Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn’s disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a ...whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier.
We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12.
Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval CI 1.68–115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34–10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria.
CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870.
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The coronavirus disease (COVID-19) pandemic affects medical care worldwide, including patients with inflammatory bowel disease (IBD). Thus, we aimed to assess its impact on health care provision, ...fear of infection, adherence to medical treatment, and compliance with preventative instructions in children and adolescents with IBD.
A cross-sectional telephonic survey using a Likert scale-based questionnaire was conducted among all pediatric patients with IBD from a single tertiary medical center.
A total of 244 pediatric patients with IBD were included in the study, reporting a high rate of fear of severe COVID-19 infection due to IBD or IBD medications (198, 81.1%). Most of the patients obeyed the Ministry of Health instructions (228, 93.4%), while almost 50% took additional protective measures including avoidance of school and complete lockdown. Concerns regarding the attendance of regular clinics (116, 47.5%) and emergency room in case of IBD exacerbation (178, 73%) were frequently reported. Only 7 patients (2.9%) changed or discontinued their IBD treatment due to COVID-19.
We noted several distinct features of the COVID-19 pandemic effect on pediatric patients with IBD including a high rate of fear of severe COVID-19 infection, fear of attending necessary medical facilities, and high rate of avoidance of social activities.
Pediatric patients with IBD have a high rate of fear of severe COVID-19 infection, fear of attending necessary medical facilities, and a high rate of avoidance of social activities. Medication adherence rate in pediatric patients with IBD during the pandemic is similar to the adherence rate among adults with IBD. Almost 50% of pediatric patients with IBD took additional protective measures including avoidance of school and voluntary lockdown during the COVID-19 pandemic.
Neutrophil extracellular traps (NETs) are an essential component of the antimicrobial repertoire and represent an effective means by which neutrophils capture, contain, and kill microorganisms. ...However, the uncontrolled or excessive liberation of NETs also damages surrounding cells and can contribute to disease pathophysiology. Alterations in the gut microbiota, as well as the presence of local and systemic markers of inflammation, are strongly associated with the manifestation of a spectrum of intestinal disorders, including chronic inflammatory bowel disease. Although probiotics exert beneficial effects on gut homeostasis, their direct effect on neutrophils, which are abundant in the setting of intestinal inflammation, remains unclear. In this study, we investigated the effects of nonpathogenic, enteropathogenic, and probiotic bacteria on the dynamics of NET formation. Using murine bone marrow-derived neutrophils and the neutrophil-differentiated human myeloid cell line d.HL-60, we demonstrate for the first time, to our knowledge, that probiotic Lactobacillus rhamnosus strain GG inhibits both PMA- and Staphylococcus aureus-induced formation of NETs. Moreover, probiotic L. rhamnosus strain GG had potent antioxidative activity: dampening reactive oxygen species production and phagocytic capacity of the neutrophils while protecting against cell cytotoxicity. Within the milieu of the gut, this represents a novel mechanism by which probiotics can locally dampen innate immune responses and confer desensitization toward luminal Ags.
The composition of the intestinal microbiome seems relevant to the pathogenesis of Crohn's disease (CD), with differences in both diversity and composition of the gut microbiota in patients with CD ...compared with healthy individuals. However, there are still conflicting reports on the importance of various bacterial taxa in the pathogenesis of CD. The aim of this study was to characterize the composition of mucosa-associated intestinal microbiota in newly diagnosed pediatric patients with CD.
Mucosa-associated bacteria were identified from ileal biopsy specimens obtained at colonoscopy of 10 patients with either ileal or ileocolonic new-onset CD and 15 controls without mucosal inflammation. Microbial composition was performed by profiling the 16S rDNA V6 region using Illumina sequencing. Samples were analyzed for differences in alpha/beta diversity and also for differentially abundant taxa.
Alpha diversity did not differ between the controls and CD cases or between CD subjects with localized ileal disease compared with those with more extensive disease. Controls also did not clearly separate from patients with CD by principal coordinate analyses; however, 117 operational taxonomic units were found to be differentially abundant between the two groups. In particular, numerous operational taxonomic units associated with Faecalibacterium prausnitzii species were increased in children with CD.
These findings contribute to emerging evidence regarding dysbiosis in pediatric CD, and provide additional evidence challenging the protective role of F. prausnitzii in CD.
Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive ...treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10–18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9–8.9) in YP compared with 14.3 years (IQR 12.8–15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 μg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0–12.9) vs. OP; 5.5 mg/kg (IQR 5.0–9.3);
p
< 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI − 1.2 to − 1.01);
p
< 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (
n
= 29) in YP vs. 58% (
n
= 45) in OP;
p
= 0.56).
Conclusion
: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years.
What is Known?
•Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers.
•In 4.5–30% of the paediatric IBD patients, infliximab treatment was stopped within the first year.
What is New?
•The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment.
•Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment.
•The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).
We aimed to assess the correlation between clinical findings, serology, endoscopic findings, and histology in children diagnosed with celiac disease. Medical records of children diagnosed with celiac ...disease (2010–2017) at the Schneider Children’s Hospital were reviewed retrospectively. Correlation between serologic measures anti-tissue transglutaminase (anti-tTG)/anti-endomysial antibodies (EMA) and other variables including mucosal damage, endoscopic findings (scalloping of duodenal folds), and clinical findings (abdominal pain, diarrhea, and anemia) was assessed. Out of 686 patients, 432 patients fulfilled the inclusion criteria (females 262, 61%; median age 6.0; interquartile range 4.0–9.0 years). Distribution of histopathology findings was Marsh IIIa 4%, Marsh IIIb 25%, and Marsh IIIc 71% with 313 (73%) patients having anti-tTG titer of ≥ 10 times the upper normal limit. Anti-tTG titer (but not EMA) positively correlated with Marsh grades, scalloping of duodenal folds and anemia. Anti-tTG ≥ 10 times the upper normal limit was associated with Marsh IIIc changes with an adjusted odds ratio of 4.5 (95% confidence interval, 1.7–12.1). Diarrhea and abdominal pain were not associated with serologic, endoscopic, or histologic markers of disease severity.
Conclusion
: Anti-tTG titers correlated with macroscopic and microscopic mucosal damage, with anemia but not with diarrhea or abdominal pain in children with celiac disease.
What is Known:
•
Tissue transglutaminase antibody titers were shown to correlate with the degree of mucosal damage in patients with celiac disease
.
•
There is a limited evidence regarding the association of celiac serologies with endoscopic and clinical measures
.
What is New:
•
Higher titers of tissue transglutaminase but not anti-endomysial antibodies are associated with more severe histologic and endoscopic damage and with the presence of anemia
.
•
Symptoms do not correlate with the severity of mucosal damage such as scalloping of duodenal folds and histopathology changes according to Marsh classification or with serologic markers
.
Background: Data on COVID-19 vaccine effectiveness among patients with coeliac disease are currently lacking because patients with immune conditions were excluded from clinical trials. We used our ...coeliac disease autoimmunity (CDA) cohort to explore the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in preventing SARS-CoV-2 infection among patients with CDA. Methods: This retrospective cohort study included patients with positive autoantibodies against tissue transglutaminase (tTG-IgA). In the primary analysis, the cohort included CDA patients who received two vaccine doses against COVID-19 and matched patients in a 1:3 ratio. Patients were divided into subgroups based on their positive tTG-IgA level at diagnosis and their current serology status. Results: The cohort included 5381 vaccinated patients with CDA and 14,939 matched vaccinated patients. The risk for breakthrough SARS-CoV-2 infection evaluated with Kaplan–Meier survival analysis via log-rank tests was similar between groups (p = 0.71). In a Cox regression survival analysis, the hazard ratio for breakthrough infection among patients with CDA compared to matched patients was 0.91 (95% confidence interval = 0.77–1.09). Conclusions: COVID-19 vaccination is effective in patients with coeliac disease autoimmunity. Vaccine effectiveness was comparable to the reference population.
Adherent-invasive Escherichia coli (AIEC) colonization has been strongly implicated in the pathogenesis of Crohn's disease. Environmental triggers such as vitamin D deficiency have emerged as key ...factors in the pathogenesis of inflammatory bowel diseases. The aim of this study was to investigate the effects of 1,25(OH)2D3 on AIEC infection-induced changes in vivo and in vitro.
Barrier function was assessed in polarized epithelial Caco-2-bbe cells grown in medium with or without vitamin D and challenged with AIEC strain LF82. Weaned C57BL/6 mice were fed either a vitamin D-sufficient or -deficient diet for 5 weeks and then infected with AIEC, in the absence and presence of low-dose dextran sodium sulphate. Disease severity was assessed by histological analysis and in vivo intestinal permeability assay. Presence of invasive bacteria was assessed by transmission electron microscopy.
Caco-2-bbe cells incubated with 1,25(OH)2D3 were protected against AIEC-induced disruption of transepithelial electrical resistance and tight-junction protein redistribution. Vitamin D-deficient C57BL/6 mice given a course of 2% dextran sodium sulphate exhibited pronounced epithelial barrier dysfunction, were more susceptible to AIEC colonization, and showed exacerbated colonic injury. Transmission electron microscopy of colonic tissue from infected mice demonstrated invasion of AIEC and fecal microbiome analysis revealed shifts in microbial communities.
These data show that vitamin D is able to mitigate the deleterious effects of AIEC on the intestinal mucosa, by maintaining intestinal epithelial barrier homeostasis and preserving tight-junction architecture. This study highlights the association between vitamin D status, dysbiosis, and Crohn's disease.
Background:
Evidence regarding the risk of immunogenicity in patients with inflammatory bowel disease (IBD) who switched anti-tumor necrosis factor alpha (anti-TNFα) therapies to a subsequent ...anti-TNFα (either infliximab or adalimumab) is conflicting. We aimed to assess the risk of consecutive immunogenicity to anti-TNFα in a large cohort of patients.
Methods:
This was a multicenter retrospective study. Medical records of adult and pediatric IBD switchers who had pharmacokinetic data for both agents between 2014 and 2020 were retrieved. Data including age, sex, disease type, duration of therapies, and concomitant use of immunomodulators (IMMs) were recorded.
Results:
Overall, 164 patients were included 52% female; 88% Crohn’s disease; mean age = 24.4 ± 14.6 years; 108 (66%) switched from infliximab to adalimumab and 56 (34%) vice versa; 120 (73.1%) patients switched due to an immunogenic failure. Among patients switching therapy from infliximab to adalimumab due to an immunogenic failure immunogenicity to infliximab was significantly associated with consecutive immunogenicity to adalimumab (p = 0.026). Forthy four out of 120 patients (36.6%) with an immunogenic failure to the first anti-TNFα started an IMM with the second anti-TNFα. This combination with IMM was not associated with reduction of consecutive immunogenicity (p = 0.31), but it was associated with longer drug retention (p = 0.007). Multivariate analysis demonstrated that older age at second anti-TNFα, adjusted to the chronology of therapy and sex, was associated with increased immunogenicity to the second anti-TNFα.
Conclusion:
Patients with IBD who switch from infliximab to adalimumab following an immunogenic failure are at increased risk for consecutive immunogenicity to adalimumab. IMM use after a switch prolongs drug retention.
Background and Aim
Oral mucosal pathologies are frequent in inflammatory bowel disease (IBD). Since host–microbiome interactions are implicated in the pathogenesis of IBD, in this study the potential ...for changes affecting the oral microbiome was evaluated using two complementary mouse models of colitis: either chemically (dextran sulfate sodium) or with Citrobacter rodentium infection.
Methods
After sacrifice, the tongue, buccal mucosa, saliva, colon, and stool samples were collected for analyses. Denaturing gradient gel electrophoresis was performed to assess bacterial 16S rRNA gene profiles. Relative changes were determined using quantitative polymerase chain reaction analysis for the phyla Bacteroidetes, Firmicutes, Spirochetes, and Actinobacteria, classes Gammaproteobacteria and Betaproteobacteria, and the genera Bacillus and Lactobacillus. These groups represent over 99% of the oral microbiota of healthy C57BL/6 mice.
Results
Both models of colitis changed the oral microbiome, with the buccal microbiome being the most resistant to alterations in composition (maximum 1.8% change, vs tongue maximum 2.5% change, and saliva which demonstrated up to 7.2% total changes in microbiota composition). Changes in the oral microbiota were greater after dextran sulfate sodium challenge, compared with C. rodentium‐induced colitis. Using cluster analysis, tongue and buccal mucosal microbiota composition changed ∼ 5%, saliva ∼ 35%, while stool changed ∼ 10%.
Conclusion
These findings indicate that dysbiosis observed in murine models of colitis is associated with changes in the composition of bacteria present in the oral cavity and in saliva. Such changes in the oral microbiota could be relevant to the etiology and management of oral mucosal pathologies observed in IBD patients.
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