Inflammatory Bowel Diseases (IBD) and the Microbiome—Searching the Crime Scene for Clues

Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

Inflammatory bowel disease in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

The pathogenesis of inflammatory bowel disease (IBD) is not well-understood; however, increased and persistent intestinal inflammation, due to inappropriate immune responses that are caused by interactions between genetic factors, gut microbiota, and environmental factors, are thought to lead to IBD. Various studies have identified more than 240 genetic variants related to IBD. These genetic variants are involved in innate and adaptive immunity, autophagy, defective bacterial handing, interleukin-23 and 10 signaling, and so on. According to several epidemiological and clinical studies, the phenotypes and clinical course of IBD differ between Asians and Europeans. Although the risk loci for IBD typically overlap between Asians and Westerners, genetic heterogeneity has been detected in many loci/genes, such as NOD2/CARD15, TNFSF15 and human leukocyte antigen, contributing to the risk of IBD. Thus, although common pathways exist between Westerners and Asians in the development of IBD, their significance may differ for individual pathways. Although genetic studies are not universally applicable in the clinical field, they may be useful for diagnosing and categorizing IBD, predicting therapeutic responses and toxicity to drugs, and assessing prognosis by risk modeling, thereby enabling precision medicine for individual patients.

We read with great interest the comprehensive review study of Mouli and Ananthakrishnan.1 The authors have evaluated and discussed current evidence regarding the roles of vitamin D deficiency in the pathogenesis and progression of inflammatory bowel disease (IBD). In this regard, different cellular and molecular mechanisms are discussed in this review. However, as mentioned by the authors, there is a strong role for environmental factors in the pathogenesis and progression of IBD. There is growing evidence that psychological factors, including psychological stress and depression, are influential in the pathogenesis and clinical course of IBD.2, 3 Growing evidence also indicates the importance of sleep disorders in the clinical course of IBD. It has been shown that sleep disturbance increases the risk of disease flares in patients.4-6 It is therefore interesting that vitamin D deficiency has been shown to play a role in both psychological7 and sleep disorders8 in non-IBD populations, although the underlying mechanisms are still unknown. There is no study till now evaluating the effects of vitamin D deficiency on psychological health or sleep quality in IBD patients. Although several factors can affect psychological health and sleep quality in IBD patients including demographic- and disease-related factors,2, 4 a role for vitamin D deficiency is also plausible. Therefore, the ‘optimal role of vitamin D supplementation as a therapeutic modality in patients with IBD’ is not only the induction and maintenance of remission as mentioned by Mouli and Ananthakrishnan1 but may also include treatment of psychological and sleep disorders in IBD patients. These issues should be added to the remaining unanswered questions regarding the role of vitamin D in IBD, and warrant evaluation in future studies. Declaration of personal and funding interests: None.

LINKED CONTENTThis article is linked to Oh et al papers. To view these articles, visit https://doi.org/10.1111/apt.17542 and https://doi.org/10.1111/apt.17608

Background/AimsLittle is known about the clinical course of hepatitis B virus (HBV)-infected patients undergoing anti-tumor necrosis factor α (TNF-α) therapy for inflammatory bowel disease (IBD). We aimed to investigate the clinical course of HBV infection and IBD and to analyze liver dysfunction risks in patients undergoing anti-TNF-α therapy.MethodsThis retrospective multinational study involved multiple centers in Korea, China, Taiwan, and Japan. We enrolled IBD patients with chronic or resolved HBV infection, who received anti-TNF-α therapy. The patients’ medical records were reviewed, and data were collected using a web-based case report form.ResultsOverall, 191 patients (77 ulcerative colitis and 114 Crohn’s disease) were included, 28.3% of whom received prophylactic antivirals. During a median follow-up duration of 32.4 months, 7.3% of patients experienced liver dysfunction due to HBV reactivation. Among patients with chronic HBV infection, the proportion experiencing liver dysfunction was significantly higher in the non-prophylaxis group (26% vs 8%, p=0.02). Liver dysfunction occurred in one patient with resolved HBV infection. Antiviral prophylaxis was independently associated with an 84% reduction in liver dysfunction risk in patients with chronic HBV infection (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.66; p=0.01). The clinical course of IBD was not associated with liver dysfunction or the administration of antiviral prophylaxis.ConclusionsLiver dysfunction due to HBV reactivation can occur in HBV-infected IBD patients treated with anti-TNF-α agents. Careful monitoring is needed in these patients, and antivirals should be administered, especially to those with chronic HBV infection.

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.

Inflammatory Bowel Disease: An Update on the Fundamental Biology and Clinical Management

A role for the appendix in inflammatory bowel disease? cut it out

Inflammatory bowel disease (IBD) is associated with chronic inflammation and increased malignancy risk; however, data on the effects of cancer therapies on the clinical course of IBD are limited. We evaluated the effects of cancer therapies on IBD activity and oncologic outcomes. This single-center, retrospective study was conducted at a tertiary care cancer center and included patients with IBD and malignancy who received cancer therapy 2015-2023. Patient characteristics and comparisons between patients who did and did not develop gastrointestinal adverse events (GI AEs) related to cancer therapy are presented. The cohort included 1153 patients, predominantly white (85.3%) and female (51.6%). GI AEs occurred in 296 (25.7%) patients. Those who developed GI AEs had more hematologic malignancies (21.6 vs. 14.6%; P = 0.005), stage III-IV cancer (55.1 vs. 45.6%; P < 0.0001), immune checkpoint inhibitor (ICI) use (19.6 vs. 10.7%; P < 0.0001) and active baseline IBD status before cancer therapy (20.0 vs. 14.5%; P = 0.025). Stage III-IV disease (hazard ratio: 2.9, P < 0.0001), GI AEs (hazard ratio: 1.3, P = 0.008), GI AE-related hospitalization (hazard ratio: 2.1, P < 0.0001), and ICI (hazard ratio: 2.0, P < 0.0001) were associated with decreased survival. Concurrent management of IBD and cancer poses clinical challenges, particularly with the higher risk of GI AEs (25.7%) that is associated with active baseline IBD status and ICI use. These interactions may compromise treatment and survival. Further research is warranted to clarify the long-term impact of cancer therapies on IBD progression and outcomes.

Background Chronic inflammatory bowel diseases (IBD) are persistent conditions characterized by alternating phases of flare-ups and remissions, ranging from mild exacerbations to severe cases, such as those in ulcerative colitis (UC), which may require colectomy and significantly affect patients’ functional and vital outcomes. Over time, several predictive markers, particularly in Crohn’s disease (CD), have been identified at diagnosis. This raises an essential question: could hypoalbuminemia be considered a prognostic factor in the clinical course of IBD? Methods This retrospective descriptive and analytical study spanned 5 years and 2 months (January 2018 to March 2023) and included all IBD patients monitored in our department. Data analysis was conducted using SPSS, with chi-square tests and multivariate logistic regression employed to evaluate relationships Results 302 IBD patients were analyzed, with a mean age of 40.7 years and a female predominance ( sex ratio = 0.7).165 had Crohn’s disease (CD), and 143 had ulcerative colitis (UC), categorized as pancolitis (61 cases), UC E2 (46 cases), and UC E1 (30 cases). In the CD cohort, 30% (50 patients) underwent ileocecal resection. Smoking and alcoholism were reported in 14.9% and 6.6% of cases, respectively, while NSAID and PPI use were noted in 11.5% and 3.3%. Additionally, 8.6% reported phytotherapy use. Hypoalbuminemia was defined as serum albumin ≤35 mg/L, with 32% (97 patients) meeting this criterion. Patients with hypoalbuminemia were treatment-naïve and had serum albumin levels assessed at diagnosis, with follow-up for at least one year. Key findings included • Steroid Use: 78.35% of hypoalbuminemic patients required at least two courses of corticosteroids, compared to 12.68% with normal albumin levels (P=0.003). • Thiopurines and Anti-TNF: Thiopurines were used in 81% of hypoalbuminemic patients vs. 45.8% (P=0.001), and anti-TNF therapy in 42.2% vs. 16.58% (P=0.006). • Colectomy: Rates were higher in hypoalbuminemic patients (17.52%) compared to those with normal albumin (0.4%, P=0.009). • Anemia: Observed in 92.78% of hypoalbuminemic cases vs. 18.53% with normal albumin levels (P=0.001). Notably, only 7.2% of hypoalbuminemic patients were treated with combined oral and rectal 5-ASA, achieving sustained clinical and endoscopic remission over three years. Conclusion In conclusion, our study highlights hypoalbuminemia as a critical prognostic marker in the progression of IBD. Assessing albumin levels at diagnosis, particularly in UC, provides valuable insight for identifying patients at higher risk of severe disease, guiding the need for intensified treatment and closer follow-up. This reinforces the importance of early, comprehensive evaluation in optimizing IBD management strategies

To the Editors, We read the report from Dr. Veloso titled, “Are Ulcerative Colitis and Diverticulitis Collected by the Same Hub?” with great interest. This is an interesting case that shares a similar clinical experience of developing de novo inflammatory bowel disease (IBD) after diverticulitis in a young patient. The described patient had an episode of complicated diverticulitis requiring surgical intervention. Seven years later, he developed ulcerative proctitis, which later progressed to symptomatic distal colitis. The current treatments for inflammatory bowel disease focus on mitigating the sequela of chronic inflammation; however, there remains a knowledge gap of complex environmental factors coupled with genetic susceptibility that interplays in the pathogenesis of IBD. There has been an increasing incidence of IBD and diverticulitis among the younger population in industrialized countries, suggesting shared environmental factors in the pathogenesis of these 2 clinical entities. Reduced dietary fiber intake, processed food, break-in mucosal integrity, and possible antibiotic exposure as part of complicated diverticulitis treatment contribute to gut microbiota dysbiosis and intestinal inflammation.1,2 Although our study did not include smoking cessation as one of the risk factors, multiple studies have shown that former smokers have a significantly high risk of ulcerative colitis development.3,4 Therefore, it is conceivable that smoking cessation could be one of the environmental determinants for IBD. As opposed to our study in which most patients had ulcerative pancolitis with some patients requiring biologics and surgical intervention, the presented case had distal colitis controlled with 5-ASA regimen. Still, it should be pointed out that ulcerative colitis has a relapsing and remitting course with nonexistent data on the long-term clinical course of IBD in patients who had a prior episode of complicated diverticulitis.5 We believe that with the evidence of growing literature, such as the case presented by Veloso et al, more extensive prospective studies with extended follow-up data and microbiome analysis would help to understand the risk factors and pathogenesis of IBD development after episodes of complicated diverticulitis. Identifying individuals at high risk for IBD development potentially allows close monitoring and early intervention to check disease progression.

Insights into the Pathogenesis of Inflammatory Bowel Diseases: Genetics and Microbiota Abstract. An inadequate immune response against bacteria of the gastrointestinal tract is the basic mechanism mediating the pathophysiology of inflammatory bowel diseases (IBD). The risk of IBD is partially heritable and approximately 12 % of patients have a family history of IBD. Large genome-wide association studies (GWAS) were able to identify 240 genetic regions associated with IBD. Many of the implicated genes have a function in the immune system, are associated with primary immunodeficiencies or the defense against mycobacteria. Together these 240 genetic regions form an excellent framework for further investigations into the pathogenesis and therapy of IBD. However, GWAS so far were able to unravel only a fraction of the genetic IBD risk. New strategies like genome wide sequencing are currently used to identify additional (rare) genetic variants. In rare cases, IBD is also inherited as a monogenetic disease. Moreover, there likely is significant interaction between genes and environmental factors which can only be unraveled if both, genes and the environment are simultaneously considered. Interestingly, the information provided by genetic risk factors for IBD is unable to predict the clinical course of IBD. New GWAS therefore focus on IBD prognosis and first insights have already been made. The gastrointestinal tract harbors a huge number of microorganisms (microbiota). It remains an enormous challenge for the immune system to contain this bacterial load while enabling the host to benefit from the many essential contributions of the microbiota. In IBD, the microbiota is altered to a dysfunctional (dysbiotic) state showing reduced diversity and a higher amount of potential pathogenic Proteobacteriae, such as Escherichia coli. In IBD, the microbiota is also more dynamic in its composition over time compared to health. Further, IBD dysbiosis is more pronounced in Crohn's disease than in ulcerative colitis. In animal experiments, dysbiosis could be transferred by fecal microbiota transplantation from one mouse to another, triggering inflammation in the recipient. In contrast, a healthy microbiota can downregulate the immune response of the host, for instance by bacterial short chain fatty acids (SCFA) synthesis. In addition, some bacteria with close physical contact to the intestinal wall also have specific immunosuppressive properties. So far, the highly complex network of microbiota, genetics, immune system and environment is only partially understood. The microbiota is a potential therapeutic target which up to now can only be non-specifically influenced by antibiotics, probiotics, prebiotics or fecal microbiota transplantation. A better understanding of the microbiota will likely yield in the discovery of new therapeutic options in the future.

ABSTRACTBackground: The incidence and prevalence of disorders such as obesity, metabolic syndrome (MS), and inflammatory bowel disease (IBD) have increased over recent decades. MS is a complex condition represented by a cluster of cardiovascular risk factors with a multifactorial origin-including genetic, behavioral, dietary factors, and alterations in gut microbiota. IBD reflects a complex and heterogeneous immune-mediated condition that typically, though not exclusively, affects the intestine. Objective: To evaluate the impact of obesity on the clinical course of IBD in a cohort of patients followed at a referral center for IBD. Methods: This was a retrospective longitudinal observational cohort study including patients of both sexes and all ethnicities, followed at the Inflammatory Bowel Disease Referral Center of the University Hospital of the Federal University of Juiz de Fora, between January 2019 and August 2023. A total of 404 adults aged 18 to 80 years with a diagnosis of IBD-established by clinical, endoscopic/histological, and/or imaging criteria-were included. IBD cases were classified as either Crohn’s disease (CD) or ulcerative colitis (UC). To assess DII annual activity, electronic medical records were reviewed for outpatient visits and hospitalizations from 2019 to 2023. CD was considered active when the Harvey-Bradshaw Index (HBI) was ≥5, and UC was considered active when the total Mayo score was ≥3 or the partial Mayo score was ≥2. Results: The mean age at IBD diagnosis was 37.79±13.44 years, with an average disease duration of 12.50±8.3 years. Biologic therapy was used in the majority of patients (58.4%), with treatment failure occurring in 56.8% of these cases during the study period. No statistically significant differences were observed in most outcomes, except for a higher frequency of biologic use in non-obese patients with CD (P=0.028). There was a trend toward a greater number of years with active disease in obese patients with CD (P=0.062). Conclusion: IBD patients with obesity were predominantly female. Among those with CD, the phenotype was mainly non-stricturing, non-penetrating, with a clinical course characterized by greater disease activity over time, suggesting that obesity may be an unfavorable factor for disease control. This trend was not observed among patients with UC.

East Meets West: The Increasing Incidence of Inflammatory Bowel Disease in Asia as a Paradigm for Environmental Effects on the Pathogenesis of Immune-Mediated Disease