Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies.

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P344 Effectiveness and safety of switching patients with inflammatory bowel disease from originator infliximab to CT-P13: systematic review and meta-analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.468 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S367-S368

Author(s):

J Hanzel ◽

A Strik ◽

K Gecse ◽

G D’Haens ◽

E Dreesen

Keyword(s):

Systematic Review ◽

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Adverse Events ◽

Random Effects ◽

Bowel Disease ◽

Clinical Remission ◽

De Novo ◽

Meta Analysis ◽

Inflammatory Bowel

Abstract Background Switching from originator infliximab (IFX) to the CT-P13 biosimilar is a widespread practice, although some concerns persist, particularly about long-term outcomes. We performed a systematic review and meta-analysis to assess the effectiveness and safety of switching from originator IFX to CT-P13 in patients with inflammatory bowel disease (IBD). Methods We systematically searched electronic databases for randomised controlled trials and prospective observational studies of adult patients with IBD who had switched from originator IFX to CT-P13 and were followed up for at least 12 months. The main outcomes were the pooled rate of clinical remission (as defined by the included studies) and adverse events at 12 months. Secondary outcomes included the rate of treatment discontinuation and de novo immunogenicity. A DerSimonian-Laird random-effects meta-analysis of proportions with double arcsine transformation was performed. Variables judged to be clinically important were studied in an exploratory random-effects meta-regression analysis. Results Eleven studies with 1204 patients (71% with Crohn’s disease [CD]) switching from originator IFX to CT-P13 were identified. Pooled rates of clinical remission at 12 months were 83.6% in ulcerative colitis (UC), 75.9% in CD, and 79.6% in mixed cohorts (Figure 1). Clinical remission at 12 months was negatively associated with combined immunosuppression at switch (7% decrease in remission at 12 months per 10% increase in patients receiving combination therapy) and positively associated with remission at switch (6% increase in remission at 12 months per 10% increase in remission at switch). The pooled rate of adverse events at 12 months was 21.0% (95% confidence interval [CI] 10.4–34.1%). Pooled rates of treatment discontinuation at 12 months were 24.4% (95% CI 12.0–39.4%) in UC, 18.6% (95% CI 8.8–30.9%) in CD, and 13.1% (95% CI 0.7–35.6%) in mixed cohorts. De novo immunogenicity was rare (3.3%, 95% CI 1.5–5.6%). All estimates had at least moderate heterogeneity. Figure 1: Meta-analysis of clinical remission rates at 12 months after switching from originator infliximab to CT-P13 in ulcerative colitis and Crohn’s disease. Conclusion Switching from originator IFX to CT-P13 appears to be effective and safe, although these findings should be interpreted in the context of the limitations of the primary publications which lacked control arms. Combined immunosuppression at switch, potentially as a marker of disease severity, was negatively associated with clinical remission at 12 months after the switch.

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Mo1845 ASSOCIATION OF COMPLICATED DIVERTICULITIS WITH SUBSEQUENT DE NOVO INFLAMMATORY BOWEL DISEASE

Gastroenterology ◽

10.1016/s0016-5085(20)33045-6 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-947

Author(s):

Asad Ur Rahman ◽

Ishtiaq Hussain ◽

Badar Hasan ◽

Kanwarpreet Tandon ◽

Fernando Castro

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

De Novo ◽

Complicated Diverticulitis ◽

Inflammatory Bowel

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Association between Thiopurines Use and Pregnancy Outcomes in Female Patients with Inflammatory Bowel Disease: A Meta-analysis

Current Pharmaceutical Design ◽

10.2174/1381612826666200916144249 ◽

2020 ◽

Vol 26 ◽

Author(s):

Yang Zhang ◽

Dandan Li ◽

Heng Guo ◽

Weina Wang ◽

Xingang Li ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Preterm Birth ◽

Spontaneous Abortion ◽

Bowel Disease ◽

Pregnancy Outcomes ◽

Congenital Malformations ◽

Meta Analysis ◽

Adverse Pregnancy Outcomes ◽

Inflammatory Bowel ◽

Adverse Pregnancy

Background: Conflicting data exist regarding the influence of thiopurines exposure on adverse pregnancy outcomes in female patients with inflammatory bowel disease (IBD). Objective: The aim of this study was to provide an up-to-date and comprehensive assessment of the safety of thiopurines in pregnant IBD women. Methods: All relevant articles reporting pregnancy outcomes in women with IBD received thiopurines during pregnancy were identified from the databases (PubMed, Embase, Cochrane Library, and ClinicalTrials.gov) with the publication data up to April 2020. Data of included studies were extracted to calculate the relative risk (RR) of multiple pregnancy outcomes: congenital malformations, low birth weight (LBW), preterm birth, small for gestational age (SGA), and spontaneous abortion. The meta-analysis was performed using the random-effects model. Results: Eight studies matched with the inclusion criteria and a total of 1201 pregnant IBD women who used thiopurines and 4189 controls comprised of women with IBD received drugs other than thiopurines during pregnancy were included. Statistical analysis results demonstrated that the risk of preterm birth was significantly increased in the thiopurine-exposed group when compared to IBD controls (RR, 1.34; 95% CI, 1.00-1.79; p=0.049; I 2 =41%), while no statistically significant difference was observed in the incidence of other adverse pregnancy outcomes. Conclusion: Thiopurines’ use in women with IBD during pregnancy is not associated with congenital malformations, LBW, SGA, or spontaneous abortion, but appears to have an association with an increased risk of preterm birth.

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Correction to: Clinical effects and gut microbiota changes of using probiotics, prebiotics or synbiotics in inflammatory bowel disease: a systematic review and meta-analysis

European Journal of Nutrition ◽

10.1007/s00394-021-02592-2 ◽

2021 ◽

Author(s):

Xiao-Feng Zhang ◽

Xiao-Xian Guan ◽

Yu-Jun Tang ◽

Jin-Feng Sun ◽

Xiao-Kai Wang ◽

...

Keyword(s):

Systematic Review ◽

Inflammatory Bowel Disease ◽

Gut Microbiota ◽

Bowel Disease ◽

Meta Analysis ◽

Clinical Effects ◽

Inflammatory Bowel

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Fr546 INTERVENTIONS TO INCREASE VACCINATIONS RATES WITH INFLAMMATORY BOWEL DISEASE AND RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Gastroenterology ◽

10.1016/s0016-5085(21)01567-5 ◽

2021 ◽

Vol 160 (6) ◽

pp. S-357

Author(s):

Jalpa Patel ◽

Dina Fakhouri ◽

Mohamed Noureldin ◽

Iris Kovar-Gough ◽

Francis A. Farraye ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systematic Review ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Meta Analysis ◽

Inflammatory Bowel

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Optimal Range of Fecal Calprotectin for Predicting Mucosal Healing in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Visceral Medicine ◽

10.1159/000514196 ◽

2021 ◽

pp. 1-11

Author(s):

Bing-Jie Xiang ◽

Min Jiang ◽

Ming-Jun Sun ◽

Cong Dai

Keyword(s):

Inflammatory Bowel Disease ◽

Diagnostic Accuracy ◽

Likelihood Ratio ◽

Sensitivity And Specificity ◽

Bowel Disease ◽

Meta Analysis ◽

Positive Likelihood Ratio ◽

Fecal Calprotectin ◽

Mucosal Healing ◽

Inflammatory Bowel

Objective: Fecal calprotectin (FC) is a promising marker for assessment of inflammatory bowel disease (IBD) activity. However, the utility of FC for predicting mucosal healing (MH) of IBD patients has yet to be clearly demonstrated. The objective of our study was to perform a meta-analysis evaluating the diagnostic accuracy of FC in predicting MH of IBD patients. Methods: We systematically searched the databases for studies from inception to April 2020 that evaluated MH in IBD. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. The extracted data were pooled using a summary receiver operating characteristic curve model. Random-effects model was used to summarize the diagnostic odds ratio, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. Results: Sixteen studies comprising 1,682 ulcerative colitis (UC) patients and 4 studies comprising 221 Crohn’s disease (CD) patients were included. The best performance of FC for predicting MH in UC was at cut-off range of 60–75 μg/g with area under the curve (AUC) of 0.88 and pooled sensitivity and specificity of 0.87 and 0.79, respectively. The pooled sensitivity and specificity values of cutoff range 180–250 μg/g for predicting MH in CD were 0.67 and 0.76, respectively. The AUC of 0.79 also revealed improved discrimination for identifying MH in CD with FC concentration. Conclusion: Our meta-analysis has found that FC is a simple, reliable noninvasive marker for predicting MH in IBD patients. FC cutoff range 60–75 μg/g appears to have the best overall accuracy in UC patients.

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IDDF2020-ABS-0094 Use of gastric acid suppressants and risk of disease activity exacerbation in adult patients with inflammatory bowel disease: a systematic review and meta-analysis

10.1136/gutjnl-2020-iddf.74 ◽

2020 ◽

Author(s):

Nikko Theodore Raymundo ◽

Enrik John Aguila ◽

Eric Yasay ◽

Marie Antoinette Lontok

Keyword(s):

Systematic Review ◽

Inflammatory Bowel Disease ◽

Disease Activity ◽

Gastric Acid ◽

Bowel Disease ◽

Meta Analysis ◽

Adult Patients ◽

Risk Of Disease ◽

Inflammatory Bowel

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Ethnic Differences in the Smoking-Related Risk of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab047 ◽

2021 ◽

Author(s):

Daniele Piovani ◽

Claudia Pansieri ◽

Soumya R R Kotha ◽

Amanda C Piazza ◽

Celia-Louise Comberg ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Latin American ◽

Bowel Disease ◽

Meta Analysis ◽

Study Data ◽

Future Research ◽

Related Risk ◽

Increased Risk ◽

Inflammatory Bowel

Abstract Background and aims The association between smoking and inflammatory bowel disease (IBD) relies on old meta-analyses including exclusively non-Jewish White populations. Uncertainty persists regarding the role of smoking in other ethnicities. Methods We systematically searched Medline/PubMed, Embase and Scopus for studies examining tobacco smoking and the risk of developing IBD, i.e., Crohn’s disease (CD) or ulcerative colitis (UC). Two authors independently extracted study data and assessed each study’s risk-of-bias. We examined heterogeneity and small-study effect, and calculated summary estimates using random-effects models. Stratified analyses and meta-regression were employed to study the association between study-level characteristics and effect estimates. The strength of epidemiological evidence was assessed through prespecified criteria. Results We synthesized 57 studies examining the smoking-related risk of developing CD and UC. Non-Jewish White smokers were at increased risk of CD (29 studies; RR: 1.95, 95% CI: 1.69‒2.24; moderate evidence). No association was observed in Asian, Jewish and Latin-American populations (11 studies; RR: 0.97; 95% CI: 0.83–1.13), with no evidence of heterogeneity across these ethnicities. Smokers were at reduced risk of UC (51 studies; RR: 0.55, 95% CI: 0.48–0.64; weak evidence) irrespectively of ethnicity; however, cohort studies, large studies and those recently published showed attenuated associations. Conclusions This meta-analysis did not identify any increased risk of CD in smokers in ethnicities other than non-Jewish Whites, and confirmed the protective effect of smoking on UC occurrence. Future research should characterize the genetic background of CD patients across different ethnicities to improve our understanding on the role of smoking in CD pathogenesis.

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