Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation of dietary fiber. Elevated ...succinate levels within the gut lumen have been reported in association with microbiome disturbances (dysbiosis), as well as in patients with inflammatory bowel disease (IBD) and animal models of intestinal inflammation. Recent studies indicate that succinate can activate immune cells via its specific surface receptor, succinate receptor 1(SUCNR1), and enhance inflammation. However, the role of succinate in inflammatory processes within the gut mucosal immune system is unclear. This review includes current literature on the association of succinate with intestinal inflammation and the potential role of succinate⁻SUCNR1 signaling in gut immune functions.
Gut microbiome community structure is associated with Crohn's disease (CD) development and response to therapy. Bile acids (BAs) play a central role in modulating intestinal immune responses, and ...changes in gut bacterial communities can profoundly alter the intestinal BA pool. The liver synthesizes and conjugates primary bile acids (priBAs) that are then deconjugated, epimerized, and dehydroxylated by gut bacteria to produce secondary bile acids (secBAs). We investigated the relationship between the gut microbiome and the fecal BA pool in stool samples obtained from a well-characterized cohort of pediatric CD patients undergoing nutritional therapy to induce disease remission. We found that fecal BA composition was altered in a sub-group of CD patients who did not sustain remission. The microbial community structures associated with priBA and secBA-dominant profiles were distinct. In addition, the fecal BA concentrations were correlated with the abundance of distinct bacterial taxonomic groups. Finally, priBA dominant samples were associated with community-level decreases in enzymes for dehydroxylation but not deconjugation.
Summary
Background
Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab ...clearance.
Aims
We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn’s disease cohort with 1‐year follow‐up.
Methods
This multi‐centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI‐positive (ATI) and ATI‐negative (no‐ATI) patients. Secondary outcomes included pre‐treatment predictors of ATI (including HLA‐DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre‐ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model.
Results
ATI were detected in 68% (53/78) patients with a median concentration of 76 ng/mL (range 23‐1828). Maximum ATI concentration was <200 ng/mL in 73.6% (39/53). Median clearance in ATI patients was higher (with higher clearance if loss of response), compared to no‐ATI patients (P < 0.001). Neutrophil CD64 ratio >6 and starting dose <7.5 mg/kg independently predicted ATI in multivariable regression, while HLA‐DQA1*05 presence did not. Dose adjustment resolved ATI in 37.5% (12/32) patients with concomitant infliximab concentration and clearance recovery. A maximum ATI level of ≤99 ng/mL predicted ATI resolution (area under the receiver operating curve 0.80 95% CI 0.64‐0.96).
Conclusions
In this real‐world cohort, ATI as low as 23 ng/mL impacted drug clearance. Our data suggest that dose optimisation for low‐level ATI can improve infliximab clearance and prevent loss of response.
Antibodies to infliximab are common and result in rapid drug clearance in pediatric Crohn's disease.
Summary
Background
Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult‐specific population pharmacokinetic models have ...identified limited covariates of drug clearance.
Aims
To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric‐specific inter‐patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients.
Methods
The study included data from 463 observed vedolizumab concentrations (59 peaks and 404 troughs) from 74 patients with IBD (52 with Crohn's disease and 22 with ulcerative colitis or unclassified IBD, median age 16 years). Pharmacokinetic analysis was conducted with non‐linear mixed effects modelling. For the evaluation of the exposure–response relationship, clinical outcomes were evaluated by trough levels, clearance and vedolizumab exposure. Whole‐genome metagenomic sequencing was conducted at baseline and week 2.
Results
A two‐compartment population pharmacokinetic model was identified with a clear correlation between CL and weight, erythrocyte sedimentation rate, and hypoalbuminemia. Trough concentrations before infusion 3 (37 μg/ml) and before infusion 4 (20 μg/ml) best predicted steroid‐free clinical remission at infusion 4. Using faecal metagenomics, we identified an early (baseline and week 2) abundance of butyrate‐producing species and pathways that were associated with an infusion 4 trough concentration >20 μg/ml.
Conclusions
This novel paediatric vedolizumab pharmacokinetic model could inform precision dosing. While additional studies are needed, an abundance of faecal butyrate producers is associated with early response to vedolizumab, suggesting that microbial analysis may be beneficial to biological selection.
Population pharmacokinetic study to identify novel predictors (blood and stool) of vedolizumab clearance in children and young adults. Specifically, low serum albumin and elevated erythrocyte sedimentation rate (ESR) resulted in accelerated drug clearance. These data suggest that children may require more frequent vedolizumab infusions to achieve therapeutic drug targets.
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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Currently, there is no consensus on how to score Crohn disease (CD) activity assessed by intestinal ultrasound (IUS) in children. This study aimed to design an easy-to-use IUS score for disease ...activity in pediatric CD.
Children undergoing ileo-colonoscopy for CD assessment underwent IUS the day before ileo-colonoscopy, assessed with simple endoscopic score for CD (SES-CD). IUS features were compared to the SES-CD on segmental level. Multiple regression analyses, separately for terminal ileum (TI) and colon, were done to assess predictors of disease activity and to develop a model.
In 74 CD patients (median 15 years, 48% female), 67 TI and 364 colon segments were assessed. Based on receiver operating characteristics curves, bowel wall thickness (BWT) was categorized into low 1 point: 2-3 mm (TI) and 1.6-2 mm (colon), medium 2 points: 3.0-3.7 mm (TI) and 2.0-2.7 mm (colon), and high 3 points: >3.7 mm (TI) and >2.7 mm (colon). In TI, only BWT was retained in the model high BWT: odds ratio (OR) 11.50, P < 0.001. In colon, BWT (high BWT: OR 8.63, P < 0.001) and mesenteric fat (1 point: OR 3.02, P < 0.001) were independent predictors. A pediatric Crohn disease IUS score (PCD-US) cut-off of 1 resulted in a sensitivity of 82% (95% confidence interval, CI: 65%-93%) and 85% (95% CI: 80%-89%) and a cut-off of 3 in a specificity of 88% (72%-97%) and 92% (87%-96%) for TI and colon, respectively. Inter-observer agreement was moderate for TI and colon ( K : 0.42, K : 0.49, respectively).
The PCD-US score is an easy-to-use and reliable score to detect or rule out CD activity on segmental level in children. External validation is needed before applying this score in clinical practice.
The aryl hydrocarbon receptor (AhR) is a nuclear protein which, upon association with certain endogenous and exogenous ligands, translocates into the nucleus, binds DNA and regulates gene expression. ...Tryptophan (Trp) metabolites are one of the most important endogenous AhR ligands. The intestinal microbiota is a critical player in human intestinal homeostasis. Many of its effects are mediated by an assembly of metabolites, including Trp metabolites. In the intestine, Trp is metabolized by three main routes, leading to kynurenine, serotonin, and indole derivative synthesis under the direct or indirect involvement of the microbiota. Disturbance in Trp metabolism and/or AhR activation is strongly associated with multiple gastrointestinal, neurological and metabolic disorders, suggesting Trp metabolites/AhR signaling modulation as an interesting therapeutic perspective. In this review, we describe the most recent advances concerning Trp metabolism and AhR signaling in human health and disease, with a focus on nutrition as a potential therapy to modulate Trp metabolites acting on AhR. A better understanding of the complex balance between these pathways in human health and disease will yield therapeutic opportunities.
The Crohn’s disease (CD) exclusion diet (CDED) plus partial enteral nutrition (PEN) and exclusive enteral nutrition (EEN) both induce remission in pediatric CD. CDED+PEN is better tolerated and able ...to sustain remission. We characterized the changes in fecal metabolites induced by CDED+PEN and EEN and their relationship with remission.
A total of 216 fecal metabolites were measured in 80 fecal samples at week (W) 0, W6, and W12, of children with mild to moderate CD in a prospective randomized trial comparing CDED+PEN vs EEN. The metabolites were measured using liquid chromatography coupled to mass spectrometry. Metagenome Kyoto Encyclopedia of Genes and Genomes Orthology analysis was performed to investigate the differential functional gene abundance involved in specific metabolic pathways. Data were analyzed according to clinical outcome of remission (W6_rem), no remission (W6_nr), sustained remission (W12_sr), and nonsustained (W12_nsr) remission.
A decrease in kynurenine and succinate synthesis and an increase in N-α-acetyl-arginine characterized CDED+PEN W6_rem, whereas changes in lipid metabolism characterized EEN W6_rem, especially reflected by lower levels in ceramides. In contrast, fecal metabolites in EEN W6_nr were comparable to baseline/W0 samples. CDED+PEN W6_rem children maintained metabolome changes through W12. In contrast, W12_nsr children in the EEN group, who resumed a free diet after week 6, did not. The metabolome of CDED+PEN differed from EEN in the purine, pyrimidine, and sphingolipid pathways. A significant differential abundance in several genes involved in these pathways was detected.
CDED+PEN– and EEN-induced remission are associated with significant changes in inflammatory bowel disease–associated metabolites such as kynurenine, ceramides, amino acids, and others. Sustained remission with CDED+PEN, but not EEN, was associated with persistent changes in metabolites. Clinicaltrials.gov, Number NCT01728870.
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Precis Crohn’s disease exclusion diet plus partial enteral nutrition– and exclusive enteral nutrition–induced remission in pediatric Crohn’s disease exhibited unique metabolome profiles. Dietary nonresponders showed metabolite profiles similar to baseline. Exposure to free diet led to return to baseline metabolomic profile.
The human oral cavity is inhabited by a diverse community of microbes, known as the human oral microbiome. These microbes play a role in maintaining both oral and systemic health and, as such, have ...been proposed to be useful biomarkers of disease. However, to identify these biomarkers, we first need to determine the composition and variation of the healthy oral microbiome. In this report, we investigate the oral microbiome of 1,049 healthy individuals to determine which genera and amplicon sequence variants are commonly found between individual oral microbiomes. We then further investigate how lifestyle, anthropometric, and dietary choices impact overall microbiome composition. Interestingly, the results from this investigation showed that while many features were significantly associated with oral microbiome composition, no single biological factor explained a variation larger than 2%. These results indicate that future work on biomarker detection may be encouraged by the lack of strong confounding factors.
ABSTRACT
More than 1,000 different species of microbes have been found to live within the human oral cavity, where they play important roles in maintaining both oral and systemic health. Several studies have identified the core members of this microbial community; however, the factors that determine oral microbiome composition are not well understood. In this study, we exam the salivary oral microbiome of 1,049 Atlantic Canadians using 16S rRNA gene sequencing to determine which dietary, lifestyle, and anthropometric features play a role in shaping microbial community composition. Features that were identified as being significantly associated with overall composition then were additionally examined for genera, amplicon sequence variants, and predicted pathway abundances that were associated with these features. Several associations were replicated in an additional secondary validation data set. Overall, we found that several anthropometric measurements, including waist-hip ratio (WHR), height, and fat-free mass, as well as age and sex, were associated with overall oral microbiome structure in both our exploratory and validation data sets. We were unable to validate any dietary impacts on overall taxonomic oral microbiome composition but did find evidence to suggest potential contributions from factors such as the number of vegetable and refined grain servings an individual consumes. Interestingly, each one of these factors on its own was associated with only minor shifts in the overall taxonomic composition of the oral microbiome, suggesting that future biomarker identification for several diseases associated with the oral microbiome can be undertaken without the worry of confounding factors obscuring biological signals.
IMPORTANCE
The human oral cavity is inhabited by a diverse community of microbes, known as the human oral microbiome. These microbes play a role in maintaining both oral and systemic health and, as such, have been proposed to be useful biomarkers of disease. However, to identify these biomarkers, we first need to determine the composition and variation of the healthy oral microbiome. In this report, we investigate the oral microbiome of 1,049 healthy individuals to determine which genera and amplicon sequence variants are commonly found between individual oral microbiomes. We then further investigate how lifestyle, anthropometric, and dietary choices impact overall microbiome composition. Interestingly, the results from this investigation showed that while many features were significantly associated with oral microbiome composition, no single biological factor explained a variation larger than 2%. These results indicate that future work on biomarker detection may be encouraged by the lack of strong confounding factors.
The intestinal epithelium not only acts as a physical barrier to commensal bacteria and foreign antigens but is also actively involved in antigen processing and immune cell regulation. The ...inflammatory bowel diseases (IBDs) are characterized by inflammation at this mucosal surface with well-recognized defects in barrier and secretory function. In addition to this, defects in intraepithelial lymphocytes, chemokine receptors, and pattern recognition receptors promote an abnormal immune response, with increased differentiation of proinflammatory cells and a dysregulated relationship with professional antigen-presenting cells. This review focuses on recent developments in the structure of the epithelium, including a detailed account of the apical junctional complex in addition to the role of the enterocyte in antigen recognition, uptake, processing, and presentation. Recently described cytokines such as interleukin-22 and interleukin-31 are highlighted as is the dysregulation of chemokines and secretory IgA in IBD. Finally, the effect of the intestinal epithelial cell on T effector cell proliferation and differentiation are examined in the context of IBD with particular focus on T regulatory cells and the two-way interaction between the intestinal epithelial cell and certain immune cell populations.
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