and risk of coeliac disease.
Størdal, K, Kahrs, C, Tapia, G, Agardh, D, Kurppa, K, Stene, LC
Alimentary pharmacology & therapeutics. 2021;(1):43-62
Abstract
BACKGROUND Coeliac disease is an immune-mediated intestinal disease characterised by lifelong intolerance to dietary gluten in genetically predisposed individuals. Microbial factors including infections or bacterial microbiota have long been suspected to be involved in the aetiology, but the scientific literature on the topic is scattered and heterogeneous. AIMS To review human observational studies on microbes and coeliac disease METHODS We identified 135 publications judged relevant. Most studies were cross-sectional, and prone to reverse causation and other biases. Only a few were prospective. Cohort studies and longitudinal studies that have sampled biological specimens before disease onset are emphasised in the review. RESULTS Infections during early childhood were associated with an increased risk of subsequent coeliac disease in nine studies , whereas maternal infections during pregnancy did not show a clear association. For the most frequently studied microbial factors, some evidence for an association was found, including Helicobacter pylori (four out of 16 studies), adenovirus (two out of nine studies) and enterovirus (two out of six studies). Rotavirus infections have been associated with disease development, and rotavirus vaccination may reduce the risk. Among the many studies of gut microbiota, most were cross-sectional and, therefore, potentially influenced by reverse causation. Only two smaller prospective case-control studies with sampling before disease onset were identified; they reported inconsistent findings regarding the faecal microbiome. CONCLUSIONS Several microbes are potentially linked to coeliac disease. As microbial factors are amenable to interventions, larger prospective studies are still warranted.
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Effects of Probiotic Bacteria Lactobacillaceae on the Gut Microbiota in Children With Celiac Disease Autoimmunity: A Placebo-Controlled and Randomized Clinical Trial.
Oscarsson, E, Håkansson, Å, Andrén Aronsson, C, Molin, G, Agardh, D
Frontiers in nutrition. 2021;:680771
Abstract
Disturbances of the gut microbiota may influence the development of various autoimmune diseases. This study investigated the effects of supplementations with the probiotic bacteria, Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700:2, on the microbial community in children with celiac disease autoimmunity (CDA). The study included 78 genetically predisposed children for celiac disease with elevated levels of tissue transglutaminase autoantibodies (tTGA) signaling for ongoing CDA. Among those children, 38 received a placebo and 40 received the probiotic supplement daily for 6 months. Fecal and plasma samples were collected at baseline and after 3 and 6 months, respectively. The bacterial community was investigated with 16S rRNA gene sequencing and terminal restriction fragment length polymorphism (T-RFLP), and tTGA levels were measured in radiobinding assays. In children that received probiotic supplementation, the relative abundance of Lactobacillaceae increased over time, while it remained unchanged in the placebo group. There was no overall correlation between tTGA levels and bacterial genus except for a positive correlation between Dialister and IgG-tTG in the probiotic group. The abundance of specific bacterial amplicon sequence variant (ASV:s) changed during the study in both groups, indicating that specific bacterial strains might be affected by probiotic supplementation.
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Effects of Lactobacillus plantarum and Lactobacillus paracasei on the Peripheral Immune Response in Children with Celiac Disease Autoimmunity: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Håkansson, Å, Andrén Aronsson, C, Brundin, C, Oscarsson, E, Molin, G, Agardh, D
Nutrients. 2019;11(8)
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An abnormal immune response to gluten may lead to lifelong digestive symptoms in patients with celiac disease. Several species of beneficial bacteria in the gut may reduce inflammation by reducing the amount of proinflammatory cytokines released in response to antigens. The purpose of this randomized, double-blind, controlled trial was to investigate the effects of Lactobacillus plantarum HEAL9 and L. paracasei 8700:2 on the development of celiac disease in children who are at high risk of developing the celiac disease while eating a gluten-containing diet. A total of seventy-eight children with celiac autoimmunity were given either 10¹ºCFU/day of L. plantarum HEAL9 and L. paracasei 8700:2 or maltodextrin for six months. It has been observed that six months of intervention with probiotics modulated the immune response in celiac disease autoimmunity. In the intervention group, there were no signs of celiac disease progression. There is a need for further robust and long-term studies to examine more specifically the benefits of Lactobacillus in the prevention of celiac disease as well as modulating effects on the intestinal mucosa. It is important to point out that healthcare professionals can use the results of this study to better understand the immunomodulatory effects of specific Lactobacillus strains in celiac disease.
Abstract
Two Lactobacillus strains have proven anti-inflammatory properties by reducing pro-inflammatory responses to antigens. This randomized double-blind placebo-controlled trial tested the hypothesis that L. plantarum HEAL9 and L. paracasei 8700:2 suppress ongoing celiac disease autoimmunity in genetically at risk children on a gluten-containing diet in a longitudinally screening study for celiac disease. Seventy-eight children with celiac disease autoimmunity participated of whom 40 received 1010 CFU/day of L. plantarum HEAL9 and L. paracasei 8700:2 (probiotic group) and 38 children maltodextrin (placebo group) for six months. Blood samples were drawn at zero, three and six months and phenotyping of peripheral blood lymphocytes and IgA and IgG autoantibodies against tissue transglutaminase (tTG) were measured. In the placebo group, naïve CD45RA+ Th cells decreased (p = 0.002) whereas effector and memory CD45RO+ Th cells increased (p = 0.003). In contrast, populations of cells expressing CD4+CD25highCD45RO+CCR4+ increased in the placebo group (p = 0.001). Changes between the groups were observed for NK cells (p = 0.038) and NKT cells (p = 0.008). Median levels of IgA-tTG decreased more significantly over time in the probiotic (p = 0.013) than in the placebo (p = 0.043) group whereas the opposite was true for IgG-tTG (p = 0.062 respective p = 0.008). In conclusion, daily oral administration of L. plantarum HEAL9 and L. paracasei 8700:2 modulate the peripheral immune response in children with celiac disease autoimmunity.
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Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk.
Andrén Aronsson, C, Lee, HS, Hård Af Segerstad, EM, Uusitalo, U, Yang, J, Koletzko, S, Liu, E, Kurppa, K, Bingley, PJ, Toppari, J, et al
JAMA. 2019;(6):514-523
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Abstract
IMPORTANCE High gluten intake during childhood may confer risk of celiac disease. OBJECTIVES To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. DESIGN, SETTING, AND PARTICIPANTS The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. EXPOSURES Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. MAIN OUTCOMES AND MEASURES The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. RESULTS Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). CONCLUSIONS AND RELEVANCE Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.
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Altered peripheral amino acid profile indicate a systemic impact of active celiac disease and a possible role of amino acids in disease pathogenesis.
Torinsson Naluai, Å, Saadat Vafa, L, Gudjonsdottir, AH, Arnell, H, Browaldh, L, Nilsson, S, Agardh, D
PloS one. 2018;13(3):e0193764
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Certain amino acids are released as a result of gluten metabolism that may be involved in chronic inflammation. With this hypothesis the study investigated the different levels of amino acids released in the blood plasma of children with celiac disease. This study found that children with celiac disease had increased levels of amino acids particularly those related with gluten metabolism. However, more research is needed as these findings are unclear to the source of inflammation and the role of amino acid levels in celiac disease pathogenesis.
Abstract
BACKGROUND We have previously performed a Genome Wide Association and linkage study that indicated a new disease triggering mechanism involving amino acid metabolism and nutrient sensing signaling pathways. OBJECTIVE The aim of this study was to investigate if plasma amino acid levels differed among children with celiac disease compared with disease controls. MATERIALS AND METHODS Fasting plasma samples from 141 children with celiac disease and 129 non-celiac disease controls, were analyzed for amino acid levels by liquid chromatography-tandem mass spectrometry (LC/MS). A general linear model using age and experimental effects as covariates was used to compare amino acid levels between children with a diagnosis of celiac disease and controls. RESULTS Seven out of twenty-three analyzed amino acids were elevated in children with celiac disease compared with controls (tryptophan, taurine, glutamic acid, proline, ornithine, alanine and methionine). The significance of the individual amino acids do not survive multiple correction, however, multivariate analyses of the amino acid profile showed significantly altered amino acid levels in children with celiac disease overall and after correction for age, sex and experimental effects (p = 8.4 × 10-8). CONCLUSION These findings support the idea that amino acids could influence systemic inflammation and play a possible role in disease pathogenesis.
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Coeliac disease in children with type 1 diabetes.
Kurppa, K, Laitinen, A, Agardh, D
The Lancet. Child & adolescent health. 2018;(2):133-143
Abstract
Coeliac disease and type 1 diabetes are the most common paediatric autoimmune disorders. Both conditions have increasing incidence and can often coexist in a patient. The diseases share many genetic and immunological features, but diagnostic and treatment approaches vary substantially worldwide. Because of the often subtle presentation of coeliac disease in children with type 1 diabetes, many are diagnosed only upon screening for coeliac disease. In this Review, we summarise approaches to diagnosis and treatment of children with type 1 diabetes and coeliac disease, with a specific emphasis on those with a double diagnosis. In particular, we examine the pros and cons of screening for coeliac disease and assess the challenges of dietary treatment in children with coexisting type 1 diabetes, which can already be a burden. Furthermore, we present the latest research on the shared genetic and pathogenic mechanisms and introduce some future perspectives.