Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

Summary Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for one year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical care.

Background-The lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children newly diagnosed with Ulcerative Colitis (UC). We hypothesized that pre-treatment clinical, transcriptomic, and microbial factors predict disease course. Methods-We performed an inception cohort study of 428 paediatric UC patients receiving standardised mesalazine or corticosteroids (CS), with pre-established criteria for escalation to thiopurines or anti-TNFα. RNA sequencing (n=206) defined pre-treatment rectal gene expression. 16S sequencing (n=343) characterized rectal/fecal microbiota. The primary outcome was Week 52 CS-free remission (SFR) with no therapy beyond mesalazine. Findings-Week 52 SFR was achieved in 150/400 (38%) participants; 74/400 (19%) received thiopurines alone, 12¾00 (31%) received anti-TNFα, and 25/400 (6%) colectomy. Lower baseline clinical severity, higher baseline hemoglobin, and Week 4 clinical remission were associated with achieving Week 52 SFR (logistic model AUC:0.70 (95% CI 0.65-0.75), specificity 77% (CI 71-82), n=386). Baseline severity and week 4 remission were validated inan independent cohort of 274 participants. An antimicrobial peptide gene signature (OR:0.6, p=0.002) and Ruminococcaceae (OR:1.4, p=0.04) and Sutterella (OR: 0.8, p=0.05) abundance were independently associated with SFR after adjusting for the clinical predictors. Amongst moderateto-severe patients, escalation to anti-TNFα was associated with increased baseline clinical severity and decreased hemoglobin, serum 25 (OH) D, and rectal eosinophils (logistic model AUC:0.78 (95% CI 0.72-0.84), specificity 85% (CI 78-93), n=232). A rectal transportgene signature (OR: 0.3, p=0.0006) and Oscillospira abundance (OR:0.6, p=0.02) were independently associated with escalation to anti-TNFα after adjusting for the clinical predictors. Interpretation-Our findings support the utility of using initial clinical activity and treatment response by 4 weeks to predict Week 52 CS-free remission with mesalazine alone in children newly diagnosed with UC. The development of personalized clinical and biological signatures holds the promise of informing UC therapeutic decisions.

Objectives To examine the association between adverse childhood experiences (ACEs) and pregnancy outcomes; to explore mediators of this association including psychiatric illness and health habits. Methods Exposure to ACEs was determined by the Early Trauma Inventory Self Report Short Form; psychiatric diagnoses were generated by the Composite International Diagnostic Interview administered in a cohort of 2303 pregnant women. Linear regression and structural equation modeling bootstrapping approaches tested for multiple mediators. Results Each additional ACE decreased birth weight by 16.33 g and decreased gestational age by 0.063. Smoking was the strongest mediator of the effect on gestational age. Conclusions ACEs have an enduring effect on maternal reproductive health, as manifested by mothers’ delivery of offspring that were of reduced birth weight and shorter gestational age.

Background Previous retrospective pediatric ulcerative colitis (UC) studies had limited ability to describe disease progression and identify predictors of treatment response. The PROTECT multicentre inception cohort aimed to identify characteristics associated with outcomes following standardized therapy after initial diagnosis. Methods We completed a prospective multicentre inception cohort study at 29 centres in the USA and Canada of paediatric patients aged 4–17 years newly diagnosed with UC who received initial standardized treatment with mesalamine or corticosteroids (CS) guided by the Pediatric UC Activity Index (PUCAI). The key outcomes for this analysis were week 12 CS-free remission, defined as PUCAI<10 and taking only mesalamine, and treatment escalation to anti-TNFα, immunomodulators or colectomy among those initially treated with intravenous (IV) CS. Independent predictors were identified through multivariable logistic regression using a per-protocol approach. Registered with clinicaltrials.gov: NCT01536535 Findings 428 children initiated mesalamine (n=136), oral CS (n=144), or IV CS (n=148) with initial mean ± standard deviation PUCAI of 31±13, 50±14, and 67±14, respectively (p<0.001). By week 12, CS-free remission taking mesalamine only was achieved by 48% (64/132) initiating with mesalamine, 33% (47/141) with oral CS, and 21% (30/143) with IV CS (p<0.001). Treatment escalation was required in 7% (9/132), 15% (21/141), and 36% (52/143), respectively (p<0.001); 8 patients, all initially treated with IV CS, received colectomy. Predictors of week 12 CS-free remission were baseline PUCAI <35 (odds ratio (OR) 2.4, 95% CI 1.4–4.2; p=0.002), higher baseline albumin by 1 g/dL increments among age < 12 years (4.1, 1.9–8.6; p=0.0003), and week 4 remission (6.3, 3.8–10.4; p<0.0001). Predictors of treatment escalation by week 12 in those initially treated with IV CS included baseline total Mayo score ≥11 (2.6, 0.9–7.2; p=0.068), rectal biopsy eosinophil count ≤32/high power field (4.6, 1.6–12.8; p=0.004), rectal biopsy surface villiform changes (3.1, 1.1–8.6; p=0.034) and not achieving week 4 remission (30.2, 6.4–144.2; p<0.0001). Interpretation Our findings provide guidelines to assess response of children newly diagnosed with UC to standardized initial therapy and identify predictors of treatment response and failure. These data suggest that additional therapeutic interventions may be warranted to improve early outcomes, especially in those presenting with severe disease and requiring intravenous corticosteroids.

Background Major depressive disorder as well as the use of serotonin reuptake inhibitors in pregnancy have been associated with preterm birth. Studies that have attempted to separate effects of illness from treatment have been inconclusive. We sought to explore the separate effects of serotonin reuptake inhibitor use and major depressive episodes in pregnancy on risk of preterm birth. Methods We conducted a prospective cohort study of 2793 pregnant women, oversampled for a recent episode of major depression or use of a serotonin reuptake inhibitor. We extracted data on birth outcomes from hospital charts and used binary logistic regression to model preterm birth (<37 weeks’ gestation). We used ordered logistic regression to model early (<34 weeks’ gestation) or late (34-36 weeks) preterm birth, and we used nominal logistic regression to model preterm birth antecedents (spontaneous preterm labor/preterm premature rupture of membranes/preterm for medical indications/term). Results Use of a serotonin reuptake inhibitor, both with (odds ratio=2.1 [95% confidence interval=1.0—4.6]) and without (1.6=[1.0—2.5]) a major depressive episode, was associated with preterm birth. A major depressive episode without serotonin reuptake inhibitor use (1.2; [0.68—2.1]) had no clear effect on preterm risk. None of these exposures was associated with early preterm birth. Use of serotonin reuptake inhibitors in pregnancy was associated with increases in spontaneous but not medically indicated preterm birth. Conclusions Serotonin reuptake inhibitor use increased risk of preterm birth. Although the effect of a major depressive episode alone was unclear, symptomatic women undergoing antidepressant treatment had elevated risk.

Objective To compare the efficacy of motivational enhancement therapy coupled with cognitive behavioral therapy (MET-CBT) to brief advice for treatment of substance use in pregnancy. Method This was a randomized, parallel, controlled trial that was yoked to prenatal care and delivered at hospital outpatient clinics. We enrolled 168 substance using women who had not yet completed an estimated 28 weeks of pregnancy. Obstetrical clinicians provided brief advice and study nurses administered manualized MET-CBT. The primary outcome was percentage of days in the prior 28 days, that alcohol and/or drugs were used immediately before and three months post delivery. Results There were no significant differences across groups in terms of self-reported percentage of days that drugs or alcohol were used prior to and three months post delivery. Biological measures showed similar results. There was a trend (p=0.08) for lower risk of preterm birth among those who received MET-CBT. Conclusions The tested interventions had similar therapeutic effects. Hence, both treatments may be suitable for pregnant substance users, depending on the population, setting, and provider availability. Interventions that are intensified after delivery may decrease postpartum ‘rebound’ effects in substance misuse.

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