Etiology Of Inflammatory Bowel Disease Research Articles

Role of Environmental Risk Factors in the Etiology of Inflammatory Bowel Diseases: A Multicenter Study.

The increasing global incidence and prevalence of inflammatory bowel disease (IBD) necessitates an investigation into the potential influence of environmental risk factors on its origin. This multicenter case-control study aimed to investigate potential environmental risk factors contributing to IBD development in Turkey. The study included 156 Crohn's disease (CD), 277 ulcerative colitis (UC) patients, and 468 controls (matched for age and gender) from six hospitals' gastroenterology departments. Data collection relied on the International Organization of IBD's questionnaire on environmental factors. Each environmental factor was initially analyzed using univariate and subsequently multivariate logistic regression models. In the multivariate model, regular coffee consumption was associated with decreased odds for both CD (OR 0.28; 95% CI 0.14-0.55) and UC (OR 0.25; 95% CI 0.15-0.42). Stress was associated with UC (OR 3.27; 95% CI 1.76-6.10) and CD (OR 4.40; 95% CI 2.12-9.10) development. A history of childhood infectious diseases (gastroenteritis, upper respiratory tract infections, etc.) raised the odds for both CD (OR 9.45; 95% CI 2.51-35.6) and UC (OR 7.56; 95% CI 1.57-36.4). Conversely, consuming well/spring water (OR 0.22; 95% CI 0.10-0.50) and childhood antibiotic use (OR 0.41; 95% CI 0.18-0.93) showed a positive association against UC. Increased consumption of refined sugar and industrial food products emerged as risk factors for IBD. Smoking increased the risk for CD (OR 2.38; 95% CI 1.16-4.91), while ex-smoking increased the risk for UC (OR 3.16; 95% CI 1.19-8.37). This study represents the first multicenter case-control study in Turkey examining the effects of environmental factors on IBD. It revealed that coffee consumption is positively associated, while stress and childhood infection-related diseases are risk factors. These findings, which are not supported by other studies, provide insight into the relationships between these factors and IBD.

Association between 23 drugs and inflammatory bowel disease: a two-sample Mendelian randomization study.

Inflammatory bowel disease (IBD) is a group of diseases characterized by chronic and recurrent inflammation of the gastrointestinal tract. The etiology of IBD remains multifaceted and poorly understood, resulting in limited treatment options that primarily target disease induction and remission maintenance. Thus, the exploration of novel therapeutic options for IBD among existing medications is advantageous. Mendelian randomization analysis (MR) serves as a valuable tool in investigating the relationship between drugs and diseases. In this study, MR analysis was employed to investigate the potential causal relationship between 23 approved drugs for the treatment of various diseases and IBD. We performed a two-sample MR analysis using publicly available genome-wide association study (GWAS) statistics. The inverse variance weighting (IVW) method was used as the main analysis method, supplemented by the remaining four methods (weighted median, MR Egger regression, simple and weighted models), and Meta-analysis was performed to expand the sample size to obtain a more reliable composite causal effect. Finally, Cochran's Q statistic and the MR-Egger test for directed pleiotropy were applied to determine whether significant heterogeneity or directed pleiotropy existed. In the main MR analysis (IVW), drugs with a negative causal association with the risk of IBD were immunosuppressant {OR (95% CI) = 0.7389 [0.6311-0.8651], p = 0.0046} and diabetes drugs {OR (95% CI) = 0.9266 [0.8876-0.9674], p = 0.0058}. A positive causal association with the risk of IBD was found for salicylic acid and derivatives {OR (95% CI) = 1.2737 [1.0778-1.5053], p = 0.0345}. Negative causal associations with UC risk were identified for immunosuppressants {OR (95% CI) = 0.6660 [0.5133-0.8640], p = 0.0169} and diabetes medications {OR (95% CI) = 0.9020 [0.8508-0.9551], p = 0.0046}; positive causal associations with UC risk were found for β-receptor blockers {OR (95% CI) = 1.1893 [1.0823-1.3070], p = 0.0046}. A negative causal association with the risk of CD was found for immunosuppressants {OR (95% CI) = 0.6957 [0.5803-0.8341], p = 0.0023}. There was no statistically significant association between the remaining 19 drugs and IBD and subtypes. This MR study provides evidence suggesting that immunosuppressants have a mitigating effect on the risk of IBD and demonstrate consistent efficacy in subtypes of ulcerative colitis (UC) and Crohn's disease (CD). Additionally, diabetes medications show potential in reducing the risk of IBD, particularly in cases of UC, while β-blockers may elevate the risk of UC. Conversely, salicylic acid and its derivatives may increase the risk of IBD, although this effect is not consistently observed in the subtypes of the disease. These findings offer new insights into the prevention and management of IBD.

Exploring the Gut Microbiome's Role in Inflammatory Bowel Disease: Insights and Interventions.

Inflammatory Bowel Disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and relapsing inflammatory condition of the intestine that significantly impairs quality of life and imposes a heavy burden on healthcare systems globally. While the exact etiology of IBD is unclear, it is influenced by genetic, environmental, immunological, and microbial factors. Recent advances highlight the gut microbiome's pivotal role in IBD pathogenesis. The microbial dysbiosis characteristic of IBD, marked by a decline in beneficial bacteria and an increase in pathogenic microbes, suggests a profound connection between microbial imbalance and disease mechanisms. This review explores diagnostic approaches to IBD that integrate clinical assessment with advanced microbiological analyses, highlighting the potential of microbiome profiling as a non-invasive diagnostic tool. In addition, it evaluates conventional and emerging treatments and discusses microbiome-targeted intervention prospects, such as probiotics, symbiotics, and faecal microbiota transplantation. The necessity for future research to establish their efficacy and safety is emphasised.

Epithelial Skiv2l deletion promotes aberrant secretory cell differentiation in the small intestine

Background: Inflammatory bowel disease (IBD) remains a global concern, with millions affected and incidence increasing. The etiology of IBD is multifaceted, but gene variants in epithelial and immune cells can contribute to its onset. Trichohepatoenteric syndrome (THES) is a form of monogenic very early onset IBD (VEO-IBD) that arises due to variants in SKIV2L and TTC37, which are components of the cytoplasmic RNA exosome involved in mRNA quality control. Patients with THES experience a decreased quality of life characterized by poor growth, intractable diarrhea, and immune defects. There are limited drugs approved by the FDA for treatment of IBD in children and those that have been approved are geared towards suppressing the immune system and have side effects. Therefore, there is a need for the development of therapeutics that target epithelial regeneration and repair. Understanding how genetic variants, such as those observed in THES, are involved in epithelial function is one avenue to improved therapies. The objective of the current study is to understand how the RNA exosome contributes to intestinal epithelial homeostasis by studying deletion of SKIV2L. Preclinical studies in mice revealed that global Skiv2l deletion resulted in increased mTOR signaling, and overactivated T cells, while B cell specific deletion of Skiv2l led to impaired B cell development. Ex vivo studies from our lab revealed that colonoids from THES patients exhibit decreased organoid formation effciency (OFE), suggesting that SKIV2L may have important roles in the intestinal stem cell self-renewal. We hypothesize that SKIV2L is required for intestinal epithelial cell growth and tissue function. Methods: We generated VillinCre;Skiv2l ( Skiv2l KO) mice with Skiv2l deletion in intestinal epithelial cells. Skiv2l WT and KO mice weights were monitored weekly, starting from ~2 weeks of age. Between 4 and 6 weeks of age, intestines were harvested for immunofluorescence, flow cytometry and OFE assays. Results and conclusion: Skiv2l KO mice experienced failure to thrive, were significantly smaller, and had shorter colons and small intestines compared to their WT counterparts. Immunofluorescence and flow cytometry revealed increased secretory cells in the small intestine of Skiv2l KO compared to WT mice, with significant accumulation of goblet cells in the crypt region in KO mice. Furthermore, Skiv2l KO mice had reduced OFE. These findings suggest that SKIV2L is essential for intestinal homeostasis and that aberrant secretory cell differentiation may underlie the decreased stem cell self-renewal observed in Skiv2l KO mice and THES patients. More broadly, these studies suggest an essential role for mRNA quality control in normal intestinal homeostasis. University of Pennsylvania, Institution of Regenerative Medicine; NIH R01DK124369. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Origin and Function of Monocytes in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disease resulting from the interaction of various factors such as social elements, autoimmunity, genetics, and gut microbiota. Alarmingly, recent epidemiological data points to a surging incidence of IBD, underscoring an urgent imperative: to delineate the intricate mechanisms driving its onset. Such insights are paramount, not only for enhancing our comprehension of IBD pathogenesis but also for refining diagnostic and therapeutic paradigms. Monocytes, significant immune cells derived from the bone marrow, serve as precursors to macrophages (Mφs) and dendritic cells (DCs) in the inflammatory response of IBD. Within the IBD milieu, their role is twofold. On the one hand, monocytes are instrumental in precipitating the disease's progression. On the other hand, their differentiated offsprings, namely moMφs and moDCs, are conspicuously mobilized at inflammatory foci, manifesting either pro-inflammatory or anti-inflammatory actions. The phenotypic spectrum of these effector cells, intriguingly, is modulated by variables such as host genetics and the subtleties of the prevailing inflammatory microenvironment. Notwithstanding their significance, a palpable dearth exists in the literature concerning the roles and mechanisms of monocytes in IBD pathogenesis. This review endeavors to bridge this knowledge gap. It offers an exhaustive exploration of monocytes' origin, their developmental trajectory, and their differentiation dynamics during IBD. Furthermore, it delves into the functional ramifications of monocytes and their differentiated progenies throughout IBD's course. Through this lens, we aspire to furnish novel perspectives into IBD's etiology and potential therapeutic strategies.

Dissecting the respective roles of microbiota and host genetics in the susceptibility of Card9−/− mice to colitis

BackgroundThe etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown.ResultsCard9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3β and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups’ own genotype.ConclusionsThese results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or “healthy” microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.-8ZHpF322gum1G2x3b5GvyVideo

Research advancements and perspectives of inflammatory bowel disease: A comprehensive review.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease with increasing incidence, such as Crohn's disease and ulcerative colitis. The accurate etiology and pathogenesis of IBD remain unclear, and it is generally believed that it is related to genetic susceptibility, gut microbiota, environmental factors, immunological abnormalities, and potentially other factors. Currently, the mainstream therapeutic drugs are amino salicylic acid agents, corticosteroids, immunomodulators, and biological agents, but the remission rates do not surpass 30-60% of patients in a real-life setting. As a consequence, there are many studies focusing on emerging drugs and bioactive ingredients that have higher efficacy and long-term safety for achieving complete deep healing. This article begins with a review of the latest, systematic, and credible summaries of the pathogenesis of IBD. In addition, we provide a summary of the current treatments and drugs for IBD. Finally, we focus on the therapeutic effects of emerging drugs such as microRNAs and lncRNAs, nanoparticles-mediated drugs and natural products on IBD and their mechanisms of action.

Akkermansia muciniphila and Parabacteroides distasonis synergistically protect from colitis by promoting ILC3 in the gut.

The contribution of the gut microbiome to the balance between homeostasis and inflammation is widely known. Nevertheless, the etiology of inflammatory bowel disease, which is known to be influenced by genetics, immune response, and environmental cues, remains unclear. Unlocking novel players involved in the dictation of a protective gut, namely, in the microbiota component, is therefore crucial to develop novel strategies to tackle IBD. Herein, we revealed a synergistic interaction between two commensal bacterial strains, Akkermansia muciniphila and Parabacteroides distasonis, which induce protection against both acute and chronic models of colitis induction, by enhancing epithelial barrier integrity and promoting group 3 innate lymphoid cells in the colonic mucosa. This study provides a novel insight on how commensal bacteria can beneficially act to promote intestinal homeostasis, which may open new avenues toward the use of microbiome-derived strategies to tackle IBD.

The Multiple Roles of Heat Shock Proteins in the Development of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), a chronic inflammatory condition of the human intestine, comprises Crohn's Disease (CD) and Ulcerative Colitis (UC). IBD causes severe gastrointestinal symptoms and increases the risk of developing colorectal carcinoma. Although the etiology of IBD remains ambiguous, complex interactions between genetic predisposition, microbiota, epithelial barrier, and immune factors have been implicated. The disruption of intestinal homeostasis is a cardinal characteristic of IBD. Patients with IBD exhibit intestinal microbiota dysbiosis, impaired epithelial tight junctions, and immune dysregulation; however, the relationship between them is not completely understood. As the largest body surface is exposed to the external environment, the gastrointestinal tract epithelium is continuously subjected to environmental and endogenous stressors that can disrupt cellular homeostasis and survival. Heat shock proteins (HSPs) are endogenous factors that play crucial roles in various physiological processes, such as maintaining intestinal homeostasis and influencing IBD progression. Specifically, HSPs share an intricate association with microbes, intestinal epithelium, and the immune system. In this review, we aim to elucidate the impact of HSPs on IBD development by examining their involvement in the interactions between the intestinal microbiota, epithelial barrier, and immune system. The recent clinical and animal models and cellular research delineating the relationship between HSPs and IBD are summarized. Additionally, new perspectives on IBD treatment approaches have been proposed.

Diagnostic criteria and case definitions for abdominal angiostrongyliasis: a systematic review from the Brazilian experience.

Although rare, Angiostrongylus costaricensis infection may be a more prevalent etiology of inflammatory bowel disease than ulcerative colitis and Chron's disease in endemic areas in Central and South America. The present study reviewed the occurrence of A. costaricensis in Brazil, its clinical presentation and pathology; and proposed diagnostic criteria and case definitions for abdominal angiostrongyliasis (AA). Southern and southeastern Brazilian regions are the main endemic areas, and AA affects both genders and all age groups. A review of all 23 published reports of 51 Brazilian patients highlighted the following features that were subsequently classified as minor diagnostic criteria: abdominal pain, palpable mass in the right lower abdominal quadrant, history of exposure, ileocecal tumor, and intestinal perforation with wall thickening. Proposed major criteria include right lower quadrant abdominal pain, blood eosinophilia, positive serology (antibody detection), intense eosinophilic infiltration that involves all strata of the intestinal wall, eosinophilic granulomatous reaction, and eosinophilic vasculitis. In addition to the definitions of suspected and possible cases according to increasing strength of evidence of this infection, demonstration of worms/eggs/larvae in tissues or Angiostrongylus DNA in tissues or serum are required for a confirmed diagnosis. The application of the proposed criteria and definitions may improve patient management, epidemiologic surveillance, and identification of new endemic areas.

Categorization of the effects of E. coli LF82 and mutants lacking the chuT and shuU genes on survival, the transcriptome, and metabolome in germ-free honeybee.

The precise etiology of inflammatory bowel diseases (IBDs) remains elusive. The Escherichia coli strain LF82 (LF82) is known to be associated with IBD, and we hypothesized that this association may be related to the chuT and shuU genes. Here we constructed a germ-free (GF) honeybee model to investigate the effects of LF82 chuT and shuU genes on the honeybee intestine and their mechanisms. The chuT and shuU gene deletion strains LF82∆chuT and LF82∆shuU were generated by CRISPR-Cas9. These strains, together with nonpathogenic E. coli MG1655 (MG1655) and wildtype LF82, were allowed to colonize the guts of GF honeybees to establish single bacterial colonization models. Intestinal permeability was assessed following the administration of a sterile Brilliant Blue (FCF) solution. Comprehensive transcriptomic and metabolomic analyses of intestinal samples indicated that MG1655 had few disadvantageous effects on honeybees. Conversely, colonization with LF82 and its gene-deletion mutants provoked pronounced activation of genes associated with innate immune pathways, stimulated defensive responses, and induced expression of genes associated with inflammation, oxidative stress, and glycosaminoglycan degradation. Crucially, the LF82∆chuT and LF82∆shuU strains perturbed host heme and iron regulation, as well as tryptophan metabolism. These findings suggest that the deletion of chuT and shuU genes in E. coli LF82 may alleviate intestinal inflammation by partially modulating tryptophan catabolism. Our study proposes that targeting iron uptake mechanisms could be a potential strategy to mitigate the virulence of IBD-associated bacteria.

A185 A GUT MICROBIOME TRANSITION: THE JOURNEY FROM INDIA TO CANADA

Abstract Background Young Indian immigrants and Indo-Canadians face a significantly higher risk of inflammatory bowel disease (IBD) in westernized countries. While the etiology of IBD remains unclear, a gut microbiome that is no longer symbiotic with its host is a key player. However, Indians are underrepresented in microbiome research, therefore we cannot accurately assess the role of their gut microbiome in IBD. To understand why Indians are at a greater risk for IBD in Canada, we must first characterize their gut microbiome. Aims This study explores how immigration to Canada impacts the gut microbiome of Indian populations, potentially elevating their risk to IBD. Methods Stool samples from healthy volunteers (ages 17-53) were collected from Indians in India, Indo-Immigrants, Indo-Canadians, Euro-Canadians and Euro-Immigrants. DNA was extracted for 16S sequencing on the Illumina MiSeq platform and shotgun sequencing on the Illumina NovaSeq platform. Dietary data was processed in ESHA. Results Weighted Unifrac revealed distinct clusters of Indian and Indo-Immigrant samples from the westernized cohorts. The most pronounced difference was between Indian and Euro-Canadians with a pseudo-F value of 49.18 (q = 0.00125). Indian versus Indo-Immigrants resulted in a pseudo-F value of 7.707 (q = 0.00125), and Indian versus Indo-Canadian had a pseudo-F value of 15.95 (q = 0.00125). BugBase estimated a significantly higher stress tolerance in the Indian gut, with Proteobacteria driving this phenotypic prediction. Compared to Euro-Canadians, a significantly higher pathogenic potential was predicted in Indians (pFDR= 1.04e-11) and Indo-Immigrants (pFDR= 1.41e-04), driven mainly from Proteobacteria and Bacteroidetes. Multiple comparisons with LDA revealed Prevotella was over 5 times more abundant in Indians residing in India. The gut microbiome in Indians were also enriched with taxa associated with a plant-based diet. Dietary data showed that 59% of Indians do not consume meat, and they also had the lowest consumption (12% caloric intake) of group 4 ultra-processed food (UPF), whereas the highest consumption of UPF was in Indo-Canadians (61% caloric intake) (pbonf ampersand:003C 0.0001). A frequent trend was observed in Indians living in Canada, which was a reduction in key nutrients including soluble fiber, zinc, iron, and folate, some of which are commonly found in plant-based foods. Conclusions Overall findings reveal that a loss of Prevotella abundance was observed in Indo-Immigrants and Indo-Canadians, which was associated with a reduction in key nutrients that are common to a plant-based diet, indicating a transition away from their traditional diet. Their dietary changes may be a driver to the displacement of Prevotella and other taxa commonly found in the Indian gut microbiome. Funding Agencies NSERC, Killam

A systematic assessment on the influence of probiotics on patients with Inflammatory Bowel Disorder

Inflammatory bowel disease (IBD) causes persistent mucosal inflammation, and mounting evidence points to the intestinal microbiota's critical involvement in this process. New molecular techniques have also helped to identify dysbiosis in these individuals. Many potential probiotic product action mechanisms counteract IBD etiological causes. The study aimed to explain the benefits of probiotics for IBD and thoroughly evaluate current trials using probiotics to treat IBD in grownups. A specific search was done using specified keywords on October 1, 2011, using the supplied date range. Only English-language, full-text articles on clinical results for adult patients were addressed. Based on disease type and disease activity, the 41 eligible studies were classified. Pooled odds ratios were calculated only when there were many available randomized controlled trials per probiotic for a particular patient group. According to well-designed randomized controlled studies, few probiotics are effective in treating IBD at this time. It was only feasible to conduct meta-analyses on a limited number of studies, which yielded an overall risk ratio of 2.70 for inducing remission in active U.C. with Bifido fermented milk versus placebo or no adjuvant treatment. Very Specific Lactic Acid Bacteria (VSL#3) enables people to go into remission active U.C. compared to placebo. To support the favorable outcomes for inactive ulcerative colitis (U.C.), it is still a need to conduct better-conducted investigations in regard to the variety of drug VSL#3 in patients with both active and dormant U.C. U.C. based on intention-to-treat analyses by many independent research organizations. According to the existing data, probiotic usage in Crohn’s Disease (CD) has yet to be shown. The location and subtypes of certain diseases should be the focus of future research. Selecting probiotic strains for certain disease entities and illness sites will be easier with more knowledge of the mechanisms of probiotic strains and the etiology of IBD.

P865 Screening for low-processed breads - compositional analysis of food additives used in commercially available breads

Abstract Background Ultra-processed food (UPF) intake has been associated with the development of inflammatory bowel diseases (IBD), particularly Crohn’s disease (CD). Of UPF subgroups, commercially available breads showed greater risk, possibly due to the increasing presence of food additives (FA) like emulsifiers. As bread is a staple food worldwide, often consumed daily, we aimed to screen the ingredients and FA used in bread industry and to assess the availability of low processed breads. Methods We consecutively screened breads available at supermarket and health food store chains popular and widely distributed in Israel. Breads, pita breads and buns (excluding products without food labels), were analyzed by dietitians and categorized into one of three categories according to their processing level and FA types. Low processed category included ingredients used in traditional, home-made breads; medium processed category included FA like malt and added fibers; high processed category included FA like emulsifiers and preservatives, previously associated with impact on microbiota composition or implications on IBD. Results A total of 233 breads were screened, 160 are available at the supermarket, 56 at the health food store, and 17 in both. We categorized 195 (84%) as highly processed, 9 (4%) as medium processed and 29 (12%) as low processed. We identified 36 different types of FA and ingredients used. Most breads contained emulsifiers- 178 (76%) and –preservatives-189 (81%). The most used emulsifier was sodium stearoyl-2-lactylate (SSL, E-481), present in 86 breads (37%), followed by mono- and diglycerides of fatty acids (E-471), DATEM (E-472e) and carboxymethyl cellulose (CMC, E-466), found in 22%, 16% and 2% of breads, respectively. Interestingly, the emulsifier E-481, previously shown to induce microbial alterations, was found in 86 breads (52%) sold in the supermarket compared to none of the breads available in the health food store. Out of the 5 common preservatives, most of the breads contained calcium propionate (E-282) found in 112 (48%) and potassium sorbate (E-202) found in 42 (18%). Additives like enzymes were present in 159 (68%), gluten was added to 148 (64%) and 88 (38%) breads had added fibers. A greater portion of the breads contained yeast (85%) compared to sourdough (47%), with 30 (13%) containing only sourdough. Conclusion Most of the commercially available breads in Israel are highly processed. The use of emulsifiers, preservatives, added gluten and fibers is very common, yet low processed breads are available. These may be more recommended to patients with IBD. Further understanding of the role of FA in IBD etiology may potentially guide dietary recommendations for specific food choices.

P1143 Per- and poly-fluoroalkyl substances (PFAS) exposure is associated with later occurrence of inflammatory bowel disease

Abstract Background Environmental chemical exposures are increasingly acknowledged as risk factors for inflammatory bowel disease (IBD). Per- and poly-fluoroalkyl substances (PFAS), a large class of persistent fluorinated organic chemicals, widely used in the modern environment, may be implicated in IBD etiology, but data are conflicting. Methods We investigated the association of PFAS mixture concentrations in pre-diagnostic serum with adult-onset IBD in a pilot study within the pre-clinical Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS) study. This is a nested case-control study of military personnel with Crohn’s disease (CD), ulcerative colitis (UC), and age-, sex-, and race-matched healthy controls with serum samples obtained at four-time points 1-10 years prior to IBD diagnosis. Using untargeted liquid-chromatography high-resolution mass spectrometry analytical approach, we conducted an untargeted metabolomic analysis and semiquantitative measurement of fluorinated compounds, including legacy PFAS and emerging PFAS chemicals. We used weighted quantile sum regression models adjusted for confounders to study the association of PFAS as a mixture with the odds of CD and UC at each time point. Results Our study sample included individuals with CD, UC, and matched healthy controls (n=25, each group, 4 samples per individual). Baseline characteristics were similar across cases and controls. We identified nine well known PFAS compounds and 27 other known fluorinated compounds. The chemical mixture of fluorinated compounds, including the known PFAS, in the serum samples within one year of diagnosis was associated with higher odds of CD and UC [odds ratio (OR) 2.13, 95% CI 1.33, 3.41, and 1.76, 95% CI 1.15, 2.68, respectively] per one unit increase in decile. These associations remained consistent for the PFAS mixture measured in serum at all four time points up to 10 years prior to diagnosis for both CD and UC (Figure). Major contributors to the overall mixture indices included legacy PFAS, as well as emerging PFAS chemicals. Conclusion We observed a substantial increase in the odds of CD and UC among individuals with higher serum PFAS mixture levels up to 10 years prior to diagnosis. Studies to understand underlying mechanisms are ongoing.

P071 Neonatal levels of inflammatory markers in individuals who later develop early onset Inflammatory Bowel Disease

Abstract Background The early life period is suggested to be important in development of Inflammatory Bowel Disease (IBD). Studies in babies from mothers with IBD observed increased faecal calprotectin and changes in the microbial compartments compared to babies from healthy mothers1,2, which suggests that changes in early life might be associated with later disease development. Prospective studies of IBD risk following early life changes at the molecular level are sparse. We aimed to investigate if individuals with early onset (EO) IBD had changes in systemic inflammatory markers shortly after birth. Methods We measured the concentration of 9 cytokines in a cohort of 464 neonatal dried blood spot samples stored at the Danish National Biobank from individuals who later developed EO IBD (median age of diagnosis 11 years), as well as matched controls. Individuals who developed IBD were identified through the use of the Danish National Patient Registry. Uni- and multivariate logistic regression with adjustment for birth year, sex, and gestational age was conducted to assess the association between 6 of the inflammatory markers with later disease development (INF-γ, TNF-α, IL-1β, IL-4, IL-6 and IL-17a). Further exploratory analyses were performed investigating risk of very early onset (VEO) IBD (onset from 0-5 years) in 88 cases and their matched controls. Results No significant association with EO IBD was observed for any of the cytokines in uni- and multivariate models when adjusting for multiple testing. In the exploratory analysis of VEO IBD, increased IL-4 was associated with significantly reduced risk of IBD (OR=0.992, p-value=0.023) and increased IL-17a was borderline-significantly associated with increased risk of IBD (OR=1.002, p-value=0.063) in a multivariate logistic model including all 6 cytokines. This association did not remain significant when adjusting for multiple testing, which may reflect limited power. Conclusion In our unique study of 464 dried blood spots from later IBD patients and controls, we could not find an association between measured cytokines and EO IBD. In contrast, patients with VEO IBD had decreased levels of IL-4 and increased levels of IL-17a. This sub-cohort was small, and significance disappeared after adjusting for multiple testing. Still, we find it important to report these findings, as they are novel and may inspire future studies into the aetiology of VEO IBD. 1. Kim, E. S. et al. Longitudinal Changes in Fecal Calprotectin Levels Among Pregnant Women With and Without Inflammatory Bowel Disease and Their Babies. Gastroenterology (2021) 2. Torres, J. et al. Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice. Gut (2020)

P104 Per- and poly-fluoroalkyl substances (PFAS) exposure in early life is associated with intestinal inflammation

Abstract Background Early life environmental exposures are linked with intestinal inflammation and inflammatory bowel disease (IBD) later in life. Per- and poly-fluoroalkyl substances (PFAS) are a large class of fluorinated organic chemicals used widely in consumer products that may be risk factors for IBD; however, the association between exposure to PFAS in early life and intestinal inflammation has not yet been studied. Dried blood spots (DBS) are archived neonatal capillary blood samples collected and stored as part of the New York State neonatal screening program and a cost-effective early life environmental exposure screening resource. Methods We measured 135 PFAS in DBS collected at birth from offsprings of women with and without IBD [n=37 (44%) and 47 (56%), respectively] enrolled in the MEChanisms Of disease traNsmission In Utero through the Microbiome (MECONIUM) cohort between January 2015 and November 2020, using untargeted metabolomics with liquid chromatography high-resolution mass spectrometry. In a subsample (n = 46), we also measured offspring fecal calprotectin (FC) at one year. We fitted exposome-wide regression models to estimate the association between each PFAS signal in the DBS and continuous FC at one year of age. For the significant associations (nominal p-value <0.05), we further explored potential effect modification by stratifying by maternal IBD status. All models were adjusted for relevant confounders. Results The mean (SE) of FC at age one year was 213.9 (23.8) ug/gm. The PFAS chemicals perfluoroundecanoic acid (PFUnDA) and N-ethyl-perfluorooctane sulfonamido acetic acid (N-Et-FOSAA) were significantly associated with increased scaled and log-transformed FC per decile increase in exposures [estimate (95% CI) = 0.52 (0.13,0.91) and 0.34 (0.05,0.63), Figure A]. Associations tended to be stronger in offspring of women with IBD relative to offspring of women without IBD (Figure B). estimate (95% CI) for the associations between PFUnDA and FC were 0.86 (0.34,1.39) and 0.12 (-0.47,0.71), respectively, and between N-Et-FOSAA and FC, these were 0.54 (-0.01,1.08) and 0.31(-0.07,0.68), respectively. Conclusion DBS can be used to measure early life exposure to toxins, and prenatal PFAS exposure is associated with elevated FC, with a slightly stronger effect in the offspring of women with IBD. Larger prospective studies are needed to validate these associations and understand potential underlying mechanisms through which early life PFAS exposures may contribute to IBD etiology.

Habitual Dietary Intake and Adherence to Dietary Guidelines of Patients with Inflammatory Bowel Diseases

Inflammatory bowel disease (IBD) belongs to a group of autoimmune conditions characterized by chronic inflammation and mucosal ulceration of the gastrointestinal tract. The etiology of IBD is complex. The etiological factors include environmental factors, among which diet is important. The aim of this study was to evaluate the diet of IBD patients. This case–control study was carried out on 82 patients with IBD; the control group consisted of 80 clinically healthy subjects. Food intake was assessed using a 24 h recall and frequency food questionnaire. Energy intake in the IBD group was insufficient and significantly lower than in the control group. The energy intake in the group of patients with active IBD was significantly lower than in the group of subjects in remission. The total fat and protein intake was significantly lower in the IBD group compared to the healthy subjects. IBD patients were characterized by underconsumption of all food groups analyzed, except for the intake of red meat and poultry. Our study showed inadequate intake of energy and most nutrients in IBD patients, even during the remission period. The study indicates the need for routine assessment of dietary intake and nutrition among IBD patients, as well as potential dietary interventions aimed at improving the energy and nutritional quality of diet in order to optimize treatment outcomes and prevent the development of accompanying diseases.

Associations of inflammatory cytokines with inflammatory bowel disease: a Mendelian randomization study.

Previous studies have confirmed a link between specific inflammatory cytokines and inflammatory bowel disease (IBD), but the causal relationship between them is not completely clear. This Mendelian Randomization (MR) study aims to evaluate the causal relationship between 18 inflammatory cytokines and inflammatory bowel disease. Two-sample Mendelian randomization utilized genetic variances associated with IBD from two extensive publicly available genome-wide association studies (GWAS) (Crohn's Disease (CD): 12,194 cases and 28,072 controls; Ulcerative Colitis (UC): 12,336 cases and 33,609 controls). The data of inflammatory cytokines was acquired from a GWAS including 8,293 healthy participants. We used inverse variance weighted method, MR-Egger, weighted median, simple model and weighted model to evaluate the causal relationship between inflammatory cytokines and IBD. Sensitivity analysis includes heterogeneity and pleiotropy analysis to evaluate the robustness of the results. The findings indicated suggestive positive associations between Interleukin-13 (IL-13) and macrophage migration inhibitory factor (MIF) with CD (odds ratio, OR: 1.101, 95%CI: 1.021-1.188, p = 0.013; OR: 1.134, 95%CI: 1.024-1.255, p = 0.015). IL-13 also displayed a significant positive correlation with UC (OR: 1.099, 95%CI: 1.018-1.186, p = 0.016). Stem cell factor (SCF) was suggested to be associated with the development of both CD and UC (OR: 1.032, 95%CI: 0.973-1.058, p = 0.012; OR: 1.038, 95%CI: 1.005-1.072, p = 0.024). This study proposes that IL-13 may be a factor correlated with the etiology of IBD (CD and UC), while MIF just be specifically associated with CD. Additionally, SCF appears more likely to be involved in the downstream development of IBD (CD and UC).

Animal models of inflammatory bowel disease: category and evaluation indexes.

Inflammatory bowel disease (IBD) research often relies on animal models to study the etiology, pathophysiology, and management of IBD. Among these models, rats and mice are frequently employed due to their practicality and genetic manipulability. However, for studies aiming to closely mimic human pathology, non-human primates such as monkeys and dogs offer valuable physiological parallels. Guinea pigs, while less commonly used, present unique advantages for investigating the intricate interplay between neurological and immunological factors in IBD. Additionally, New Zealand rabbits excel in endoscopic biopsy techniques, providing insights into mucosal inflammation and healing processes. Pigs, with their physiological similarities to humans, serve as ideal models for exploring the complex relationships between nutrition, metabolism, and immunity in IBD. Beyond mammals, non-mammalian organisms including zebrafish, Drosophila melanogaster, and nematodes offer specialized insights into specific aspects of IBD pathology, highlighting the diverse array of model systems available for advancing our understanding of this multifaceted disease. In this review, we conduct a thorough analysis of various animal models employed in IBD research, detailing their applications and essential experimental parameters. These include clinical observation, Disease Activity Index score, pathological assessment, intestinal barrier integrity, fibrosis, inflammatory markers, intestinal microbiome, and other critical parameters that are crucial for evaluating modeling success and drug efficacy in experimental mammalian studies. Overall, this review will serve as a valuable resource for researchers in the field of IBD, offering insights into the diverse array of animal models available and their respective applications in studying IBD.