Epidemiology Publications // 2022
Wang H, Labus JS, Griffin F, Gupta A, Bhatt RR, Sauk JS , Turkiewicz J, Bernstein CN, Kornelsen J, Mayer EA. Functional Brain Rewiring and Altered Cortical Stability in Ulcerative Colitis. Molecular Psychiatry 2022; in press.
Despite recent advances, there is still a major need to better understand the interactions between brain function and chronic gut inflammation and its clinical implications. Alterations in executive function have previously been identified in several chronic inflammatory conditions, including inflammatory bowel diseases. Inflammation-associated brain alterations can be captured by connectome analysis. Here, we used the resting-state fMRI data from 222 participants comprising three groups (ulcerative colitis (UC), irritable bowel syndrome (IBS), and healthy controls (HC), N = 74 each) to investigate the alterations in functional brain wiring and cortical stability in UC compared to the two control groups and identify possible correlations of these alterations with clinical parameters. Globally, UC participants showed increased functional connectivity and decreased modularity compared to IBS and HC groups. Regionally, UC showed decreased eigenvector centrality in the executive control network (UC < IBS < HC) and increased eigenvector centrality in the visual network (UC > IBS > HC). UC also showed increased connectivity in dorsal attention, somatomotor network, and visual networks, and these enhanced subnetwork connectivities were able to distinguish UC participants from HCs and IBS with high accuracy. Dynamic functional connectome analysis revealed that UC showed enhanced cortical stability in the medial prefrontal cortex (mPFC), which correlated with severe depression and anxiety-related measures. None of the observed brain changes were correlated with disease duration. Together, these findings are consistent with compromised functioning of networks involved in executive function and sensory integration in UC
Targownik LE, Bernstein CN, Benchimol EI, Kaplan GG, Singh H, Tennakoon A, Nugent Z, Coward SB, Kuenzig ME, Murthy SK. Earlier Anti-TNF initiation leads to long term lower health care utilization in Crohn’s disease but not in ulcerative colitis. Clinical Gastroenterology and Hepatology 2022; in press.
The timing of initiating biologic therapy in persons with Crohn’s disease and ulcerative colitis is an area of ongoing controversy. In particular, there is concern that delaying the initiation of biologic therapy may lead to more treatment resistant disease, which can result in more complications and hospitalizations. We used the University of Manitoba IBD Epidemiologic Database derived from health administrative data to identify all persons with a new diagnosis of IBD between 2001 and 2018 who received anti-TNF therapy and had at least one year of post anti-TNF initiation follow-up. We measured the rates of hospitalization, surgery, and outpatient visits, prior to and for up to 5 years following anti-TNF initiation. We compared the rates of these health care utilization outcomes between persons receiving anti-TNFs at less than 2 years following diagnosis and those receiving anti-TNFs at more than 2 years following IBD diagnosis. We used inverse probability treatment weighting (IPTW) to adjust for baseline differences in risk between the two groups. In persons with Crohn’s disease, early anti-TNF initiators had fewer IBD-specific and overall hospitalizations over the 5 years following the start of therapy. Incidence of resective surgery was also lower in earlier anti-TNF initiators with Crohn’s disease if the first year following initiation was excluded from the analysis. There was no impact of the timing of anti-TNF therapy on the rates of hospitalization and surgery for persons with ulcerative colitis.
Earlier administration of anti-TNF therapy is associated with reduced downstream health care resource utilization in Crohn’s disease, though these impacts are not as evident in ulcerative colitis.
Liang G, Zhu F, Mirza AI, Arnold D, Bar-Or A, Bernstein CN, Bonner C, Forbes JD, Graham M, Hart J, Knox NC, Marrie RA,Mahony JO, Van Domselaar G, Yeh EA, Zhao Y, Banwell B, Waubant E, Tremlett H, and the Canadian Paediatric Demyelinating Disease Network. Stability of the gut microbiota in persons with pediatric-onset multiple sclerosis and related demyelinating diseases. Multiple Sclerosis Journal 2022; in press.
We aimed to determine if the gut microbiota composition changes across repeated samples collected over the short-term in individuals with pediatric-onset MS or monophasic acquired demyelinating syndromes (monoADS). Individuals who provided stool samples on at least 2 occasions were eligible. Stool samples were collected across the Canadian Pediatric Demyelinating Disease Network and banked at the University of Manitoba IBD Clinical and Research Centre Biobank. Metagenome analysis was undertaken at the National Microbiology Laboratory, Winnipeg, Canada. Stool sample-derived DNA was amplified, sequenced, and clustered into amplicon sequence variants (ASVs). Alpha/beta diversities were explored, and genus-level ASVs were analysed using nonparametric microbial interdependence tests (NMIT) and linear mixed effect models. 36 individuals were eligible (18 MS/18 monoADS). 15 MS/16 monoADS participants provided two samples, and the remainder three, totalling 77 samples. Alpha/beta diversities did not differ between stool samples (P>0.09). Solobacterium genus varied significantly over-time (P=0.001). Nonparametric microbial interdependence tests revealed no difference in longitudinal sample composition between MS and monoADS participants (P>0.2).
We concluded that the gut microbiota composition in individuals with pediatric-onset MS and monoADS exhibited stability between stool samples over a 2-25 month period. While preliminary, findings suggest that procurement of single stool samples is a reasonable first approach.
Tandon P, Tennakoon A, Huang V, Bernstein CN, Goetgebuer R, Targownik L. Pregnancy and live birth rates in women with inflammatory bowel disease: A Canadian population-based cohort study. Journal of Canadian Association of Gastroenterology 2022; in press.
IBD negatively affects fertility and fecundity. We aimed to determine longitudinal trends in and factors that affect pregnancy rates in women with ulcerative colitis and Crohn’s disease. Women in the University of Manitoba IBD Epidemiology Database aged 15-45, in Manitoba, Canada were identified between 1992-2018 and matched up to 10 non-IBD controls. Pregnancy and live birth rates were compared between women with and without ulcerative colitis or Crohn’s disease stratified by time period, disease duration, and maternal age at conception. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were calculated. Poisson regression was used to adjust these rates for year of pregnancy, disease duration, maternal age, severity of IBD, and prior IBD-related surgery. Compared to controls, women with ulcerative colitis had lower rates of pregnancies (IRR 0.91, 95% CI, 0.82-0.99) and women with Crohn’s disease had lower rates of pregnancies (IRR 0.85, 95% CI, 0.79-0.93) and live births (IRR 0.83, 95% CI, 0.75-0.92). There were no differences in rates of pregnancies between cases and controls from 2010 to 2018. Factors that significantly lowered pregnancy rates included a new IBD diagnosis and maternal age at conception less than 35 for Crohn’s disease. Furthermore, prior IBD-related surgery and active disease at conception also appeared to lower pregnancy rates in women with ulcerative colitis and Crohn’s disease respectively.
In conclusion shorter disease duration, younger age at conception, active disease, and prior IBD-surgery negatively impact pregnancy and live birth rates in women with ulcerative colitis and Crohn’s disease.
Li Y, Bernstein CN, Xu W, Hu P. Polygenic risk and causal inference of psychiatric comorbidity in inflammatory bowel disease among patients with European ancestry. Journal of Translational Medicine 2022; in press
Approximately 40% of persons with IBD experience psychiatric comorbidities. Previous studies demonstrated the polygenetic effect on both IBD and psychiatric comorbidities. In this study, we evaluated the contribution of genetic variants to psychiatric comorbidities among the IBD population. Additionally, we evaluated whether this effect is mediated by the expression level of the RBPMS gene, which was identified in our previous studies as a potential risk factor of psychiatric comorbidities in persons with IBD.
The polygenic risk score was estimated among persons with IBD of European ancestry (n = 240) from the Manitoba IBD Cohort Study by using external genome-wide association studies (GWAS). The association and prediction performance were examined between the estimated polygenic risk score and psychiatric comorbidities status among persons with IBD. Finally, regression-based models were applied to explore whether the imputed expression level of the RBPMS gene is a mediator between estimated polygenic risk score and psychiatric comorbidities status in IBD.
The estimated polygenic risk score had a significantly positive association with psychiatric comorbidities status (for the highest effect: P-value threshold = 5 × 10-3, odds ratio = 2.0, P-value = 1.5 × 10-5). Around 13% of the causal effect between the polygenic risk score and psychiatric comorbidities status in IBD was mediated by the expression level of the RBPMS gene. The area under the curve of the PRS-based psychiatric comorbidities prediction model is around 0.7 at the threshold of 5 × 10-4.
PC status in IBD depends on genetic influences among persons with European ancestry. The polygenic risk score could potentially be applied to psychiatric comorbidities risk screening to identify persons with IBD at a high risk of psychiatric comorbidities. Around 13% of this genetic influence could be explained by the expression level of the RBPMS gene.
Mirza AI, Zhu F, Knox N, Forbes JD, Van Domselaar G, Bernstein CN, Graham M, Marrie RA, Hart, J Yeh EA, Arnold D, Bar-Or A, O’Mahony J, Zhao Y, Hsiao W, Banwell B, Waubant E, Tremlett H. Metagenomic analysis of the pediatric-onset multiple sclerosis gut microbiome. Neurology 2022; in press.
This study examined the gut metagenome in individuals with and without pediatric-onset multiple sclerosis (MS). Stool samples were collected across the Canadian Pediatric Demyelinating Disease Network and banked at the University of Manitoba IBD Clinical and Research Centre Biobank. Metagenome analysis was undertaken at the National Microbiology Laboratory, Winnipeg, Canada. Study participants were 21 years old or younger, with MS (disease-modifying drug [DMD] exposed and naïve) or unaffected controls all less than age 22. 20 MS patients (McDonald criteria) with symptom onset prior to age18 years were matched to 20 controls by sex, age, stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha-diversity, relative abundance, and prevalence using Wilcoxon rank-sum, ALDEx2 and Fisher's exact tests, respectively. Alpha-diversity of enzymes and proteins did not differ by disease or DMD status (p>0.20), but metabolic pathways, gene annotations and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio=10, p=0.044), and Methanobrevibacter abundance (log2 fold-change [LFC]=1.7, p=0.0014), but lower homolactic fermentation abundance (LFC=-0.48, p=0.039). Differences by DMD status included lower phosphate butyryltransferase for DMD-naïve vs exposed MS patients (LFC=-1.0, p=0.033).
We concluded that the gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS versus controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.
Furer P, Graff LA, Jackson GL, Kredenster M, Anderson S, Dirkse D, Pryor T, Bernstein CN. Development of an Internet-delivered Cognitive Behavioral Program for Inflammatory Bowel Disease: A Pilot Study. Journal of Depression and Anxiety Disorders 2022; 4(1):106-114.
The prevalence of IBD varies worldwide and is rapidly rising, with the highest rates being reported in Europe and North America. The approximately 2 million individuals with IBD in the US and Canada are projected to double over the next decade. The disease has a high burden for patients, with unpredictable, painful symptoms that can interfere with home and work life.
It is well established that individuals with IBD have significantly higher rates of anxiety and depression than the general population. Persistent high levels of stress predict worsening IBD symptoms, which in turn increases the risk of developing chronic anxiety and depression.
This pilot study examined a new internet-delivered cognitive behavior therapy program (iCBT) for anxiety, depression and/or stress in adults with inflammatory bowel disease (IBD).
The internet-delivered cognitive behavioral therapy (iCBT) intervention tailored for adults with IBD to address stress, anxiety and/or depression is outlined in Table 1. The program included 9 core modules and 1 optional module. Modules took approximately 1-2 hours each to complete and included
text, patient videos illustrating learning points, and practice exercises to complete between modules.
Adults were recruited from the Manitoba sample of the Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects (IMAGINE) study, a large cohort of Canadian patients with physician-confirmed IBD. Eighteen of 21 participants completed the 9-module program.
Measures of anxiety, depression, and stress were administered at baseline, and at 6-, 12-, and 24-weeks post-baseline.
Compared to baseline, there was a significant reduction in anxiety (HADS-A) and in stress (PSS-4) over time. There were no statistically significant changes in depression scores (HADS-D). However, inspection of average depression scores over time suggests a trend for a decrease in scores at the 6- and 12-week points, with a subsequent increase at 24 weeks.
Participant satisfaction on the CSQ-8 ranged from 18 to 28 with a mean of 23.65 reflecting good satisfaction with the online intervention.
The results of this pilot study suggest it is a promising clinical intervention and support further investigation of this online CBT intervention for adults with IBD. Clinically meaningful reductions in anxiety and stress were achieved with this relatively low-resource intensity and accessible intervention. Participant engagement was high, with an excellent completion rate.
Shen B, Kochhar GS, Rubin DT, Kane SV, Navaneethan U, Bernstein CN, Cross RK, Sugita A, Schairer J, Kiran RP, Fleshner P, McCormick JT, D'Hoore A, Shah SA, Farraye FA, Kariv R, Liu X, Rosh J, Chang S, Scherl E, Schwartz DA, Kotze PG, Bruining DH, Philpott J, Abraham B, Segal J, Sedano R, Kayal M, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sehgal P, Picoraro JA, Vermeire S, Sandborn WJ, Silverberg MS, Pardi DS. Treatment of pouchitis, Crohn's disease, cuffitis, and other inflammatory disorders of the pouch: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterology and Hepatology 2022 Jan;7(1):69-95.
Pouchitis, Crohn's disease of the pouch, cuffitis, polyps, and extraintestinal manifestations of inflammatory bowel disease are common inflammatory disorders of the ileal pouch. Acute pouchitis is treated with oral antibiotics and chronic pouchitis often requires anti-inflammatory therapy, including the use of biologics. Aetiological factors for secondary pouchitis should be evaluated and managed accordingly. Crohn's disease of the pouch is usually treated with biologics and its stricturing and fistulising complications can be treated with endoscopy or surgery. The underlying cause of cuffitis determines treatment strategies. Endoscopic polypectomy is recommended for large, symptomatic inflammatory polyps and polyps in the cuff. The management principles of extraintestinal manifestations of IBD in patients with pouches are similar to those in patients without pouches.
Ananthakrishnan AN, Kaplan GG, Bernstein CN, Burke KE, Lochhead PJ, Sasson AN, Agrawal M, Tion HT, Steinberg J, Kruis W, Steinwurz F, Ahuja V, Ng SC, Rubin DT, Colombel JF, Gearry R, International Organization for the Study of Inflammatory Bowel Diseases. IOIBD consensus on lifestyle, behavior, and environmental modification for the management of patients with inflammatory bowel diseases. Lancet Gastroenterology and Hepatology 2022; in press.
The external environment plays an important role in the natural history of Crohn’s disease (CD) and ulcerative colitis (UC). There is no comprehensive guidance on the role of beneficial lifestyle and behavioral modifications while avoiding adverse influences as part of the treatment of these diseases.
Under the auspices of the International Organization for Study of Inflammatory Bowel Diseases (IOIBD), we developed a series of consensus statements addressing various lifestyle and behavioral modifications in patients with established CD or UC. A review of literature was performed. International experts participated in a two-stage voting process to arrive at the final set of consensus statements. Statements that achieved at least 75% agreement among the panel members were considered adopted.
We generated a series of 20 consensus statements that were voted on by 62 experts in the first stage, and 41 in the second stage. Nineteen of the statements were considered adopted, achieving > 70% agreement (range 76 – 100%). The statements advocated for smoking cessation in both CD and UC, recognition of the adverse impact and systematic evaluation for mood disturbances and stress, an informed choice for selection of therapeutic diets while monitoring inflammation and deficiencies, encouraging physical activity and normal body weight, as well as minimizing use of high-dose NSAIDs. The statements identified lack of sufficient data on safety of e-cigarettes and use of cannabis to treat CD or UC. A shared decision-making approach maximizing therapeutic adherence was also determined to be important.
We identified a series of consensus statements addressing behavior and lifestyle that are beneficial in the management of patients with CD or UC.
Shen B, Kochhar GS, Kariv R, Rex DR, Sugita A, Rubin DT, Navaneethan U, Hull TL, Ko HM, Liu X, Kachnic LA, Strong S, Iacucci M, Bemelman W, Fleshner P, Safyan RA, Kotze PG, D'Hoore A, Faiz O, Lo S, Ashburn JH, Spineli A, Bernstein CN, Kane SV, Cross RK, Schairer J, McCormick JT, Farraye FA, Chang S, Scherl E, Schwartz DA, Bruining DH, Philpott J, Bentley-Hibbert S, Tarabar D, El-Hachem S, Sandborn WJ, Silverberg MS, Pardi DS, Church J, Kiran RP. Management of Pouch Neoplasia: A Consensus Guideline from the International Ileal Pouch Consortium. Lancet Gastroenterology and Hepatology 2022; in press.
Stone JA, Shafer LA, Graff LA, Witges K, Lix L. Sexton KA, Haviva C, Targownik LE, Bernstein CN. The association of efficacy, optimism, uncertainty and health anxiety with inflammatory bowel disease activity. Journal of Psychosomatic Research 2022; in press.
Positive and negative psychological attributes have been shown to influence disease outcomes in many chronic health conditions. We aimed to evaluate the association between self-efficacy, optimism, health anxiety and intolerance of uncertainty and disease activity in IBD. Adults with confirmed and recently active IBD enrolled in a prospective cohort study. Demographics, disease information, validated measures of psychological functioning related to general self-efficacy, optimism, health anxiety and intolerance of uncertainty were collected at baseline, week 26 and week 52. Clinical disease activity was assessed using the Inflammatory Bowel Disease Symptom Inventory (IBDSI), self-reported flares, and intestinal inflammation using fecal calprotectin (FCAL), collected at baseline, weeks 26 and 52. Generalized estimating equations were used to test the association between psychological functioning and disease activity. There were 154 participants of whom 64.1% had Crohn's disease. Adjusting for demographic variables, higher self-efficacy was associated with lower likelihood of flare by self-report (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.71, 0.91) and IBDSI (OR 0.89, 95% CI 0.80, 0.99), while higher health anxiety was associated with greater likelihood of flare by self-report (OR 1.07, 95% CI 1.01, 1.18) and higher symptomatic disease activity (IBDSI; OR 1.14, 95% CI 1.05, 1.24). The psychological attributes were not significantly associated with active disease as measured by inflammation (FCAL).
We concluded that general self-efficacy and health anxiety are relevant in understanding patient experience with disease activity, and may be appropriate targets for psychological intervention in the care of individuals with IBD.
Wan A, Bernstein CN, Graff LA, Patten SB, Sareen J, Fisk JD, Bolton JM, Hitchon C, Marriott JJ, Marrie RA. Childhood maltreatment and psychiatric comorbidity in immune-mediated inflammatory disorders. Psychosomatic Medicine 2022; 84:10-19.
To determine whether childhood maltreatment is associated with immune-mediated inflammatory disorders (multiple sclerosis [MS], IBD and rheumatoid arthritis). We further aimed to determine the relationship between maltreatment and psychiatric comorbidity in immune-mediated inflammatory and whether these relationships differed across immune-mediated inflammatory. 925 participants (MS: 232, IBD: 216, rheumatoid arthritis: 130, healthy controls: 103) completed a structured psychiatric interview to identify psychiatric disorders, and the Childhood Trauma Questionnaire to evaluate five types of maltreatment: emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. We evaluated associations between maltreatment, immune-mediated inflammatory and psychiatric comorbidity using multivariable logistic regression models. The prevalence of having ≥1 maltreatment was similar across immune-mediated inflammatory, but higher than in controls (MS: 63.8%, IBD: 61.6%, rheumatoid arthritis: 62.3%, healthy controls: 45.6%). Emotional abuse was associated with having an immune-mediated inflammatory (adjusted odds ratio [aOR] 2.37; 1.15-4.89). In the sex-specific analysis, this association was only present in women. History of childhood maltreatment was associated with a lifetime diagnosis of a psychiatric disorder in the immune-mediated inflammatory cohort (OR 2.24; 1.58-3.16), but this association did not differ across diseases. In those with immune-mediated inflammatory, total types of maltreatments (aOR 1.36; 1.17-1.59) and emotional abuse (aOR 2.64; 1.66-4.21) were associated with psychiatric comorbidity.
We concluded that childhood maltreatment is more common in immune-mediated inflammatory than in a healthy population, and is associated with psychiatric comorbidity. Given the high burden of psychiatric disorders in the immune-mediated inflammatory population, clinicians should be aware of the contribution of maltreatment and the potential need for trauma-informed care strategies.
Pratt M, Forbes JD, Knox NC, Van Domselaar G, Bernstein CN. Colorectal cancer screening in IBD - can characterization of GI microbiome signatures enhance neoplasia detection? Gastroenterology. 2022 Jan 5: S0016-5085.
Current non-invasive colorectal cancer screening methods are not optimized for persons with IBD, requiring patients to undergo frequent interval screening via colonoscopy. Although colonoscopy-based screening reduces colorectal cancer incidence in IBD patients, rates of interval colorectal cancer remain relatively high, highlighting the need for more targeted approaches. In recent years, the discovery of disease-specific microbiome signatures for both IBD and colorectal cancer has begun to emerge, suggesting that stool-based biomarker detection using metagenomics and other culture-independent technologies may be useful for personalized, early, non-invasive colorectal cancer screening in IBD patients. Here we discuss the utility of the stool microbiome as a non-invasive colorectal cancer screening tool. Comparing the performance of multiple microbiome-based colorectal cancer classifiers, including several multi-cohort meta-analyses, we find that non-invasive detection of colorectal adenomas and carcinomas from microbial biomarkers is an active area of study with promising early results.