The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease

Olivares, Marta; Neef, Alexander; Castillejo, Gemma; Palma, Giada De; Varea, V.; Capilla, Amalia; Palau, Francesc; Nova, Esther; Marcos, Ascensión; Polanco, Isabel; Ribes-Koninckx, Carmen; Ortigosa, Luís; Izquierdo, L.; Sanz, Yolanda

doi:10.1136/gutjnl-2014-306931

Cited by 262 publications

(210 citation statements)

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“…7 , 8 Besides, we observed that infants with a high genetic risk (HLA-DQ2) had a higher relative abundance of Proteobacteria, and of unclassified Enterobacteriaceae. 8 However, all the preceding studies were taxonomy-based, and the pathogenic potential of the increased abundance of the family Enterobacteriaceae remained unexplored. Here, we describe that, at 4 months of age, the infants with the highest genetic risk of CD development showed a higher prevalence of ETEC, irrespective of milk feeding practices, although this result was only detected by applying a Chi-square test and was not corroborated by the CRT analysis.…”

Section: Discussionmentioning

confidence: 72%

“…Correlation analysis of our previous data shows negative associations between Bifidobacterium and Clostridium , and between Bifidobacterium and Escherichia/Shigella . 8 Then, it can be hypothesized that the higher prevalence of C. perfringens and C. difficile , and of enterotoxigenic E. coli might be a consequence of the reductions in Bifidobacterium numbers as previously observed in formula-fed infants and the carriers of the HLA-DQ2 genotype. 7 , 8 Unravelling which is the cause or the consequence, as well as the mechanisms that favor the colonization of certain bacterial groups and the co-exclusion of others should be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…7 , 8 In particular, we described that breast-fed infants with a high genetic risk (HLA-DQ2) of developing CD had reductions in Bifidobacterium spp., a feature that theoretically could be related to the development of the disease in the later life. 7 , 8 Besides, we observed that infants with a high genetic risk (HLA-DQ2) had a higher relative abundance of Proteobacteria, and of unclassified Enterobacteriaceae. 8 However, all the preceding studies were taxonomy-based, and the pathogenic potential of the increased abundance of the family Enterobacteriaceae remained unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…5 , 6 Associations have also been established between the HLA-DQ2/DQ8 genotype and the gut microbiota composition, suggesting that the microbiota could also act as a predisposing factor for CD. 7 , 8 Early viral and bacterial infections have been associated with the subsequent development of CD. 9 , 10 A population-based cohort study estimated that children who suffered from more than ten episodes of respiratory or gastrointestinal infections presented a higher risk of developing CD compared to children with less than four infection events.…”

Section: Introductionmentioning

confidence: 99%

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Increased prevalence of pathogenic bacteria in the gut microbiota of infants at risk of developing celiac disease: The PROFICEL study

et al. 2018

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Celiac disease (CD) is an immune-mediated enteropathy involving genetic and environmental factors, whose interaction influences disease risk. The intestinal microbiota, including viruses and bacteria, could play a role in the pathological process leading to gluten intolerance. In this study, we investigated the prevalence of pathogens in the intestinal microbiota of infants at familial risk of developing CD. We included 127 full-term newborns with at least one first-degree relative with CD. Infants were classified according to milk-feeding practice (breastfeeding or formula feeding) and HLA-DQ genotype (low, intermediate or high genetic risk). The prevalence of pathogenic bacteria and viruses was assessed in the faeces of the infants at 7 days, 1 month and 4 months of age. The prevalence of Clostridium perfringens was higher in formula-fed infants than in breast-fed over the study period, and that of C. difficile at 4 months. Among breastfed infants, a higher prevalence of enterotoxigenic E. coli (ETEC) was found in infants with the highest genetic risk compared either to those with a low or intermediate risk. Among formula-fed infants, a higher prevalence of ETEC was also found in infants with a high genetic risk compared to those of intermediate risk. Our results show that specific factors, such as formula feeding and the HLA-DQ2 genotype, previously linked to a higher risk of developing CD, influence the presence of pathogenic bacteria differently in the intestinal microbiota in early life. Further studies are warranted to establish whether these associations are related to CD onset later in life.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Increased prevalence of pathogenic bacteria in the gut microbiota of infants at risk of developing celiac disease: The PROFICEL study

et al. 2018

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“…The microbiota development is affected by a number of factors including genetics, mode of delivery and gestational age, antibiotic usage, breast feeding (BF)/formula feeding and long-term diet after weaning (Penders et al, 2006;Grönlund et al, 2007;Dominguez-Bello et al, 2010;Ladirat et al, 2013;Azad et al, 2014;Nylund et al, 2014;Olivares et al, 2014;Voreades et al, 2014). During the colonization process, facultative anaerobic bacteria, such as Enterobacteria, are gradually replaced by anaerobic bacteria, such as the genera Bifidobacterium, Clostridium and Bacteroides (Weber and Polanco, 2012;Matamoros et al, 2013;Arrieta et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Discordant temporal development of bacterial phyla and the emergence of core in the fecal microbiota of young children

et al. 2015

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The colonization pattern of intestinal microbiota during childhood may impact health later in life, but children older than 1 year are poorly studied. We followed healthy children aged 1-4 years (n = 28) for up to 12 months, during which a synbiotic intervention and occasional antibiotics intake occurred, and compared them with adults from the same region. Microbiota was quantified with the HITChip phylogenetic microarray and analyzed with linear mixed effects model and other statistical approaches. Synbiotic administration increased the stability of Actinobacteria and antibiotics decreased Clostridium cluster XIVa abundance. Bacterial diversity did not increase in 1-to 5-year-old children and remained significantly lower than in adults. Actinobacteria, Bacilli and Clostridium cluster IV retained child-like abundances, whereas some other groups were converting to adult-like profiles. Microbiota stability increased, with Bacteroidetes being the main contributor. The common core of microbiota in children increased with age from 18 to 25 highly abundant genus-level taxa, including several butyrate-producing organisms, and developed toward an adult-like composition. In conclusion, intestinal microbiota is not established before 5 years of age and diversity, core microbiota and different taxa are still developing toward adult-type configuration. Discordant development patterns of bacterial phyla may reflect physiological development steps in children.

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HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome

Asquith¹,

Sternes

Costello

et al. 2019

Arthritis & Rheumatology

127

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Objective HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype–disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA–B27 and HLA–DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. Methods Five hundred sixty‐eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. Results Associations were observed between the overall microbial composition and both the HLA–B27 genotype and the HLA–DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). Conclusion This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA‐B27 and HLA–DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.

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The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease

Cited by 262 publications

References 45 publications

Increased prevalence of pathogenic bacteria in the gut microbiota of infants at risk of developing celiac disease: The PROFICEL study

Increased prevalence of pathogenic bacteria in the gut microbiota of infants at risk of developing celiac disease: The PROFICEL study

Discordant temporal development of bacterial phyla and the emergence of core in the fecal microbiota of young children

HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome

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