Inflammatory bowel diseases (IBD) are increasing worldwide, requiring multidisciplinary care and coordinated research infrastructures. Leveraging Israel's integrated healthcare system with IBD centers of specific and complementary research expertise, a national collaborative consortium was established: the Israeli IBD Research Nucleus (IIRN). In this narrative article, we review a decade of IIRN structure, scientific outputs, and lessons learned. The IIRN included five tertiary academic IBD referral centers across Israel, with expertise in epidemiology, mucosal immunology, diet and microbiome, imaging, and psychosocial care. We summarized the IIRN key activities, findings, and contributions across these domains. Publications (2015-2025) were identified using a structured bibliometric approach and included studies aligned with core research programs of the IIRN. This collaborative consortium has been supported since its inauguration by the Leona M. and Harry B. Helmsley Charitable Trust, providing funding, advice, and partnership. The IIRN provided significant contributions in several domains. It established a population-based nationwide registry (epi-IIRN) that integrates data from the four national health maintenance organizations, enabling studies of disease prevalence, course, comorbidities, and treatment patterns. Prospective cohorts of patients with Crohn's disease provided longitudinal insights linking multidisciplinary programs, Mediterranean diet and lifestyle, and psychosocial interventions with patient-reported outcomes, inflammatory markers, and microbiome features. Integrating imaging, video-capsule endoscopy, and biomarker assessment informed monitoring strategies and treat-to-target concepts. Exploratory translational work in microbiome, transcriptomics, and therapeutic drug monitoring refined insights regarding treatment response and sequencing. Artificial intelligence applications explored image and report interpretation to predict Crohn's disease. The IIRN experience illustrates how coordinated national collaborations can leverage epidemiology, prospective cohorts, translational research, and multidisciplinary care programs. This experience highlights both the opportunities and challenges of shared research infrastructure and may inform similar collaborative efforts in other healthcare settings.

Background and Objective: Crohn’s Disease (CD) is a chronic inflammatory condition with significant physical and psychological impacts, often requiring comprehensive self-management. This study examines the effects of COBMINDEX (Cognitive–Behavioral and Mindfulness Intervention with Daily Exercise) on coping strategies and life satisfaction in CD patients, focusing on gender-specific responses. Study objectives were to assess the impact of COBMINDEX on adaptive and maladaptive coping strategies and life satisfaction in CD patients, and to examine gender differences in these outcomes. Materials and Methods: A pre-planned secondary analysis of a randomized controlled trial, conducted from 2018 to 2021, at two public tertiary hospitals in Israel. A total of 120 CD patients (45 men and 75 women) were randomly assigned to either theCOBMINDEX group or a wait-list control group. Participants were assessed at baseline and post-intervention for coping strategies, mindfulness, psychological symptoms, and life satisfaction using validated scales. Quantile regression explored the gender-specific predictors of life satisfaction. This study was registered at ClinicalTrials.gov (NCT05085925) and Israel Ministry of Health (MOH_2020- 02- 24_008721. asp). Results: Both genders showed significant improvements in mindfulness, emotion-focused coping, and active coping (p < 0.05). Women exhibited reduced dysfunctional coping and greater emotional support use. For men, emotion-focused coping and mindfulness positively predicted life satisfaction, while for women, reductions in psychological symptoms and dysfunctional coping were significant predictors (p < 0.01). Conclusions: COBMINDEX enhances coping strategies and life satisfaction in CD patients, with notable gender differences. These findings highlight the importance of gender-tailored psychological interventions to improve overall patient well-being.

BACKGROUNDData regarding patients with ulcerative colitis (UC) not receiving maintenance treatment are scarce. In this nationwide study, we aimed to explore the frequency and long-term outcomes of untreated patients with UC vs treated patients.METHODSWe retrieved data from Israel's Health Maintenance Organizations, covering 98% of the population. No maintenance treatment (NMT) was defined as lack of treatment during the period from 3 to 6 months from diagnosis, allowing at most 3 months for induction treatment.RESULTSA total of 15 111 patients have been diagnosed with UC since 2005, of whom 4410 (29%) have had NMT, with 36 794 person-years of follow-up. NMT was more likely in adults (31%) and in elderly-onset UC (29%) than in pediatric-onset UC (20%; P < .001) and decreased from 38% in 2005 to 18% in 2019 (P < .001). The probability of remaining without treatment was 78%, 49%, and 37% after 1, 3, and 5 years from diagnosis, respectively. In propensity score-matched analysis of 1080 pairs of treated (93% with 5-aminosalicylic acid) and untreated patients, outcomes were comparable for time to biologics (P = .6), surgery (P = .8), steroid dependency (P = .09), and hospitalizations (P = .2). Multivariable modeling indicated that failing NMT was less likely in adults or elderly-onset patients who received at most rectal therapy or antibiotics as induction therapy.CONCLUSIONSNowadays, 18% of patients with UC do not receive maintenance therapy, of whom half remain without treatment after 3 years. Matched pairs of patients on NMT and 5-aminosalicylic acid, representing the mildest patients of the latter, had similar outcomes. Prospective studies are needed to further explore the role of NMT in UC.

Crohn's disease (CD) is a chronic inflammatory bowel disease associated with psychological distress and intestinal microbial changes. Here, we examined whether a 3-month period of Cognitive Behavioral and Mindfulness with Daily Exercise (COBMINDEX) intervention, which improves the wellbeing and inflammatory state of CD patients, may also affect their gut microbiome. Gut microbiota, circulating inflammatory markers and hormones were analyzed in 24 CD patients before (T1) and after 3 months of COBMINDEX (T2), and in 25 age- and sex-matched wait-list control patients at the corresponding time-points. Microbiota analysis examined relative taxonomical abundance, alpha and beta diversity, and microbiome correlations with inflammatory and psychological parameters. At T1, CD patients exhibited a characteristic microbial profile mainly constituted of Proteobacteria (17.71%), Firmicutes (65.56%), Actinobacteria (8.46%) and Bacteroidetes (6.24%). Baseline bacterial abundances showed significant correlations with psychological markers of distress and with IFN$\gamma $gamma. Following COBMINDEX, no significant changes in alpha and beta diversity were observed between both study groups, though a trend change in beta diversity was noted. Significant changes occurred in the abundance of phyla, families and genera only among the COBMINDEX group. Furthermore, abundance of phyla, families and genera that were altered following COBMNIDEX, significantly correlated with levels of cytokines and psychological parameters. Our results demonstrated that a short-term intervention of COBMINDEX was associated with changes in microbial indices, some of which are linked to psychological manifestations and systemic inflammation in CD patients. Psychological interventions to reduce chronic stress, such as COBMINDEX, appear to be beneficial in mitigating the pathobiology of CD patients, and may thus provide a useful adjunct to pharmacological therapy.

Summary Background Chronic abdominal pain and fatigue are characteristics of Crohn's disease (CD) and contribute to functional impairments. Aims To examine whether CD‐tailored cognitive‐behavioural and mindfulness intervention (COBMINDEX) is effective in reducing abdominal pain and fatigue in patients with CD and whether changes in abdominal pain and fatigue mediate any beneficial effects of COBMINDEX on impairments in work productivity and daily activities. Methods This is a secondary analysis of a parallel‐group multicentre randomised controlled trial. Patients with mild‐to‐moderate CD ( n = 142) were randomised into either intervention group receiving COBMINDEX, or control group receiving treatment‐as‐usual for 3 months followed by COBMINDEX. Complete data were collected from 120 patients (34.0 ± 10.7 years, 62.5% female, intervention = 60, control = 60). Analysis of covariance assessed group differences in 3‐month follow‐up scores, controlling for baseline scores. Multiple parallel mediation analysis assessed the proposed mechanisms for the entire sample. Results The intervention group demonstrated significantly lower levels of abdominal pain ( F = 17.46, p < 0.001, η 2 p = 0.13), fatigue ( F = 7.26, p = 0.008, η 2 p = 0.06) and impairments at work ( F = 4.82, p = 0.032, η 2 p = 0.07) and daily activities ( F = 6.26, p = 0.014, η 2 p = 0.05), compared with treatment‐as‐usual. Moreover, changes in abdominal pain and fatigue significantly mediated the beneficial effects of COBMINDEX on patients' work productivity ( b = −9.90, SE = 2.86, 95% CI: −16.11 to −4.94) and daily activities ( b = −9.65, SE = 1.91, 95% CI: −13.77 to 6.35), independent of changes in disease activity. Conclusions COBMINDEX is effective at reducing abdominal pain and fatigue in patients with CD, which in turn leads to improvement in functioning. Clinicians should incorporate screening for severe abdominal pain and fatigue and consider offering cognitive‐behavioural and mindfulness training. ClinicalTrials.gov , Number: NCT05085925. Ministry of Health in Israel ( https://my.health.gov.il/CliniTrials/Pages/MOH_2020‐02‐24_008721.aspx ).

Objectives Cognitive behavioral and mindfulness interventions have been shown to promote well-being in individuals with chronic illness. However, the underlying psychological processes through which these interventions impact well-being are not fully explored. This secondary analysis study aimed to examine the role of perceived social support, interpersonal sensitivity, and perceived stress as mediators of the positive effect of individualized online Cognitive Behavioral and Mindfulness Intervention (COBMINDEX) on life satisfaction among patients with Crohn’s disease (CD). Method Patients with mild or moderately active disease ( n =142) were randomly assigned to either COBMINDEX intervention or treatment-as-usual control group. After a period of 3 months, the control group also received the COBMINDEX intervention. Complete data were collected from 120 patients (COBMINDEX=60, TAU=60). Analysis of covariance assessed group differences in post-intervention scores, controlling for baseline scores. Multiple parallel mediation analysis assessed the proposed mechanisms for the entire sample. Results Individuals in the COBMINDEX condition reported significantly lower levels of perceived stress ( F =28.06, p <0.01) and interpersonal sensitivity ( F =12.78, p <0.01) than those in the control condition. The COBMINDEX group also had significantly higher levels of life satisfaction ( F =9.79, p <0.01) compared to the control group. Perceived social support did not differ across groups ( F =2.73, p =0.10). Analysis of indirect effects revealed significant effects of perceived stress ( b =0.52, 95% CI [0.16, 1.03]) and interpersonal sensitivity ( b =0.73, 95% CI [0.31, 1.35]); thus, the positive effect of COBMINDEX on life satisfaction was mediated by changes in interpersonal sensitivity and perceived stress. Conclusions The findings highlight the importance of targeting mental processes such as interpersonal sensitivity to enhance patients’ life satisfaction. These findings suggest that practitioners might consider COBMINDEX as an adjunct intervention for patients with CD. Preregistration The study was registered with ClinicalTrials.gov (Identifier: NCT05085925) and with the Ministry of Health in Israel ( https://my.health.gov.il/CliniTrials/Pages/MOH_2020-02-24_008721.aspx ).

BACKGROUND:Patients with Crohn disease have debilitating psychological symptoms, mental fatigue, and poor quality of life. Psychological intervention may improve these symptoms. METHODS:We performed a randomized parallel-group physician-blinded trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) on quality of life and psychological symptoms in adults with mild-moderate Crohn disease. COBMINDEX was taught by social workers in one-on-one video conferences over 3 months; quotidian home practice was mandated. RESULTS:Fifty-five COBMINDEX and 61 waitlist control patients completed the study; mean age was 33 years and 65% of participants were women. At 3 months, COBMINDEX patients had significantly reduced disease activity (per Harvey-Bradshaw Index score, C-reactive protein level, and calprotectin level), increased quality of life (Short Inflammatory Bowel Disease Questionnaire [SIBDQ] score increased from baseline 41 to 50; P < 0.001), decreased psychological symptoms (Global Severity Index [GSI], 0.98-0.70; P < 0.001), reduced fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue, 26-33; P < 0.001), and increased mindfulness disposition (Freiburg Mindfulness Inventory, 33-38; P < 0.001). Waitlist patients had a significant but small change in Harvey-Bradshaw Index, SIBDQ, and GSI scores, without improvement in fatigue or mindfulness. There were significant correlations (0.02 > P < 0.002) in COBMINDEX patients between baseline SIBDQ, GSI, Freiburg Mindfulness Inventory, and Functional Assessment of Chronic Illness Therapy-Fatigue scores with a relative change (baseline to 3 months) of the SIBDQ score, but none among waitlist patients. Predictors of relative change of the SIBDQ score in COBMINDEX patients included the GSI score (90% quantile; coefficient 0.52; P < 0.001), somatization (90%; 0.20; P = 0.001), depression (75%; 0.16; P = 0.03), and phobic anxiety (75%; 0.31; P = 0.008). CONCLUSIONS:COBMINDEX was effective in increasing patients' quality of life and reducing psychological symptoms and fatigue. Patients with severe baseline psychological symptoms benefited the most from COBMINDEX.

Background and aims: Crohn's disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the hypothalamus-pituitary-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) impacts their inflammatory process. Methods: Circulating inflammatory markers and a wide range of psychological parameters related to stress and well-being were measured in CD patients before and after COBMINDEX. Inflammatory markers in CD patients were also compared to age- and sex-matched healthy controls (HCs). Results: CD patients exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by interconnected inflammatory modules represented by IL-6, TNFα, IL-17, MCP-1 and IL-18. Notably, higher IL-18 levels correlated with higher score of stress and a lower score of wellbeing in CD patients. COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 and IFNα and negatively with those of MCP-1. Furthermore, inflammatory markers of CD patients at baseline predicted COBMINDEX efficacy, as higher levels of distinct cytokines and cortisol at baseline, correlated negatively with changes in disease activity (by Harvey-Bradshaw Index) and psychological distress (global severity index measure) following COBMINDEX. Conclusion: CD patients have a characteristic immunological profile that correlates with psychological stress, and disease severity. We suggest that COBMINDEX induces stress resilience in CD patients, which impacts their well-being, and their disease-associated inflammatory process.

Abstract Background Medical and psychological factors contribute to the heightened psychological distress and reduced health-related quality of life in patients with Crohn’s disease. Whether Social Support plays a role in this scenario is unknown. We used the Multidimensional Scale of Perceived Social Support (MSPSS) to investigate whether Social Support associates with psychological distress and quality of life in Crohn’s disease. Methods Consecutive adult patients with Crohn’s disease, presenting at specialist gastroenterology services or recruited by advertising, with mild to moderate disease activity by the Harvey-Bradshaw Index (HBI), were enrolled into the study. Patients completed the 12-item MSPSS questionnaire that measures psychological support in three categories: Family, Friends and Significant Other, and provides individual category scores and a total score (range of all scores 1–7; a higher score indicates more social support). Patients also completed the following questionnaires: psychological distress (Brief Symptom Inventory, with Global Severity Index, GSI), quality of life (Short Inflammatory Bowel Disease Questionnaire, SIBDQ), satisfaction with life (SWLS), family stress (Family Assessment Device, FAD), coping strategies (Brief-COPE), and presenteeism and work activity (WPAI). Statistics: Spearman rho. *p<0.05, **p<0.01. Results The cohort comprised 126 patients, mean (SD) age 33.7 (10.6) years, females 79%, HBI 8.4 (2.5), CRP 1.2 (2.3), calprotectin 394 (674). MSPSS scores were as follows: Total score 5.72 (1.14), Friends 5.36 (1.34), Family 5.73 (1.14), and Significant Other 6.07 (1.15); Cronbach’s α ≥ .877. MSPSS scores correlated negatively with family stress measure FAD: Friends -.258**, Family -.732**, Significant Other -.401**; and with GSI psychological stress measure: Friends -305**, Family -.352**, Significant Other -.245**. MSPSS correlated positively with SIBDQ quality of life: Friends .300**, Family .188*, Significant Other .200*; and with satisfaction with life SWLS: Friends .379**, Family .333**, Significant Other .245**. MSPSS correlations with emotion-focused coping were: Friends -.337**, Family -.263**, Significant Other -.329**. MSPSS Family score correlated negatively with WPAI presenteeism -.270*, and WPAI work activity -.294**. Conclusion In mild to moderate Crohn’s disease, strong social support was associated with better quality of life, more satisfaction with life, and better performance in the work arena. Social support was associated with reduced psychological distress, reduced family stress, and less use of emotion-focused coping. This research shows the importance of social support in improving the psychological condition of patients with Crohn’s disease.

Introduction: Abdominal pain is a cardinal symptom of Crohn's disease.Patients often use opiates and cannabis to assuage pain when standard and biologic medication does not produce adequate relief.Psychological stress is known to accentuate the individual's perception of pain.We found that a program of cognitive behavioral and mindfulness-based stress reduction (COBMINDEX) diminishes psychological stress in patients with Crohn's disease. 1 It was therefore of interest to perform an ad hoc analysis to examine whether COBMINDEX could reduce pain in these patients.Aims & Methods: We performed a double-blind trial of COBMINDEX in mild/moderately active Crohn's disease patients who were randomized to COBMINDEX or waitlist controls.Patients were assessed at study entry (time T1) and again at 3 months (T2).At T1 and T2 a clinician completed the Harvey-Bradshaw Index (HBI) and patients filled in the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), MOS 12-Item Short Form Survey Instrument Physical Health (SF-12 PH), and EuroQual 5-Dimensional Questionnaire (EQ-5D-3L).COBMINDEX was taught by specially trained social workers using a one-on-one internet platform between T1 and T2; daily self-practice by the patients was required.Waitlist patients remained on follow-up only.Pain frequency and severity at T1 and T2 were compared between COBMINDEX and waitlist patients.For the analysis the range of responses to the pain questions in HBI (abdominal pain the previous day, 4 responses), SIBDQ (abdominal pain in last 4 weeks, 7 responses) and SF-12 PH (pain in last 2 weeks, 5 responses) were re-coded into 4 responses: none, mild, moderate, severe pain.The pain question in EQ-5D-3L has 3 responses.Statistics: Pearson chi square test, logistic regression controlling for age and gender with pain decrease as the dependent variable.Results: COBMINDEX (n=60) and waitlist (n=66) patients' characteristics were: mean age 34.4y vs 33.1y, biologics 45% vs 40%, immunomodulators 20% vs 15%, respectively.For both groups: women 63%, HBI range 5-7 in 47%, HBI range 8-16 in 53%, opiate use 0. COBMINDEX patients exhibited reduced pain frequency and intensity at T2 vs waitlist by HBI and SIBDQ scales.Pain frequencies (%) in the order as none, mild, moderate, severe were as follows.By HBI, COBMINDEX T1: 8, 23, 57, 12; T2

Objective: The Brief Symptom Inventory (BSI) is a self-report measure of psychological symptoms in clinical and non-clinical populations. However, norms for BSI are lacking for patients with chronic illness, such as Crohn's disease (CD). This study aimed to provide BSI clinical norms using a cohort of CD patients. Design: Adult Israeli CD patients (n = 430) completed questionnaires regarding clinical, demographic and psychological aspects of disease, including BSI. Their BSI data were compared with published norms from adult Israeli population and British psychiatric outpatients. Results: CD patients in active disease state had higher levels of mental health symptoms than those in remission. Interestingly, levels of symptomatology did not differ with respect to disease duration. No significant sex differences in BSI dimensions were found, with the exception of somatization. Being younger than 60 years and having lower economic status were associated with more severe psychological symptoms. Psychological symptom levels in CD patients were high in comparison to the Israeli general population, but low compared to British psychiatric outpatients. Conclusion: Results confirm the link between CD and elevated psychological symptoms. The findings highlight the need to use appropriate BSI norms when assessing clinically significant levels of psychological symptoms in non-psychiatric patients with chronic illness.

Abstract Background Therapy in IBD is recommended in order to treat or prevent complications. In this nationwide study we aimed to assess the incidence of patients with IBD who were not receiving maintenance treatment after diagnosis and the duration of non-treatment. Methods This study was performed on data from four Health Maintenance Organizations (HMOs), covering 98% of the Israeli population. We included all patients with IBD diagnosed from 2005 to 2019. Non-treatment was defined as lack of drug prescription of maintenance medication for at least six months from diagnosis. Sustainability was defined as lack of maintenance medications and without IBD-related surgeries. Cox regression model was used to explore estimated predictors of sustainability. Results A total of 30,168 patients were diagnosed with IBD in Israel since 2005 (16,936 [56%] Crohn’s disease [CD] and 13,231 [44%] ulcerative colitis [UC]). A total of 5,448 (32%) patients with CD were untreated, compared to 5,158 (39%) with UC (OR 1.35 [95%CI 1.3–1.4]; p<0.001). Non-treatment was more likely in adult compared to pediatric-onset (34% vs 21%, respectively, p<0.001 in CD; and 41%% vs 22%, respectively, in UC; p<0.001) (Figure 1). Sustainability rate in CD was 72%, 46%, 36% and 28% after one, two, five and ten years from diagnosis, while in UC the corresponding rates were 59%, 39%, 24% and 16%. In CD, sustainability was associated with older age at diagnosis (HR 0.996 [95%CI 0.994–0.998]) and no induction therapy (HR 0.7 [95%CI 0.6–0.9] compared to steroids). In UC, sustainability was associated only with female sex (HR 0.9 [95%CI 0.88–0.98]). Conclusion Most patients with IBD eventually require maintenance therapy. Lack of maintenance treatment is more common in UC. Nevertheless, a third of patients with CD and one quarter with UC who had no medical treatment at six months from diagnosis remained untreated for five years, especially in older patients with CD and those who did not require induction therapy, suggesting milder disease.

BACKGROUND:There are currently no nationwide data on the epidemiology of inflammatory bowel diseases (IBD) in Israel. We aimed to determine the population-based epidemiological trends of IBD in the diverse Israeli population.METHODS:Health-administrative data were retrieved from all 4 Israeli health maintenance organizations, insuring 98% of the population, using validated identification algorithms. National trends were determined using Joinpoint regression analysis calculating annual percent change and average annual percent change (AAPC).RESULTS:By 2019, there were 46,074 patients with IBD in Israel, corresponding to a national prevalence of 519/100,000 (0.52%), of whom 54.1% had Crohn disease (CD) and 45.9% had ulcerative colitis (UC). The number of Jewish patients doubled from 18,701 in 2005 (354/100,000) to 38,950 (589/100,000) in 2018 (AAPC, +4.0%; P < 0.05), and the number of Arab patients increased 3-fold from 1096 (102.1/100,000) to 3534 (240.7/100,000; AAPC, +6.8%; P < 0.05) during the same years. However, the increase rate has gradually decelerated over time (annual percent change during 2005-2008, 2009-2014, and 2005-2018 was +6.7%, +4.2%, and +2.3%, respectively; P < 0.05). Pediatric prevalence increased from 37.4 to 52.2/100,000, with CD predominating in both Jews and Arabs. The incidence of CD remained stable (from 15.9/100,000 to 14.9/100,000) and the incidence of UC decreased (15.4/100,000 to 10.5/100,000 (AAPC, -3.2%; P < 0.001)). In contrast, pediatric incidence of CD increased from 7.3/100,000 to 8.3/100,000 (AAPC, +1.9%; P < 0.05) and that of UC increased from 2.6 to 4.4/100,000 (AAPC, +5.8%; P < 0.05).CONCLUSIONS:The IBD prevalence rate in Israel is still increasing but gradually decelerating, probably due to the decreasing overall IBD incidence. Nonetheless, incidence rate in children is still increasing. Ongoing narrowing in the rates between Jews and Arabs over time may indicate shared environmental factors.

Patients with Crohn’s disease, an inflammatory bowel disease, struggle with chronic somatic symptoms that could bring about emotional distress. This study assessed the relative role of somatization, and depressive and anxiety symptoms in disease activity among 619 Crohn’s patients (18–79 years; 58.3% women). Structural equation modeling revealed that somatization was the only unique predictor of disease activity beyond depression and anxiety. In addition, the effect of somatization on disease activity was stronger in men compared to women. Findings suggest that somatization represents a distinct domain of psychological distress that may play a role in the health of patients with Crohn’s disease.

Abstract Background Crohn’s disease (CD) is associated with psychological stress and alteration of gut microbiota as compared to healthy individuals. Previous work has reported imbalances in CD patients across four major bacterial phyla including Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. We aimed to determine the effect on gut microbiota of a 3-month period of Cognitive Behavioral and Mindfulness-Based Stress Reduction (COBMINDEX), a psychological intervention shown to improve the wellbeing and inflammatory state of CD patients. Methods Microbial analysis of stool samples, circulating inflammatory markers and a wide range of psychological parameters related to stress, well-being and daily activities were measured and compared among 25 CD patients before (T1) and after (T2) COBMINDEX, and 25 matched CD wait-list controls at the corresponding time-points T1 and T2. Stool DNA extracts were subjected to 16S amplicon sequencing (Illumina) and analysed for taxonomical abundance, alpha and beta diversity using the QIIME2 pipeline and correlated with inflammatory and clinical parameters. Results Microbial alpha diversity among all CD patients at T1 significantly correlated to the 3 key cytokines: IL-10 (p=0.04, correlation=0.48), INFg (p=0.02, correlation=0.53), and INFa (p=0.02, correlation=0.51). At T2, while beta diversity was significantly increased in the COBMINDEX group (p=0.03), it was significantly decreased (p=0.0001) among the wait-list controls (Figure 1). Furthermore, compared with the wait-list controls, changes in inflammatory and clinical markers such as INFg, TNFa, IL-6, calprotectin and CRP, occurring following COBMINDEX, were accompanied by changes in the 4 main phyla including Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria (Figure 2). Lastly, changes in a variety of unique taxa, not previously implicated in CD, were also associated with changes in inflammatory and clinical markers such as INFg, TNFa, IL-6, calprotectin and CRP in the COBMINDEX but not in wait-list controls (Figure 2). Conclusion Our results show that microbial diversity is connected to the inflammatory profile of CD patients, and is significantly altered by COBMINDEX. Moreover, changes in the 4 main phyla that are known to be different among CD patients are linked to changes in various inflammatory markers, demonstrating the microbial-inflammatory relationship among CD patients. Lastly, we found that changes in the abundancies of 7 taxa, hitherto untied to CD in the literature, correlate with inflammatory markers, hinting at new microbial targets in CD.

Crohn’s disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the pituitary-hypophysis-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month period of Cognitive Behavioral and Mindfulness-Based Stress Reduction (COBMINDEX) impacts their inflammatory process. Circulating inflammatory markers (IFN-α, IFN-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-18, IL-23, and IL-33) and a wide range of psychological parameters were measured before (T1) and after (T2) COBMINDEX in CD patients. Inflammatory parameters were also compared to age- and sex-matched healthy controls (HCs) at T1, and to wait-list CD patients (at T1 and T2) who were followed for 3 months but did not receive COMBINDEX. Psychological symptoms were assessed by two questionnaires: the Perceived Stress Scale PSS4, and the Brief Symptom Inventory of psychological distress with Global Severity Index GSI. Statistical significance was assessed using Spearman correlation. CD patients (N=100, mean age 33.6 ± 13 years, 69% female, Harvey-Bradshaw Index mean 31± 55) exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by higher serum levels of interleukin (IL)-6 (mean 4.084± 8.4) and IL-18 (mean 302.09± 286) shown in Figure 1. Notably, IL-18 levels correlated with a higher stress score and a lower wellbeing score in CD patients (Figure 2). COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 (0.32, p<0.05) and INFα (0.36, p<0.05) and correlated negatively with those of MCP-1 (-0.34, p<0.05). Finally, baseline inflammatory markers of CD patients predicted COBMINDEX efficacy, as changes in HBI were negatively correlated with cytokines levels of IFNa (p=0.046), IFNg (p=0.03), IL-10 (p=0.002), IL-23 (p=0.025), IL33 (p=0.009) and IL12p70 (p=0.037) at T1 in the COBMINDEX group, but not in the wait-list group. In addition, basal levels of circulating cortisol at T1 negatively correlated with changes in GSI (-0.33, p<0.05) between T1 and T2 in the COBMINDEX group, but not in the wait-list group. Our results show that CD patients have a characteristic immunological profile that correlates with psychological stress and disease activity, and predicts COBMINDEX outcomes. We suggest that COBMINDEX induces stress resilience in CD patients, which not only impacts their well-being, but also their disease-associated inflammatory process.

Abstract Background Health-related quality-of-life by the self-report, disease-specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is increasingly used as an outcome measure in Crohn`s disease (CD) patients in clinical trials. Higher SIBDQ scores indicate better quality-of-life; the range is 10 to 70. However, the construct validity of SIBDQ and its responsiveness to change of disease status require validation. Methods Adult (≥18 years) CD patients (n = 108) with Harvey–Bradshaw Index (HBI) >4 and <16 prospectively filled in the SIBDQ at two time-points (T1, T2) 3 months apart. Medical data at T1 and T2 were collected, and recorded by their physicians in the HBI. Biomarkers of disease activity included Calprotectin and C-reaction protein (CRP), measured at T1 and T2. The construct validity of SIBDQ in relation to biomarkers and HBI was determined by Pearson correlations and group comparisons using Student`s t-test. Statistical significance was taken as p < 0.05. Patients’ medications were prescribed without regard to the study protocol. Results Demographic and medical characteristics (median, %) of the cohort were: age 30 years; females 65%, married/partner 48%; higher education 83%; BMI 22; non-smokers/past-smokers 92%; disease duration 5 years; past Crohn’s disease-related surgery 17%; Montreal classification A2 89%, L2+L3 89%, B1+B2 89%, perianal disease 18%; medications: corticosteroids 4%, 5-ASA 5%, immunomodulators 21%, biologicals 43%. HBI and SIBDQ median scores at T1 and T2 were: HBI: 9 and 4 (p < 0.001); SIBDQ: 43 and 49 (p < 0.001). SIBDQ scores correlated inversely with Calprotectin (r = −0.395, p = .002), CRP (r = −0.208, p = .046), and HBI (r = −0.345, p < 0.001). Baseline HBI scores were used to divide the cohort into two groups for comparison: mild disease (5–7) vs. moderate disease (8–16). Mild disease patients reported higher SIBDQ scores than those with moderate disease (42.7 vs. 39.7, t = 1.96, p = 0.05). Regarding sensitivity of SIBDQ to clinical changes between T1 and T2, we found that change in SIBDQ correlated significantly with change in CRP across these two administrations (r = −0.232, p = 0.042). Finally, defining clinical response in CD as a decrease from baseline HBI score by ≥3 points, SIBDQ change scores were significantly larger in treatment responders (n = 51, M = 6.25) than non-responders (n = 30, M = 1.13, t = −3.042, p = 0.003). Conclusion The SIBDQ measure is a valid assessment of quality-of-life in CD, correlating with biomarkers and sensitive to change of disease activity, with potential for use as a patient-reported outcome in both clinical practice and as a primary end-point in clinical trials.

Abstract Background Crohn’s disease (CD) patients have reduced quality-of-life (QoL) in physical, emotional and social domains, and diminished work and leisure activities. We examined whether Mindfulness-Based Stress Reduction and Cognitive Intervention (‘Intervention’) can improve QoL and ability to work. Methods Patients (≥18 years), Harvey–Bradshaw Index (HBI) >4 and <16, were randomised to Intervention or Control groups. Intervention was taught in 8 weekly sessions by social workers via SKYPETM with twice-daily practice and back-report required. Medications were not controlled. HBI was completed at entry (T1) and 12 weeks (T2), and these questionnaires: (1) Short inflammatory bowel disease questionnaire (SIBDQ), disease-specific HRQoL measure. (2) Short-Form 12 (SF-12) questionnaire, generic HRQoL measure of physical health (PH) and mental health (MH). (3) EQ-5D-3L HRQoL questionnaire. (4) Work Productivity and Activity Impairment (WPAI) questionnaire, measuring absenteeism, presenteeism (reduced productivity), work impairment (composite of absenteeism and presenteeism), and leisure activity impairment. Statistics: Pearson Chi-squared, Wilcoxon signed-rank test. Results There were 39 Intervention and 43 Control patients. Demographic and medical characteristics (median, %) were: age 30 y; women 65%, married/partner 48%; higher education 83%; BMI 22; non- or past-smokers 92%; disease duration 5 y; HBI 8 (range 5–15); past surgery 17%; Montreal A2 89%, L2+L3 89%, B1+B2 89%, perianal disease 18%; drugs: corticosteroids 4%, 5-ASA 5%, immunomodulators 21%, biologics 43%; (p = ns between groups). Socio-economic status was higher in Intervention (87% = good/very good) than Control (58%, p = 0.016). HBI, SIBDQ and SF PH improved in both groups, but SF MH, EQ-5D-3L and all WPAI measures improved only in Intervention group (Table). Non-significance of WPAI indices between groups resulted from small sample size. Conclusion Mindfulness-Based Stress Reduction and Cognitive Intervention led to increased QoL and less work and activity impairment. If confirmed in a large cohort the intervention may be offered to all CD patients.