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• W2896352400 abstract "The gut microbiota is composed of a huge amount and diversity of microorganisms playing major roles in physiological and pathological settings such as inflammatory bowel disease (IBD). The triggering role of the gut microbiota on intestinal inflammation is known and an intestinal dysbiosis (ie, an imbalance in the microbiota composition and function) has been pointed out in IBD 15 years ago. Moreover, a positive efficacy signal has been observed in studies evaluating fecal microbiota transplantation in IBD, demonstrating that the gut microbiota alterations is an actor in the inflammatory process and not simple consequence.1Pigneur B. Sokol H. Fecal microbiota transplantation in inflammatory bowel disease: the quest for the holy grail.Mucosal Immunol. 2016; 9: 1360-1365Crossref PubMed Scopus (51) Google Scholar Environmental factors have an important effect on gut microbiota composition, but host genetic has an impact, too. This effect has been demonstrated in knockout mouse for innate immunity genes. Microbiome genome-wide association studies have identified several associations between genetic polymorphisms and the gut microbiota composition, offering some clues for the effects of genes on microbiota composition in humans.2Hall A.B. Tolonen A.C. Xavier R.J. Human genetic variation and the gut microbiome in disease.Nat Rev Genet. 2017; 18: 690-699Crossref PubMed Scopus (272) Google Scholar However, the effect of major specific disease-causing genetic defects on gut microbiota has never been studied in humans yet. Here, we characterized the fecal microbiota composition of patients with 3 types of rare primary immunodeficiency (PID) causing IBD conditions, chronic granulomatous disease (CGD, 11 samples), X-linked inhibitor of apoptosis (XIAP, 7 samples) deficiency, and partial Tetratricopeptide Repeat Domain 7A (TTC7A, 7 samples) deficiency, in comparison to patients with non–genetic-determined IBD (18 samples) and healthy subjects (HS, 23 samples; see Table E1 in this article's Online Repository at www.jacionline.org). The microbiota composition was assessed by 16S sequencing. As seen previously, gut microbiota composition was influenced by age and antifungal and antibiotic treatment3Morgan X.C. Tickle T.L. Sokol H. Gevers D. Devaney K.L. Ward D.V. et al.Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.Genome Biol. 2012; 13: R79Crossref PubMed Scopus (532) Google Scholar (see Fig E1 in this article's Online Repository at www.jacionline.org). Beta diversity analysis showed a remarkable clustering of samples according to disease phenotypes (Fig 1, A). The difference with HS was statistically significant for CGD and TTC7A groups, whereas it did not reach significance for the XIAP group (Fig 1, A-D). Interestingly, the difference with patients with IBD was statistically significant for all 3 PID patients groups (Fig 1, A). Age was very heterogeneous in patients from TTC7A and XIAP groups (0.62-18 and 1.3-34 years, respectively). The gut microbiota composition changes constantly between birth and the age of 3 years when it reaches an adult-like configuration.4Tamburini S. Shen N. Wu H.C. Clemente J.C. The microbiome in early life: implications for health outcomes.Nat Med. 2016; 22: 713-722Crossref PubMed Scopus (622) Google Scholar We thus performed the same analysis after segregating the patients according to their age (younger or older than 3 years). The difference with HS was maintained for patients with TTC7A deficiency in both age groups and reached significance in patients with XIAP deficiency older than 3 years (only 2 patients with XIAP deficiency younger than 3 years) (see Fig E2 in this article's Online Repository at www.jacionline.org). Patients with CGD and XIAP and TTC7A deficiency can experience intestinal inflammation mimicking IBD.5Uhlig H.H. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease.Gut. 2013; 62: 1795-1805Crossref PubMed Scopus (157) Google Scholar In our study population, samples were taken from patients with (PIDIBD) or without (PIDno-IBD) IBD involvement. In addition, patients with IBD could be in active phase (flare) or remission (PID, IBD flare/inactive). Microbiota from patients with active intestinal inflammation (PIDIBD (flare)) was significantly different from the one of patients with PIDno-IBD (Fig 1, E). We observed a significant diversity reduction in patients with PIDIBD compared with HS (Fig 1, F; see Fig E3, A, in this article's Online Repository at www.jacionline.org). Moreover, this reduction was even stronger in patients with active intestinal inflammation (Fig 1, G; Fig E3, B). These effects were seen in the 3-studied PID although the numbers were too low to reach statistical significance when analyzing each PID independently (see Fig E4 in this article's Online Repository at www.jacionline.org). In accordance with the published literature, the bacterial microbiota of all groups was dominated by bacteria from Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria phyla. Differences were noticed between patients with PID and HS, with notably a dramatic increase in Proteobacteria from the Enterobacteriaceae family in the TTC7A group and an increase in proportion in bacteria from the Bacteroidetes phylum and from the Clostridiaceae family in the CGD and XIAP groups, respectively (Fig 1, H; Fig E3, C). These alterations were found both in patients younger and older than 3 years (Fig E4, B and D) and were clearly stronger in patients with IBD and PIDIBD with active inflammation (Fig 1, I; Fig E4, C and E). We then looked for the microbial features associated with the 3-studied PID and used a multivariate association test (MaAsLin) to control for potential confounding factors such as age, sex, smoking, intestinal inflammation, and treatment. We observed several alterations specific to each PID compared with HS. Patients with TTC7A deficiency exhibited an increased abundance of Proteobacteria involving several components of the Gammaproteobacteria and Epsilonproteobacteria classes (Fig 2, A). However, bacteria from the Ruminococcaceae family and notably the Oscillospira genera were decreased. Patients with XIAP deficiency exhibited an increased abundance of several bacterial taxa including members of the Proteobacteria, Firmicutes, Actinobacteria, and Fusobacteria phyla (Fig 2, B). Four of these taxa (Scardovia, Fusobacterium, Rothia dentocariosa, and Veillonella) are not usually found in the gut but are known members of the oral microbiota that are implicated not only in dental caries but also in IBD, colorectal cancer, and liver diseases.6Kummen M. Holm K. Anmarkrud J.A. Nygård S. Vesterhus M. Høivik M.L. et al.The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls.Gut. 2017; 66: 611-619Crossref PubMed Scopus (233) Google Scholar Interestingly, an increased abundance of oral bacteria in the gut has been observed in several intestinal and extraintestinal diseases.7Atarashi K. Suda W. Luo C. Kawaguchi T. Motoo I. Narushima S. et al.Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation.Science. 2017; 358: 359-365Crossref PubMed Scopus (384) Google Scholar Moreover, a recent study showed that some members of the oral microbiota can have proinflammatory effects when colonizing the gut,7Atarashi K. Suda W. Luo C. Kawaguchi T. Motoo I. Narushima S. et al.Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation.Science. 2017; 358: 359-365Crossref PubMed Scopus (384) Google Scholar suggesting a possible direct effect of these oral bacteria in the intestinal inflammatory phenotype observed in patients with XIAP deficiency. Another important specificity in patients with XIAP deficiency was the presence of Lactococcus garvieae, which is a highly virulent pathogen affecting saltwater fish8Vendrell D. Balcázar J.L. Ruiz-Zarzuela I. de Blas I. Gironés O. Múzquiz J.L. Lactococcus garvieae in fish: a review.Comp Immunol Microbiol Infect Dis. 2006; 29: 177-198Crossref PubMed Scopus (290) Google Scholar and is rarely involved in human infection. L garvieae was found at a high level (0.23%-0.5% of all reads) in patients with XIAP deficiency with active intestinal inflammation but not in all other patients in this study. Patients with CGD exhibited an increased abundance of Ruminococcus gnavus, which has also been associated with ileal Crohn disease9Sokol H. Leducq V. Aschard H. Pham H.-P. Jegou S. Landman C. et al.Fungal microbiota dysbiosis in IBD.Gut. 2017; 66: 1039-1048Crossref PubMed Scopus (645) Google Scholar (Fig 2, C). In summary, we showed that the gut microbiota of patients with CGD and TTC7A and XIAP deficiency have distinct alterations, suggesting a primary defect in host immune system as a basis of dysbiosis. Although it remains to be experimentally documented, the microbial alterations induced by the host genetic defect might play a role in some aspects of the PID phenotype and particularly intestinal involvement. The number of subjects studied was low because of the extreme rarity of the studied diseases. However, independent and ideally larger and longitudinal studies are required to confirm our findings. Controlling for potential confounding factors such as diet, treatment, age, delivery mode, socioeconomic features, and gastrointestinal symptoms is particularly difficult in studies aiming at discriminating genetic factors from environmental and inflammation influences. Similarly, identification of ideal controls is not trivial. Although nonaffected healthy siblings sharing similar lifestyles would be attractive, there are obvious limitations in term of feasibility. Finally, if these observations are confirmed, the alteration in gut microbiota composition might have clinical interest as diagnosis biomarkers. Patients with PID were recruited at Necker-Enfants Malades University Hospital, Paris, France (Pediatric Immunology-Hematology-Rheumatology Unit, Adult Hematology Unit, Adult Infectious Disease Unit), Saint-Louis Hospital, Paris, France, and Lille Regional University Hospital, Lille, France, and provided informed consent. Pediatric HS were recruited from the Pediatric Orthopedic Surgery Unit, Necker-Enfants Malades University Hospital. Approval was obtained from the local ethics committee (Comité de Protection des Personnes III; Ref. 3149, June 10, 2014, Dipobiota study, ClinicalTrials.gov Identifier: NCT02909244). Patients with IBD in remission were recruited at the Gastroenterology Department of the Saint Antoine Hospital (Paris, France) and provided informed consent (local ethics committee: Comité de Protection des Personnes Ile-de-France IV, Suivitheque study). None of the patients with IBD and the HS reported having taken antibiotics or probiotics, or using colon-cleansing products for at least 1 month before enrollment. Patient characteristics are presented in Table E1. Whole stools were collected in sterile boxes and immediately homogenized, and 0.2-g aliquots were frozen at −80°C for further analysis. Patients' data were collected, including clinical, treatment, and immunological and genetic diagnosis. Enrolled patients with PID had damaging causal mutation, respectively, in the TTC7A gene (“ELA syndrome”),E1Lemoine R. Pachlopnik-Schmid J. Farin H.F. Bigorgne A. Debré M. Sepulveda F. et al.Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.J Allergy Clin Immunol. 2014; 134: 1354-1364.e6Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar BIRC4 (XIAP deficiency), or CYBBNox2 (X-linked CGD). None of the subjects received probiotics.Table E1Characteristics of patientsCharacteristicHS (n = 23)IBD (n = 18)CGD (n = 10)TTC7A (n = 5)XIAP (n = 6)Sample n23181177Age (y), median (min-max)9 (0.83-32)28.5 (10-41)10 (6-31)1.8 (0.62-18)8 (1.3-34)Sex: male14 (61)16 (89)11 (100)3 (43)7 (100)Gut inflammation history018 (100)9 (82)7 (100)3 (43)Active gut inflammation007 (64)5 (71)5 (71)Smoking1 (4)4 (22)003 (43)Sulfamethoxazole/trimethoprim0011 (100)2 (29)3 (50)Other antibiotics003 (27)02 (29)Itraconazole0010 (91)00Posaconazole001 (9)005-ASA06 (33)2 (18.2)00Corticosteroid00002 (33)Azathioprin09 (50)000Methotrexate001 (9)01 (17)Anti–TNF-α011 (61)000Anti–IL-1 therapy000011 (17)Natalizumab (anti-α4) therapy00001 (17)Any immunosuppressant011 (61)1 (9)03 (50)PPI0001 (14)0Immunoglobulin substitution0007 (100)1 (17)Enteral nutrition0003 (43)0Hydroxychloroquine001 (9)00Values are n (%) unless indicated otherwise; 1 patient with CGD, 1 patient with XIAP deficiency, and 2 patients with TTC7A deficiency experienced flare during the follow-up and were then sampled twice.5-ASA, 5 Aminosaclicylate; PPI, proton pump inhibitor. Open table in a new tab Values are n (%) unless indicated otherwise; 1 patient with CGD, 1 patient with XIAP deficiency, and 2 patients with TTC7A deficiency experienced flare during the follow-up and were then sampled twice. 5-ASA, 5 Aminosaclicylate; PPI, proton pump inhibitor. Genomic DNA was extracted from 200 mg of feces as previously described.E2Lamas B. Richard M.L. Leducq V. Pham H.-P. Michel M.-L. Da Costa G. et al.CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.Nat Med. 2016; 22: 598-605Crossref PubMed Scopus (735) Google Scholar Following microbial lysis with both mechanical and chemical steps, nucleic acids were precipitated in isopropanol for 10 minutes at room temperature, incubated for 15 minutes on ice, and centrifuged for 30 minutes at 15,000g and 4°C. Pellets were suspended in 112 μL of phosphate buffer and 12 μL of potassium acetate. After RNase treatment and DNA precipitation, nucleic acids were recovered via centrifugation at 15,000g and 4°C for 30 minutes. The DNA pellet was suspended in 100 μL of TE buffer. Fecal DNA was extracted from the weighted feces before and during the infection as previously described.E2Lamas B. Richard M.L. Leducq V. Pham H.-P. Michel M.-L. Da Costa G. et al.CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands.Nat Med. 2016; 22: 598-605Crossref PubMed Scopus (735) Google Scholar Microbial diversity was determined for each sample by targeting a portion of the ribosomal genes. A 16S rRNA gene fragment comprising V3 and V4 hypervariable regions (16S; 5′-TACGGRAGGCAGCAG-3′ and 5′-CTACCNGGGTATCTAAT-3′) was amplified using an optimized and standardized 16S-amplicon-library preparation protocol (Metabiote, GenoScreen). Briefly, 16S rRNA gene PCR was performed using 5 ng genomic DNA according to the manufacturer's protocol (Metabiote) using 192 bar-coded primers (Metabiote MiSeq Primers, GenoScreen) at final concentrations of 0.2 μM and an annealing temperature of 50°C for 30 cycles. The PCR products were purified using an Agencourt AMPure XP-PCR Purification system (Beckman Coulter, Villepinte, France), quantified according to the manufacturer's protocol, and multiplexed at equal concentrations. Sequencing was performed using a 250-bp paired-end sequencing protocol on an Illumina MiSeq platform (Illumina, Paris, France) at GenoScreen. Raw paired-end reads were subjected to the following process: (1) quality filtering using the PRINSEQ-lite PERL scriptE3Uhlig H.H. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease.Gut. 2013; 62: 1795-1805Crossref PubMed Scopus (228) Google Scholar by truncating the bases from the 3′ end that did not exhibit a quality < 30 based on the Phred algorithm; (2) paired-end read assembly using FLASH (fast length adjustment of short reads to improve genome assemblies) with a minimum overlap of 30 bases and a 97% overlap identity; and (3) searching and removing both forward and reverse primer sequences using CutAdapt, with no mismatches allowed in the primer sequences. Assembled sequences for which perfect forward and reverse primers were not found were eliminated. The sequences were demultiplexed and quality filtered using the Quantitative Insights Into Microbial Ecology (QIIME, version 1.9.1) software package,E4Caporaso J.G. Kuczynski J. Stombaugh J. Bittinger K. Bushman F.D. Costello E.K. et al.QIIME allows analysis of high-throughput community sequencing data.Nat Methods. 2010; 7: 335-336Crossref PubMed Scopus (24570) Google Scholar and the forward and reverse Illumina reads were joined using the fastq-join method (http://code.google.com/p/ea-utils). The sequences were assigned to Operational Taxonomic Units (OTUs) using the UCLUST algorithmE5Edgar R.C. Search and clustering orders of magnitude faster than BLAST.Bioinformatics. 2010; 26: 2460-2461Crossref PubMed Scopus (13945) Google Scholar with a 97% threshold of pairwise identity and classified taxonomically using the Greengenes reference database.E6McDonald D. Price M.N. Goodrich J. Nawrocki E.P. DeSantis T.Z. Probst A. et al.An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea.Isme J. 2012; 6: 610-618Crossref PubMed Scopus (3433) Google Scholar Principal-component analyses of the Bray-Curtis distance were built and used to assess the variation between experimental groups (beta diversity). Significance was assessed using ANOSIM (9999 permutations). The Shannon and Chao1 diversity index values were calculated using rarefied data (depth = 17,000 sequences/sample) and used to characterize species diversity in a community. GraphPad Prism version 6.0 (San Diego, Calif) was used for all analyses and graph preparation. For all graph data, the results are expressed as the mean ± SEM, and statistical analyses were performed using the 2-tailed nonparametric Mann-Whitney U-test or Kruskal-Wallis test with Dunn Multiple Comparison Test. Statistical significance of sample grouping for beta diversity analysis was performed using the ANOSIM method (9999 permutations). Differences with a P value of less than .05 were considered significant. Multivariate Analysis by Linear Models (MaAsLin), a multivariate statistical framework, was used to find associations between clinical metadata and microbial community abundance.E7Morgan X.C. Tickle T.L. Sokol H. Gevers D. Devaney K.L. Ward D.V. et al.Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.Genome Biol. 2012; 13: R79Crossref PubMed Scopus (1726) Google Scholar We took into account as many factors as possible in the analysis to control for the effects of potential confounding factors including age, sex, smoking, intestinal inflammation and treatment, and enteral nutrition.Fig E2Beta diversity analysis according to age. Principal-coordinate analysis of Bray-Curtis distance with each sample colored according to the studied group and stratified by age (< or >3 years). PC1, PC2, and PC3 represent the top 3 principal coordinates that captured most of the diversity. The fraction of diversity captured by the coordinate is given as a percentage. Groups were compared using the ANOSIM method (9999 permutations). A and B, All the studied groups plotted together. C and D, The TTC7A group compared with HS. E and F, The XIAP group compared with HS. *P < .05; **P < .01; ***P < .001; ****P < .0001.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E3Abnormal microbiota composition at the family level in PID. Bacterial diversity based on Chao1 index (A and B) in the fecal samples of indicated groups. Statistical significance was assessed using ANOVA with a post hoc Dunn test. *P < .05; **P < .01; ***P < .001; ****P < .0001. Global composition of bacterial microbiota at the levels for the indicated groups (C and D).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig E4Alpha diversity and microbiota composition according to age and IBD intestinal inflammation. Bacterial diversity based on the Shannon index (A) and the Chao1 index (B) in the fecal samples of indicated groups. Global composition of bacterial microbiota at the phylum (C and D) and family (E and F) levels for the indicated groups.View Large Image Figure ViewerDownload Hi-res image Download (PPT)" @default.
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• W2896352400 date "2019-02-01" @default.
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• W2896352400 title "Intestinal dysbiosis in inflammatory bowel disease associated with primary immunodeficiency" @default.
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