Differences in the intestinal microbiome of healthy children and patients with newly diagnosed Crohn’s disease

AbstractThe aetiology of inflammatory bowel diseases (IBD) seems to be strongly connected to changes in the enteral microbiome. The dysbiosis pattern seen in Crohn’s disease (CD) differs among published studies depending on patients’ age, disease phenotype and microbiome research methods. The aims was to investigate microbiome in treatment-naive paediatric patients to get an insight into its structure at the early stage of the disease in comparison to healthy. Stool samples were obtained from controls and newly diagnosed patients prior to any intervention. Microbiota was analysed by 16SrRNAnext-generation-sequencing (NGS). Differences in the within-sample phylotype richness and evenness (alpha diversity) were detected between controls and patients. Statistically significant dissimilarities between samples were present for all used metrics. We also found a significant increase in the abundance of OTUs of the Enterococcus genus and reduction in, among others, Bifidobacterium (B. adolescentis), Roseburia (R.faecis), Faecalibacterium (F. prausnitzii), Gemmiger (G. formicilis), Ruminococcus (R. bromii) and Veillonellaceae (Dialister). Moreover, differences in alpha and beta diversities in respect to calprotectin and PCDAI were observed: patients with calprotectin <100 µg/g and with PCDAI below 10 points vs those with calprotectin >100 µg/g and mild (10–27.7 points), moderate (27.5–40 points) or severe (>40 points) CD disease activity had higher richness and diversity of gut microbiota. The results of our study highlight reduced diversity and dysbiosis at the earliest stage of the disease. Microbial imbalance and low abundance of butyrate-producing bacteria, including Bifidobacterium adolescentis, may suggest benefits of microbial modification therapy.

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Tu1793 – Eukaryotic Microbial Dysbiosis in Treatment-Naïve Patients with Newly Diagnosed Crohn's Disease

Gastroenterology ◽

10.1016/s0016-5085(19)39779-3 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-1126

Author(s):

Idan Goren ◽

Lihi Godny ◽

Leah Reshef ◽

Keren M. Rabinowitz ◽

Uri Gophna ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Newly Diagnosed ◽

Microbial Dysbiosis ◽

Treatment Naïve

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P403 Treatment naïve newly diagnosed patients with Crohn's disease have microbial dysbiosis correlated with disease activity and faecal calprotectin—results from a prospective inception cohort

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjx180.530 ◽

2018 ◽

Vol 12 (supplement_1) ◽

pp. S308-S309

Author(s):

H Yanai ◽

I Goren ◽

L Reshef ◽

L Godny ◽

K Yadgar ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Newly Diagnosed ◽

Inception Cohort ◽

Faecal Calprotectin ◽

Microbial Dysbiosis ◽

Treatment Naïve

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Neutralization of IL-1α ameliorates Crohn’s disease-like ileitis by functional alterations of the gut microbiome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1915043116 ◽

2019 ◽

Vol 116 (52) ◽

pp. 26717-26726 ◽

Cited By ~ 7

Author(s):

Paola Menghini ◽

Daniele Corridoni ◽

Ludovica F. Buttó ◽

Abdullah Osme ◽

Sushma Shivaswamy ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Gut Microbiome ◽

Bacterial Species ◽

Intestinal Microbiome ◽

Lactobacillus Salivarius ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Antiinflammatory Effects

Crohn’s disease and ulcerative colitis are chronic and progressive inflammatory bowel diseases (IBDs) that are attributed to dysregulated interactions between the gut microbiome and the intestinal mucosa-associated immune system. There are limited studies investigating the role of either IL-1α or IL-1β in mouse models of colitis, and no clinical trials blocking either IL-1 have yet to be performed. In the present study, we show that neutralization of IL-1α by a specific monoclonal antibody against murine IL-1α was highly effective in reducing inflammation and damage in SAMP mice, mice that spontaneously develop a Crohn’s-like ileitis. Anti-mouse IL-1α significantly ameliorated the established, chronic ileitis and also protected mice from developing acute DSS-induced colitis. Both were associated with taxonomic divergence of the fecal gut microbiome, which was treatment-specific and not dependent on inflammation. Anti–IL-1α administration led to a decreased ratio ofProteobacteriatoBacteroidetes, decreased presence ofHelicobacterspecies, and elevated representation ofMucispirillum schaedleriandLactobacillus salivarius. Such modification in flora was functionally linked to the antiinflammatory effects of IL-1α neutralization, as blockade of IL-1α was not effective in germfree SAMP mice. Furthermore, preemptive dexamethasone treatment of DSS-challenged SAMP mice led to changes in flora composition without preventing the development of colitis. Thus, neutralization of IL-1α changes specific bacterial species of the intestinal microbiome, which is linked to its antiinflammatory effects. These functional findings may be of significant value for patients with IBD, who may benefit from targeted IL-1α–based therapies.

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P676 The small intestinal microbiome in Crohn’s disease is characterised by increased luminal diversity and stable mucosa-associated communities

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.796 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S597-S598

Author(s):

L Wauters ◽

R Tito ◽

M Ceulemans ◽

A Moens ◽

A Outtier ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Multiple Testing ◽

Alpha Diversity ◽

Intestinal Microbiome ◽

Genus Level ◽

Α Diversity ◽

Small Intestinal ◽

Community Variation ◽

Lower Endoscopy

Abstract Background Crohn’s disease (CD) may affect the entire gut but the composition and optimal sampling of the small intestinal microbiome are understudied. We assessed the variation in small intestinal luminal and mucosal microbiota in CD compared to healthy volunteers (HV) and functional dyspepsia (FD) patients. Methods Duodenal biopsies were collected with the Brisbane aseptic biopsy device1 followed by sterile brushing of the lumen/mucus layer. Aseptic ileal biopsies and brushes were also collected in CD patients with synchronous lower endoscopy. Acid- (proton pump inhibitors, PPIs) or immune-suppression (IS) and macro- (erosions/ulcers) and/or microscopic inflammation (CD) were recorded. Contamination was minimised during sample and data processing2 with further analysis at genus level. Microbiota covariates were studied using distance-based redundancy analysis (dbRDA, genus-level Aitchison distance) and PERMANOVA. Alpha-diversity (α) was compared between sampling types (biopsy/brush), disease groups, PPIs (off/on), IS (yes/no) or location (CD). Genera abundance profiles were compared transversally (sampling type) and regionally (CD) with correction for multiple testing (FDR<.1). Results A total of 99 participants (21 CD, 48 FD and 30 HV) with similar demographics were included. Only sampling type and subject were associated with duodenal community variation (table). Transversal variation was also evident from the more significant clustering for sampling type vs. groups (fig 1). Within CD, sampling type (8.5%) and location (17.8%, both p=.005) but not treatment or inflammation were associated with community variation. Duodenal α-diversity of brushes was lower vs. biopsies (p<2*10–9) and higher in CD vs. controls (fig 2). Compared to untreated subjects, α-diversity was lower with PPI in brushes (fig 3) and higher with IS in biopsies (CD) (fig 4). The 42 differentially abundant genera between sampling types of the duodenum were largely shared between groups vs. only 3 different genera for the ileum (CD). In CD, regional differences were found for 24 genera in brushes vs. only 6 in biopsies, with inflammation driving minor changes in brush and not biopsy samples of the duodenum only. Conclusion Small intestinal microbiota variation is significant, especially between duodenal luminal and mucosal communities. Luminal α-diversity was highest in CD but lower than that of the mucosa with an effect of treatment. Despite regional variation, mucosal genera profiles were more conserved and less affected by inflammation in CD. References 1. Shanahan et al., AP&T 2016 2. Davis et al., Microbiome 2018

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The Assessment of Plasma Fatty Acid Profiles in Newly Diagnosed Treatment-Naïve Paediatric Crohn’s Disease

Physiological Research ◽

10.33549/physiolres.934665 ◽

2021 ◽

pp. 799-808

Author(s):

J SCHWARZ ◽

M VECKA ◽

F STOŽICKÝ ◽

R POMAHAČOVÁ ◽

B STAŇKOVÁ ◽

...

Keyword(s):

Fatty Acids ◽

Crohn’S Disease ◽

Fatty Acid ◽

Crohn's Disease ◽

Disease Activity ◽

Inflammatory Markers ◽

Activity Index ◽

Methyl Esters ◽

Newly Diagnosed ◽

Treatment Naïve

Fatty acid (FA) profiles as potentially relevant components of Crohn’s disease (CD) have been insufficiently analysed. We sought to explore the plasma profiles of n-3 and n-6 polyunsa-turated fatty acids (PUFAs) in newly diagnosed untreated active CD. We included 26 consecutive CD pediatric patients (<19 years) and 14 healthy controls (HCs). Disease characteristics, including inflammatory markers, dietary histories, and the Pediatric Crohn’s Disease Activity Index (PCDAI), were obtained. The profiles of plasma FAs in plasma lipid classes were analysed by gas chromatography with FID detection of methyl esters. The erythrocyte sedimentation rate, C-reactive protein level and fecal calprotectin level (all p<0.001) were significantly higher in CD patients than in HCs. Most changes were observed in plasma phospholipids (PLs), such as a higher content of n-3 and changes in n-6 long-chain PUFAs in the CD group. The CD group had a lower ratio of n-6/n-3 PUFAs in PLs (p<0.001) and triacylglycerols (TAGs) (p<0.01). Correlations of the FA content in plasma PLs with disease activity scores of CD were also observed, which were positive for the sum of monounsaturated fatty acids (MUFAs) as well as oleic acid (18:1n-9) (both p<0.05). The metabolism of PUFAs is significantly altered even in treatment-naïve newly diagnosed active pediatric CD, and the content of major FAs in PLs correlates with disease activity and inflammatory markers, thus probably contributing to the still unclear early disease pathogenesis.

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DOP19 Urinary metabolome in newly diagnosed treatment-naïve Crohn’s Disease patients: Results from the IBDomics study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab073.058 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S057-S058

Author(s):

L Aldars-García ◽

R Gil-Redondo ◽

N Embade ◽

S Riestra ◽

M Rivero ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Healthy Subjects ◽

Smoking Habit ◽

Univariate Analysis ◽

Urinary Metabolites ◽

Proton Nuclear Magnetic Resonance ◽

Newly Diagnosed ◽

Non Invasive ◽

Treatment Naïve

Abstract Background The urinary metabolome of patients with Crohn’s disease (CD) differs significantly from healthy subjects and, among other features, reflects the specific gut dysbiosis affecting these patients. However, most of the studies included established and treated CD patients. Our aim was to characterize the urinary metabolome of onset and treatment-naïve CD patients and to identify the metabolic profile related to the different CD clinical classifications. Methods Patients newly diagnosed with CD (n=131) were prospectively included. Control healthy subjects (HC, n=338) were recruited among the general population and matched for sex, age and BMI to the IBD subjects. Fasting urine was obtained before starting any treatment. Metabolomic analysis was performed by proton nuclear magnetic resonance (1H NMR). We performed a comparative assessment of the urinary metabolome profile using a linear regression model for each metabolite, including sex, age, BMI, and smoking habit as covariates to control for confounding. The different subgroup comparisons within CD were made as follows: (1) CD; (2) CD location (Montreal Classification): L1 (ileal) + L4 (ileal and upper-intestinal), L2 (colonic) and L3 (ileocolonic); (3) endoscopic CD activity: 0, 1, 2 and 3; and (4) CD phenotype: B1 (inflammatory), B2 (stricturing) and B3 (penetrating), versus HC. In addition, data analysis was carried out using partial least squares-discriminate analysis (PLS-DA) to determine class membership based on distinct metabolomic profile. Results The primary characteristics of the CD patients and HC are shown in Table 1. Several metabolites were identified to be differently abundant in each group (Table 2). These metabolites are involved in relevant processes related to energy and aminoacids metabolism, and also include gut-derived metabolites. The PLS-DA model separated patients within the different clinical subgroups (Figures 1–4). Figures 1–4(b) show the main metabolites involved in each group separation. Many of these metabolites are in accordance with the differential metabolites obtained using the univariate analysis (Table 2), showing the potential of this approach to group CD patients and to identify potential biomarkers. Conclusion Analysis of urinary metabolites can help to understand the etiopathological mechanisms in CD. It has the potential to provide a non-invasive means of diagnosing CD, and can differentiate between CD clinical expressions.

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Changes in the Intestinal Microbiota Are Seen Following Treatment with Infliximab in Children with Crohn’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm9030687 ◽

2020 ◽

Vol 9 (3) ◽

pp. 687 ◽

Cited By ~ 1

Author(s):

Kinga Kowalska-Duplaga ◽

Przemysław Kapusta ◽

Tomasz Gosiewski ◽

Agnieszka Sroka-Oleksiak ◽

Agnieszka H. Ludwig-Słomczyńska ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Biological Treatment ◽

Intestinal Microbiome ◽

Sequencing Analysis ◽

Healthy Children ◽

Core Microbiome ◽

Tnf Α ◽

Before And After ◽

The Impact

The aim of the study was to determine the impact of biological treatment with tumor necrosis factor α antibodies (anti-TNF-α) on the intestinal microbiome of children with severe Crohn’s disease (CD) and to evaluate the differences in the intestinal microbiome between patients treated with biological therapy and healthy children. Microbiota composition was analyzed by 16S next-generation sequencing (NGS) and microbial profiles were compared between studied groups. Fifty-four samples (from 18 patients before and after anti-TNF-α induction therapy and 18 healthy children) were used in the sequencing analysis. Shannon’s diversity index (p = 0.003, adj. p = 0.010) and observed operational taxonomic units (OTUs) (p = 0.007, adj. p = 0.015) were different between controls and patients with prior therapy for CD. Statistically significant dissimilarities between beta diversity metrics, indicating distinct community composition across groups, were observed in patients with CD before and after therapy. We did not observe any differences between controls and patients with CD after therapy. Core microbiome analysis at species level showed that 32 species were present only in patients with CD but not in controls. The results show that biological treatment is associated with changes in the intestinal microbiome of patients with CD: these changes result in an intestinal microbiome pattern similar to that seen in healthy children. Long-term observation is necessary to determine whether treatment can lead to full restoration of a healthy-like microbiome.

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