Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment

Luo J., Xu Z., Noordam R., van Heemst D., Li-Gao R.

Abstract Background and Aims Observational studies have suggested a bidirectional association between depression and inflammatory bowel disease [IBD], including Crohn’s disease [CD] and ulcerative colitis [UC]. However, it remains unclear whether the observed associations are causal due to the difficulties of determining sequential temporality. We investigated the association between depression and IBD by using bidirectional two-sample Mendelian randomization [MR]. Methods Independent genetic variants for depression and IBD were selected as instruments from published genome-wide association studies [GWAS] among individuals of predominantly European ancestry. Summary statistics for instrument–outcome associations were retrieved from three separate databases for both depression [Psychiatric Genomics Consortium, FinnGen and UK Biobank] and IBD [the largest GWAS meta-analysis, FinnGen and UK Biobank], respectively. MR analyses included the inverse-variance-weighted method, weighted-median estimator, MR-Egger regression, and sensitivity analyses of Steiger filtering and MR PRESSO. From either direction, analyses were performed per outcome database and were subsequently meta-analysed using a fixed-effect model. Results Genetically predicted depression [per log-odds ratio increase] was associated with a higher risk of IBD; odds ratios [95% confidence interval] for IBD, CD and UC were 1.20 [1.05, 1.36], 1.29 [1.07, 1.56] and 1.22 [1.01, 1.47] in a combined sample size of 693 183 [36 507 IBD cases], 212 172 [13 714 CD cases] and 219 686 [15 691 UC cases] individuals, respectively. In contrast, no association was observed between genetically influenced IBD and depression in 534 635 individuals [71 466 depression cases]. Conclusions Our findings corroborated a causal association of depression on IBD, which may impact the clinical decision on the management of depression in patients with IBD. Though our results did not support a causal effect of IBD on depression, further investigations are needed to clarify the effect of IBD activity on depression [with different symptomology].

Fairbrass K.M., Lovatt J., Barberio B., Yuan Y., Gracie D.J., Ford A.C.

ObjectiveThe role of the brain–gut axis is of increasing interest in IBD, as the link between common mental disorders and GI inflammation may be bidirectional. We performed a systematic review examining these issues.DesignWe searched EMBASE Classic and EMBASE, Medline, and APA PsychInfo (to 11 July 2021) for longitudinal follow-up studies examining effect of symptoms of anxiety or depression on subsequent adverse outcomes in IBD, or effect of active IBD on subsequent development of symptoms of anxiety or depression. We pooled relative risks (RRs) and HRs with 95% CIs for adverse outcomes (flare, escalation of therapy, hospitalisation, emergency department attendance, surgery or a composite of any of these) according to presence of symptoms of anxiety or depression at baseline, or RRs and HRs with 95% CIs for new onset of symptoms of anxiety or depression according to presence of active IBD at baseline.ResultsWe included 12 separate studies, recruiting 9192 patients. All 12 studies examined brain-to-gut effects. Anxiety at baseline was associated with significantly higher risks of escalation of therapy (RR=1.68; 95% CI 1.18 to 2.40), hospitalisation (RR=1.72; 95% CI 1.01 to 2.95), emergency department attendance (RR=1.30; 95% CI 1.21 to 1.39), or a composite of any adverse outcome. Depression at baseline was associated with higher risks of flare (RR=1.60; 95% CI 1.21 to 2.12), escalation of therapy (RR=1.41; 95% CI 1.08 to 1.84), hospitalisation (RR=1.35; 95% CI 1.17 to 1.57), emergency department attendance (RR=1.38; 95% CI 1.22 to 1.56), surgery (RR=1.63; 95% CI 1.19 to 2.22) or a composite of any of these. Three studies examined gut-to-brain effects. Active disease at baseline was associated with future development of anxiety or depression (RR=2.24; 95% CI 1.25 to 4.01 and RR=1.49; 95% CI 1.11 to 1.98, respectively).ConclusionBidirectional effects of the brain–gut axis are present in IBD and may influence both the natural history of the disease and psychological health.

Carloni S., Bertocchi A., Mancinelli S., Bellini M., Erreni M., Borreca A., Braga D., Giugliano S., Mozzarelli A.M., Manganaro D., Fernandez Perez D., Colombo F., Di Sabatino A., Pasini D., Penna G., et. al.

Locking down access to the brain Inflammatory bowel disease is best known for intestinal symptoms but can also cause a variety of extraintestinal manifestations in other organs. It can also be associated with cognitive and psychiatric effects, including anxiety and depression. Using mouse models of intestinal inflammation, Carloni et al . uncovered a potential pathogenic link between these aspects of inflammatory bowel disease. The inflammatory process causes the gut vascular barrier to become more permeable, resulting in the spread of inflammation beyond the intestine, while the vascular barrier in the choroid plexus shuts down, helping protect the brain from inflammation but also potentially impairing communication between organs and impairing some brain functions. —YN

Barberio B., Zamani M., Black C.J., Savarino E.V., Ford A.C.

SummaryBackground Inflammatory bowel disease (IBD) is a lifelong condition with no cure. Patients with IBD might experience symptoms of common mental disorders such as anxiety and depression because of bidirectional communication via the gut–brain axis and chronicity of symptoms, and because of impaired quality of life and reduced social functioning. However, uncertainties remain about the magnitude of this problem. We aimed to assess prevalence of symptoms of anxiety or depression in adult patients with IBD. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, Embase Classic, and PsycINFO for papers published from inception to Sept 30, 2020, reporting observational studies that recruited at least 100 adult patients with IBD and that reported prevalence of symptoms of anxiety or depression according to validated screening instruments. We excluded studies that only used a structured interview to assess for these symptoms and studies that did not provide extractable data. We extracted data from published study reports and calculated pooled prevalences of symptoms of anxiety and depression, odds ratios (OR), and 95% CIs. Findings Of 5544 studies identified, 77 fulfilled the eligibility criteria, including 30 118 patients in total. Overall, pooled prevalence of anxiety symptoms was 32·1% (95% CI 28·3–36·0) in 58 studies (I2=96·9%) and pooled prevalence of depression symptoms was 25·2% (22·0–28·5) in 75 studies (I2=97·6%). In studies that reported prevalence of anxiety or depression in patients with Crohn's disease and ulcerative colitis within the same study population, patients with Crohn's disease had higher odds of anxiety symptoms (OR 1·2, 95% CI 1·1–1·4) and depression symptoms (1·2, 1·1–1·4) than patients with ulcerative colitis. Overall, women with IBD were more likely to have symptoms of anxiety than were men with IBD (pooled prevalence 33·8% [95% CI 26·5–41·5] for women vs 22·8% [18·7–27·2] for men; OR 1·7 [95% CI 1·2–2·3]). They were also more likely to have symptoms of depression than men were (pooled prevalence 21·2% [95% CI 15·4–27·6] for women vs 16·2% [12·6–20·3] for men; OR 1·3 [95% CI 1·0–1·8]). The prevalence of symptoms of anxiety (57·6% [95% CI 38·6–75·4]) or depression (38·9% [26·2–52·3]) was higher in patients with active IBD than in patients with inactive disease (38·1% [30·9–45·7] for anxiety symptoms and 24·2% [14·7–35·3] for depression symptoms; ORs 2·5 [95% CI 1·5–4·1] for anxiety and 3·1 [1·9–4·9] for depression). Interpretation There is a high prevalence of symptoms of anxiety and depression in patients with IBD, with up to a third of patients affected by anxiety symptoms and a quarter affected by depression symptoms. Prevalence was also increased in patients with active disease: half of these patients met criteria for anxiety symptoms and a third met criteria for depression symptoms. Encouraging gastroenterologists to screen for and treat these disorders might improve outcomes for patients with IBD. Funding None.

Ludvigsson J.F., Olén O., Larsson H., Halfvarson J., Almqvist C., Lichtenstein P., Butwicka A.

Abstract Background and Aims Inflammatory bowel disease [IBD] is linked to psychiatric morbidity, but few studies have assessed general population comparators. We aimed to investigate the risk of psychiatric morbidity and suicide in adult-onset IBD patients. Methods We used a nationwide population-based cohort study in Sweden [1973–2013]. We studied the risk of psychiatric disorders and suicide in 69,865 adult-onset IBD patients [ulcerative colitis, UC: n = 43,557; Crohn’s disease, CD: n = 21,245; and IBD-unclassified: n = 5063] compared to 3,472,913 general population references and 66 292 siblings. Results During a median follow-up of 11 years, we found 7465 [10.7%] first psychiatric disorders in IBD [incidence rate, IR/1000 person-years 8.4] and 306 911 [9.9%] in the general population [IR 6.6], resulting in 1.8 extra psychiatric morbidity per 100 patients followed-up for 10 years and a hazard ratio [HR] of 1.3 [95% confidence interval, 95%CI = 1.2–1.3]. The highest risk of overall psychiatric morbidity was seen in the first year after IBD diagnosis [HR = 1.4, 95%CI = 1.2–1.6] and in patients with extraintestinal manifestations [HR = 1.6, 95%CI = 1.5–1.7]. Psychiatric morbidity was more common in all IBD subtypes [HR 1.3–1.5]. An increased risk of suicide attempts was observed among all IBD types [HR = 1.2–1.4], whereas completed suicide was explicitly associated with CD [HR = 1.5] and elderly-onset [diagnosed at the age of > 60 years] IBD [HR = 1.7]. Conclusion Adult-onset IBD was associated with an increased risk of psychiatric disorders and suicide attempts. Psychological follow-up should be provided to patients with IBD, especially those with extraintestinal manifestations and elderly-onset IBD. This follow-up should be within the first year after IBD diagnosis.

Marrie R.A., Graff L.A., Fisk J.D., Patten S.B., Bernstein C.N.

Abstract Brackground We aimed to examine associations between elevated symptoms of depression and anxiety and disease activity in inflammatory bowel disease (IBD). Previous findings have been inconsistent and have not accounted for variability in the courses of these conditions over time. Methods We followed 247 participants with IBD (153 Crohn’s disease [CD], 94 ulcerative colitis [UC]) for 3 years. Annually, participants underwent an abdominal examination, reported therapies used for IBD, and completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. We evaluated associations of elevated symptoms (scores ≥11) of anxiety (HADS-A) and depression (HADS-D) with the presence of active IBD as measured using the Powell Tuck Index for UC and the Harvey-Bradshaw Disease Activity Index for CD. We employed logistic regression with generalized estimating equations, simultaneously estimating between-person and within-person effects. Results Of 247 participants, 15 (6.1%) had elevated symptoms of depression (HADS-D ≥11) at enrollment, 41 (16.6%) had elevated symptoms of anxiety (HADS-A ≥11), and 101 (40.9%) had active IBD. On average, individuals with elevated symptoms of depression (odds ratio [OR], 6.27; 95% CI, 1.39–28.2) and anxiety (OR, 2.17; 95% CI, 1.01–4.66) had increased odds of active IBD. Within individuals, elevations in symptoms of depression over time were associated with increased odds of active IBD (OR, 2.70; 95% CI, 1.15–6.34), but elevated symptoms of anxiety were not. After adjustment for covariates (including disease activity), elevated symptoms of depression were also associated with increased odds of biologic therapy use (OR, 2.02; 95% CI, 1.02–4.00). Conclusion Symptoms of depression and anxiety are associated with disease activity in IBD over time. Reducing these symptoms should be incorporated into the management of IBD.

Lores T., Goess C., Mikocka-Walus A., Collins K.L., Burke A.L., Chur-Hansen A., Delfabbro P., Andrews J.M.

Background & Aims Inflammatory bowel diseases (IBD) are associated with high psychosocial burden and economic cost. Integrating psychological care into routine management might lead to savings. We performed a 2-year investigation of the effects of integrated psychological care in reducing healthcare use and costs. Methods We performed a prospective study of 335 adult patients treated at a hospital-based IBD service in Australia. Participants were recruited between September 2015 and August 2016 and completed screening instruments to evaluate mental health and quality of life. Data on healthcare use and costs for the previous 12 months were also collected. Patients found to be at risk for mental health issues were offered psychological intervention. Patients were followed up 12 months after screening (between September 2016 and August 2017). Results A significantly higher proportion of subjects at risk for mental health issues had presented to an emergency department in the 12 months before screening (51/182; 28%) compared to psychologically healthy subjects (28/152; 18%; X2(1) = 4.23; P = .040). Higher levels of depression and general distress (but not anxiety) were related to increased odds of hospital admission (adjusted odds ratios, 1.07 and 1.05, respectively). Among the patients who accepted psychological intervention, the number who presented to emergency departments was reduced significantly in the 12 months after screening (follow-up) compared to the 12 months before screening (P = .047), resulting in a cost saving of AU$30,140 ($20,816 USD). A cost-benefit analysis of the integrated psychological care model revealed a net saving of AU$84,905 ($58,647 USD) over a 2-year period. Conclusions Risk for mental health issues is associated with higher healthcare costs in people with IBD. Providing integrated psychological care to individuals at risk for mental health issues can reduce costs, particularly by decreasing visits to emergency departments. Further studies are required to determine the best care to provide to reduce costs.

Marcondes Ávila P.R., Fiorot M., Michels M., Dominguini D., Abatti M., Vieira A., de Moura A.B., Behenck J.P., Borba L.A., Botelho M.E., Réus G.Z., Dal-Pizzol F., Ritter C.

• Fecal Microbiota Transplant regulate brain inflammation in the CMS paradigm. • Fecal Microbiota Transplant regulate behavioral changes in the CMS paradigm. • The vagus nerve could be a signaling pathway in the gut-brain axis. Currently, there is a growing emphasis on the study of intestinal signaling as an influencer in the pathophysiology of neuropsychiatric diseases, and the gut–brain axis is recognized as a communication route through endocrine, immune, and neural pathways (vagus nerve). Studies have shown that diets that modify the microbiota can reduce stress-related behavior and hypothalamic–pituitary–adrenal axis activation. Investigators have used fecal microbiota transplantation (FMT) approaches to demonstrate that stress-related microbiota composition plays a causal role in behavioral changes. We hypothesized that FMT may present immunomodulatory, biochemical, endocrine, cognitive, and behavioral benefits in stress situations and that these changes can be mediated via the vagus nerve. Animals were subjected to a chronic mild stress (CMS) protocol. In one experiment, animals were divided into five groups: control, control + FMT, control + FMT + CMS, CMS + saline, and CMS + FMT. The animals received FMT, and behavioral tests were performed; cytokine and carbonyl levels were measured. In a second experiment, animals were submitted to vagotomy and divided into two groups: CMS + FMT and CMS + vagotomy + FMT. Animals submitted to the CMS protocol or that received FMT from stressed animals showed behavioral changes and changes in neuroactive substances (increased IL-6 and TNF-α levels and carbonyl proteins). The FMT of healthy donors improved the analyzed parameters. In addition, vagotomy influenced beneficial FMT results, confirmed by behavioral testing and protein carbonyl in the hippocampus. Manipulation of the microbiota reversed the behavioral and biochemical changes induced by the CMS protocol, and the vagus nerve influenced the gut–brain axis response.

Blackwell J., Saxena S., Petersen I., Hotopf M., Creese H., Bottle A., Alexakis C., Pollok R.C.

ObjectiveDepression is a potential risk factor for developing IBD. This association may be related to GI symptoms occurring before diagnosis. We aimed to determine whether depression, adjusted for pre-existing GI symptoms, is associated with subsequent IBD.DesignWe conducted a nested case–control study using the Clinical Practice Research Datalink identifying incident cases of UC and Crohn’s disease (CD) from 1998 to 2016. Controls without IBD were matched for age and sex. We measured exposure to prevalent depression 4.5–5.5 years before IBD diagnosis. We created two sub-groups with prevalent depression based on whether individuals had reported GI symptoms before the onset of depression. We used conditional logistic regression to derive ORs for the risk of IBD depending on depression status.ResultsWe identified 10 829 UC cases, 4531 CD cases and 15 360 controls. There was an excess of prevalent depression 5 years before IBD diagnosis relative to controls (UC: 3.7% vs 2.7%, CD 3.7% vs 2.9%). Individuals with GI symptoms prior to the diagnosis of depression had increased adjusted risks of developing UC and CD compared with those without depression (UC: OR 1.47, 95% CI 1.21 to 1.79; CD: OR 1.41, 95% CI 1.04 to 1.92). Individuals with depression alone had similar risks of UC and CD to those without depression (UC: OR 1.13, 95% CI 0.99 to 1.29; CD: OR 1.12, 95% CI 0.91 to 1.38).ConclusionsDepression, in the absence of prior GI symptoms, is not associated with subsequent development of IBD. However, depression with GI symptoms should prompt investigation for IBD.

Morais L.H., Schreiber H.L., Mazmanian S.K.

In a striking display of trans-kingdom symbiosis, gut bacteria cooperate with their animal hosts to regulate the development and function of the immune, metabolic and nervous systems through dynamic bidirectional communication along the ‘gut–brain axis’. These processes may affect human health, as certain animal behaviours appear to correlate with the composition of gut bacteria, and disruptions in microbial communities have been implicated in several neurological disorders. Most insights about host–microbiota interactions come from animal models, which represent crucial tools for studying the various pathways linking the gut and the brain. However, there are complexities and manifest limitations inherent in translating complex human disease to reductionist animal models. In this Review, we discuss emerging and exciting evidence of intricate and crucial connections between the gut microbiota and the brain involving multiple biological systems, and possible contributions by the gut microbiota to neurological disorders. Continued advances from this frontier of biomedicine may lead to tangible impacts on human health. In this Review, Morais, Schreiber and Mazmanian discuss emerging and exciting evidence of intricate and potentially important connections between the gut microbiota and the brain involving multiple biological systems, and possible contributions by the gut microbiota to complex behaviours.

Thillard E., Gautier S., Babykina E., Carton L., Amad A., Bouzillé G., Beuscart J., Ficheur G., Chazard E.

Introduction: Infliximab (IFX) was the first anti-tumor necrosis factor (TNFα) antibody to be used in the treatment of severe chronic inflammatory diseases, such as Crohn’s disease and rheumatoid arthritis. A number of serious adverse drug reactions are known to be associated with IFX use; they include infections, malignancies, and injection site reactions. Although a few case reports have described potential psychiatric adverse events (including suicide attempts and manic episodes), the latter are barely mentioned in IFX’s summary of product characteristics. The objective of the present retrospective study was to detect potential psychiatric adverse events associated with IFX treatment by analyzing a national discharge abstract database. Materials and methods: We performed an historical cohort study by analyzing data from the French national hospital discharge abstract database (PMSI) between 2008 and 2014. All patients admitted with one of the five diseases treated with IFX were included. Results: Of the 325,319 patients included in the study, 7,600 had been treated with IFX. The proportion of hospital admissions for one or more psychiatric events was higher among IFX-exposed patients (750 out of 7,600; 9.87%) than among non-exposed patients (17,456 out of 317,719; 5.49%). After taking account of potential confounders in the cohort as a whole, a semi-parametric Cox regression analysis gave an overall hazard ratio (HR) [95% confidence interval] (CI) of 4.5 [3.95; 5.13] for a hospital admission with a psychiatric adverse event during treatment with IFX. The HR [95%CI] for a depressive disorder was 4.97 [7.35; 6.68]. Even higher risks were observed for certain pairs of adverse events and underlying pathologies: psychotic disorders in patients treated for ulcerative colitis (HR = 5.43 [2.01; 14.6]), manic episodes in patients treated for severe psoriasis (HR = 12.6 [4.65; 34.2]), and suicide attempts in patients treated for rheumatoid arthritis (HR = 4.45 [1.11; 17.9]). Discussion: The present retrospective, observational study confirmed that IFX treatment is associated with an elevated risk of psychiatric adverse events. Depending on the disease treated, physicians should be aware of these potential adverse events.

Mikocka-Walus A., Ford A.C., Drossman D.A.

Gut–brain dysregulation has been recognized by the scientific community as being crucial to the understanding of chronic gastrointestinal conditions, and this has translated into the practice of a newly established discipline, psychogastroenterology. Along with psychotherapy, antidepressants (a subtype of central neuromodulators) have been proposed as treatments for gut–brain disorders that might benefit both psychological and gastrointestinal health. Antidepressants have been found to be effective for the treatment of comorbid anxiety and depression, pain and impaired sleep. Although the efficacy of antidepressants is well established in disorders of gut–brain interaction (DGBI), evidence is only now emerging in IBD. This Perspective discusses the use of antidepressants in DGBI and IBD, focusing on how what we have learnt about the role of antidepressants in DGBI could be applied to help optimize the management of IBD. This Perspective discusses the use of antidepressants in disorders of gut–brain interaction (DGBI) and IBD, focusing on how what we have learnt about the role of antidepressants in DGBI could help optimize the management of IBD.

Frenkel S., Bernstein C.N., Sargent M., Jiang W., Kuang Q., Xu W., Hu P.

Recent studies discovered many genetic variants associated with both psychiatric and inflammatory disorders, but the role of genetic factors in the development of psychiatric comorbidity (PC) in inflammatory bowel disease (IBD) is underexplored. Particularly, it has been shown that some of the genetic variants have been linked to the concentrations of circulating cytokines and symptoms of the inflammatory cytokine-associated depression. We analysed genomic features of individuals with IBD by comparing IBD patients with PC with those who have IBD but without PC. We hypothesized that cytokine related signalling pathways may be significantly associated with the psychiatric comorbidity in patients with IBD. Individuals enrolled in the Manitoba IBD Cohort Study were separated to two groups accordingly to the presence of PC. A sample set comprising 97 IBD individuals with PC (IBD + PC) and 146 IBD individuals without PC (IBD) was first used to identify copy number variations (CNVs) from genome-wide genetic data using three different detection algorithms. IBD + PC and IBD groups were compared by the number of CNVs overlapping each gene; deletions and duplications were analysed separately. Gene set overrepresentation analysis was then conducted using CNV-overlapped genes and the candidate gene sets of neurological and immunological relevance. Medium-sized CNV (size between 100 and 500 kilobase pairs)-burden is significantly higher in IBD + PC than IBD groups. Gene-based CNV association analysis did not show significant differences between the two IBD groups. Gene set overrepresentation analysis demonstrated the significant enrichment of gene sets related to cytokine signalling pathways by the genes overlapped by deletions in the IBD individuals with PC. Our results confirm the role of cytokine signalling pathways in the development of PC in IBD. Additionally, our results warrant further study with a larger sample size focusing on cytokine SNPs to further understand the relationship between inflammatory and psychiatric disorders. • CNV analysis was performed in a cohort of 243 IBD sample with Caucasian ethnicity; • Medium-sized CNV burden is significantly higher in IBD patients with psychiatric comorbidity (PC) than those without PC; • Cytokine signalling pathways by deletions-overlapped genes are significantly overrepresented in the IBD patients with PC.

Butwicka A., Olén O., Larsson H., Halfvarson J., Almqvist C., Lichtenstein P., Serlachius E., Frisén L., Ludvigsson J.F.

Inflammatory bowel disease (IBD) has been associated with psychiatric morbidity in adults, although previous studies have not accounted for familial confounding. In children, IBD has an even more severe course, but the association between childhood-onset IBD and psychiatric morbidity remains unclear.To examine the risk of psychiatric morbidity in individuals with childhood-onset IBD, controlling for potential confounding shared between siblings.A population-based cohort study was conducted using data from the Swedish national health care and population registers of all children younger than 18 years born from 1973 to 2013. The study included 6464 individuals with a diagnosis of childhood-onset IBD (3228 with ulcerative colitis, 2536 with Crohn disease, and 700 with IBD unclassified) who were compared with 323 200 matched reference individuals from the general population and 6999 siblings of patients with IBD. Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% CIs. Statistical analysis was performed from January 1, 1973, to December 1, 2013.The primary outcome was any psychiatric disorder and suicide attempt. Secondary outcomes were the following specific psychiatric disorders: psychotic, mood, anxiety, eating, personality, and behavioral disorders; substance misuse; attention-deficit/hyperactivity disorder; autism spectrum disorders; and intellectual disability.The study included 6464 individuals with a diagnosis of childhood-onset IBD (2831 girls and 3633 boys; mean [SD] age at diagnosis of IBD, 13 [4] years). During a median follow-up time of 9 years, 1117 individuals with IBD (17.3%) received a diagnosis of any psychiatric disorder (incidence rate, 17.1 per 1000 person-years), compared with 38 044 of 323 200 individuals (11.8%) in the general population (incidence rate, 11.2 per 1000 person-years), corresponding to an HR of 1.6 (95% CI, 1.5-1.7), equaling 1 extra case of any psychiatric disorder per 170 person-years. Inflammatory bowel disease was significantly associated with suicide attempt (HR, 1.4; 95% CI, 1.2-1.7) as well as mood disorders (HR, 1.6; 95% CI, 1.4-1.7), anxiety disorders (HR, 1.9; 95% CI, 1.7-2.0) eating disorders (HR, 1.6; 95% CI, 1.3-2.0), personality disorders (HR, 1.4; 95% CI, 1.1-1.8), attention-deficit/hyperactivity disorder (HR, 1.2; 95% CI, 1.1-1.4), and autism spectrum disorders (HR, 1.4; 95% CI, 1.1-1.7) Results were similar for boys and girls. Hazard ratios for any psychiatric disorder were highest in the first year of follow-up but remained statistically significant after more than 5 years. Psychiatric disorders were particularly common for patients with very early-onset IBD (

Schirmer M., Garner A., Vlamakis H., Xavier R.J.

Perturbations in the intestinal microbiome are implicated in inflammatory bowel disease (IBD). Studies of treatment-naive patients have identified microbial taxa associated with disease course and treatment efficacy. To gain a mechanistic understanding of how the microbiome affects gastrointestinal health, we need to move from census to function. Bacteria, including those that adhere to epithelial cells as well as several Clostridium species, can alter differentiation of T helper 17 cells and regulatory T cells. Similarly, microbial products such as short-chain fatty acids and sphingolipids also influence immune responses. Metagenomics and culturomics have identified strains of Ruminococcus gnavus and adherent invasive Escherichia coli that are linked to IBD and gut inflammation. Integrated analysis of multiomics data, including metagenomics, metatranscriptomics and metabolomics, with measurements of host response and culturomics, have great potential in understanding the role of the microbiome in IBD. In this Review, we highlight current knowledge of gut microbial factors linked to IBD pathogenesis and discuss how multiomics data from large-scale population studies in health and disease have been used to identify specific microbial strains, transcriptional changes and metabolic alterations associated with IBD. Perturbations in the intestinal microbiome are implicated in inflammatory bowel disease (IBD). In this Review, Xavier and colleagues highlight current knowledge of gut microbial factors linked to IBD pathogenesis and discuss how multiomics data from large-scale population studies in health and disease have been used to identify specific microbial strains, transcriptional changes and metabolic alterations associated with IBD.

Lin H., Xiao Y., Liu Y., Lin X., Liu X.

Wang J., Hu Y., Cao Z.

Feng J., Cao W., Wang Z., Xu B., Li G., Li M.

Liu Y., Jiang X., Zhuang S., Zhu L., Zhu B., Rui K., Tian J.

Cao S., Guo X., Xin M., Wang X., Huo J., Yue Y., Li X., Xu D., Liu L.

Valvano M., Faenza S., Cortellini F., Vinci A., Ingravalle F., Calabrò M., Scurti L., Di Nezza M., Valerio S., Viscido A., Latella G.

Background and aim: Inflammatory bowel diseases (IBD) are chronic conditions that affect the gastrointestinal tract. The chronic inflammatory state promotes a catabolic environment that contributes to undernutrition, while mucosal damage often impairs nutrient absorption. The aim of this study is to evaluate the relationship between nutritional status—including micronutrient deficiencies—and clinical as well as laboratoristics disease activity in a cohort of patients with IBD. Methods: This is a cross-sectional study conducted across three care centers in Italy. Baseline data, clinical disease activity, and laboratory test results were collected. Micronutrient evaluation included measurements of iron, ferritin, vitamin B12, vitamin D, and folate. In addition, hemoglobin and albumin levels were assessed. Pearson correlation analysis was performed to explore the relationship between disease activity and nutritional status. Additionally, receiver operating characteristics (ROC) analysis were performed to identify patients with active diseases. Results: 110 IBD patients (40 Crohn Disease; 70 Ulcerative Colitis) were included. The serum level of Hb, iron, ferritin and vitamin D was different among the active and inactive group (p: 0.007; p: 0.001; p: 0.005; p: 0.003) while no difference was found among the other micronutrients evaluated (folic acid, vitamin B12) and albumin. Iron and vitamin D levels demonstrated the highest accuracy in the ROC analysis, with Area Under the Curve (AUC) of 0.76 (p < 0.001) and 0.68 (p = 0.013), respectively. Vitamin D and Ferritin showed the better performance (based on calprotectin levels). However, their AUC were sub-optimal (AUC 0.68; p < 0.001; AUC 0.66; p = 0.19. Conclusions: Hemoglobin, iron, ferritin, and vitamin D were associated with disease activity status. However, despite this correlation, their accuracy in discriminating between active and inactive disease appeared to be suboptimal. Folic acid, vitamin B12, and albumin showed poor concordance with disease activity status.

Lyu S., Zhong G., Shi R., Sun Y., Li J., Li M., Chen Y.

BACKGROUND Diamine oxidase (DAO) is secreted by epithelial cells in the intestinal villi, and its serum levels are elevated after intestinal mucosal damage. d-lactate (D-LA) is a gut microbial metabolite that can enter the systemic circulation if intestinal barrier function is impaired. Both DAO and D-LA are serum markers of small bowel mucosal integrity, and can be valuable biomarkers of intestinal barrier damage in inflammatory bowel disease (IBD). Intestinal barrier dysfunction was recently found to contribute to psychological symptoms in IBD patients. However, the correlations among DAO, D-LA, psychological symptoms, and disease activity in IBD remain unexplored. AIM To explore the correlations between serum markers of intestinal barrier dysfunction and psychological symptoms in IBD. METHODS We enrolled of 126 participants in this study. Psychological symptom questionnaires (depression, patient health questionnaire-9; anxiety, generalized anxiety disorder-7; and stress, perceived stress scale) and a quality of life (QOL) questionnaire (IBD questionnaire 32) were collected at the baseline. Serum DAO and D-LA levels were measured to assess intestinal barrier integrity. Receiver operating characteristic (ROC) curves were used to identify candidate markers of psychological symptoms and disease activity in IBD patients. Logistic regression was applied, with DAO as an independent variable for predicting psychological symptoms in IBD. RESULTS Serum DAO levels were significantly higher in IBD patients with moderate-to-severe psychological symptoms than in patients with mild or no psychological symptoms. DAO was positively correlated with depression and negatively correlated with QOL in IBD patients. ROC curves revealed that DAO was independently associated with psychological symptoms and clinical activity in patients with IBD. Additionally, logistic regression analysis revealed that each 1-ng/mL increase in DAO levels was significantly associated with an increased risk of psychological symptoms in IBD patients (OR: 1.019, 95%CI: 1.002-1.037). These results highlight the potential of DAO as a novel biomarker for both depression and disease activity in IBD patients. CONCLUSION This study indicates that DAO may be associated with depression and disease activity in IBD patients; however, prospective studies are required to validate its causal relationship.

Hu H., Su X., Dong Q., Yuan S., Ding S., Liu J., Xu B., Tu L., Liu X., Cao Y., Wang X., Yang G., Guo W., Fu S., Chao D.

Chaosheng Y., Haowen S., Jingjing R., Yuanyuan D., Wenhui D., Yingyue S., Yuzheng X.

Abstract Background Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disorder triggered by immune responses and genetic factors. Currently, there is no cure for IBD, and its etiology remains unclear. As a result, early detection and diagnosis of IBD pose significant challenges. Therefore, investigating biomarkers in peripheral blood is highly important, as they can assist doctors in the early identification and management of IBD. Methods We used a multichip joint analysis approach to explore the database thoroughly. On the basis of methods such as artificial neural networks (ANNs), machine learning techniques, and the SHAP model, we developed a diagnostic model for IBD. To select genetic features, we utilized three machine learning algorithms, namely, least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF), to identify differentially expressed genes. Additionally, we conducted an in-depth analysis of the enriched molecular pathways of these differentially expressed genes through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Moreover, we used the SHAP model to interpret the results of the machine learning process. Finally, we examined the relationships between the differentially expressed genes and immune cells. Results Through machine learning, we identified four crucial biomarkers for IBD, namely, LOC389023, DUOX2, LCN2, and DEFA6. The SHAP model was used to elucidate the contribution of the differentially expressed genes to the diagnostic model. These genes were associated primarily with immune system modulation and microbial alterations. GO and KEGG pathway enrichment analyses indicated that the differentially expressed genes demonstrated associations with molecular pathways such as the antimicrobial and IL-17 signaling pathways. By performing correlation and differential analyses between differentially expressed genes and immune cells, we found that M1 macrophages exhibited stable differential changes in all four differentially expressed genes. M2 macrophages, resting mast cells, neutrophils, and activated memory CD4 T cells all showed significant differences in three of the differentially expressed genes. Conclusion We identified differentially expressed genes (LOC389023, DUOX2, LCN2, and DEFA6) with significant immune-related effects in IBD. Our findings suggest that machine learning algorithms outperform ANNs in the diagnosis of IBD. This research provides a theoretical foundation for the clinical diagnosis, targeted therapy, and prognostic evaluation of IBD.

Shi W., Yang X.

Di Petrillo A., Favale A., Onali S., Kumar A., Abbracciavento G., Fantini M.C.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Although the aetiology of IBD remains largely unknown, several studies suggest that an individual’s genetic susceptibility, external environmental factors, intestinal microbial flora, and immune responses are all factors involved in and functionally linked to the pathogenesis of IBD. Beyond the gastrointestinal manifestations, IBD patients frequently suffer from psychiatric comorbidities, particularly depression and anxiety. It remains unclear whether these disorders arise solely from reduced quality of life or whether they share overlapping biological mechanisms with IBD. This review aims to explore the bidirectional relationship between IBD and depressive disorders (DDs), with a focus on four key shared mechanisms: immune dysregulation, genetic susceptibility, alterations in gut microbiota composition, and dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis. By examining recent literature, we highlight how these interconnected systems may contribute to both intestinal inflammation and mood disturbances. Furthermore, we discuss the reciprocal pharmacologic interactions between IBD and DDs: treatments for IBD, such as TNF-alpha and integrin inhibitors, have demonstrated effects on mood and anxiety symptoms, while certain antidepressants appear to exert independent anti-inflammatory properties, potentially reducing the risk or severity of IBD. Overall, this review underscores the need for a multidisciplinary approach to the care of IBD patients, integrating psychological and gastroenterological assessment. A better understanding of the shared pathophysiology may help refine therapeutic strategies and support the development of personalized, gut–brain-targeted interventions.

Hou J., Zhao M., Zou A., Zhu X., Fu R., Xianyu Y.

AbstractInflammatory bowel disease is chronic gastrointestinal disorder characterized by persistent intestinal inflammation, which can lead to severe complications such as impaired intestinal barrier function and dysbiosis. Conventional therapies have challenges such as oxidative stress and insufficient intestinal colonization that hinder the treatment efficacy. Therapeutic strategies based on micro‐nano robotic delivery are promising to address the limitations of current treatments by enabling precise targeting, enhancing bioavailability, and improving therapeutic outcomes. Herein, an orally administered micro‐nano robot is developed utilizing Spirulina platensis as a carrier for nanozyme‐armed probiotic Lactobacillus plantarum (SP@LP@AuCe) to enhance the efficacy of oral probiotics and nanomedicine in treating intestinal diseases. SP@LP@AuCe exhibits strong fluorescence imaging capability due to its chlorophyll‐rich content, allowing for non‐invasive and real‐time monitoring following oral administration. The helical structure of Spirulina platensis facilitates entrapment in intestinal villi that enhances intestinal retention. Importantly, SP@LP@AuCe scavenges reactive oxygen species and modulates inflammatory responses, thereby alleviating intestinal inflammation, improving bacterial viability, and restoring the balance of intestinal microbiota. This strategy integrates microalgae, probiotics, and nanozymes within a micro‐nano robotic framework, presenting a promising approach to enhancing drug bioavailability and exerting potent anti‐inflammatory effects in the treatment of intestinal diseases.

Zhang Y., Luo X., Zhou Y., Xue Q., Wu S., Xu J., Li G., Liu B., Zhang M., Tong G., Ao H., Liao M.

Li S., Zhou X., Yu S., Liu Z., Sun M., Si Z., Zhu W.

Chen C., Yu K., Hsu L., Chiu W., Hsu K.