Inflammatory Bowel Disease
ICD-10 Code K50-K50.9 and K51.0-51.9
What is the clinical spectrum of Inflammatory Bowel Disease?
Inflammatory Bowel Disease (IBD) is a chronic autoimmune disorder that includes two main disease forms, ulcerative colitis (UC) and Crohn’s disease (CD). It is characterized by repetitive episodes of inflammation of the gastrointestinal tract (GI), intestinal barrier dysfunction, and increased risk of colitis-associated cancer, posing a significant social, economic and personal burden.
IBD’s forms UC and DC differ in their location within GI, in clinical features and in therapeutic strategy. While CD can affect any part of the GI tract, UC is limited to the colon and the rectum. In addition, there is heterogeneity in location of pathological changes within IBD types, producing variation in the disease phenotype.
For example, when it is the ileum that is impacted in CD, complications such as stricture can arise, producing symptoms of abdominal pain, cramps, bloating, nausea, constipation, and vomiting. Individuals with CD can also present with penetrating disease behavior, characterized by inflammation masses across entire thickness of intestinal wall, abscesses, and fistulas.
In the proctitis form of UC, the inflammation is limited to the rectum, while in left-sided colitis the inflammation extends up to the splenic flexure. Pancolitis, in which the inflammation affects the entire colon, is considered as the most severe form of UC and is associated with a higher risk of complications.
Ophthalmological, rheumatological, cutaneous, and hepatobiliary extra-intestinal manifestations (EIM) may also occur in parallel with the intestinal disease.
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What do we know about the etiology of Inflammatory Bowel Disease?
IBD is believed to arise and progress through a complex interaction between internal (genetic) and external (diet, hazardous substances, medication, infection, smoking) triggering and contributing factors.
The weight of genetic and environmental factors has an impact on the severity of IBD. For instance, sporadic IBD, that occurs without a clear genetic predisposition or family history, typically presents later in life than familial IBD and tends to have a less severe disease course and lower rates of EIMs compared to very early onset IBD (VEO-IBD).
Genetic triggering factors - Genome-wide association studies (GWAS) have identified more than 300 genes associated with IBD. Genes associated with UC notably play a role in major histocompatibility complex, immune regulation and epithelial barrier.
Diet triggering factor - An unbalanced diet can cause damage to intestinal barrier directly through excess intake of saturated fats/refined sugars, vitamin deficiency, and production of reactive oxygen species (ROS), triggering an inflammatory response.
Contributing factors include microbiome dysbiosis, epithelial barrier damage, immune response and oxidative stress, that participate to a pathological loop that exacerbates the intestinal inflammation and tissue destruction in IBD. For instance, dysregulation of transcription of junctional proteins that are essential for epithelial barrier function was found in both UC and CD. Intestinal goblet cells, that produce a protective barrier mucus, can be damaged through dysbiosis, prolonged use of antibiotics, persistent inflammation, and high fat/sugar diets.
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How similar are human and animal digestive systems?
Below are some of the examples of species-specific differences that are likely to negatively affect the face, construct, and predictive validity of animal models of IBD.
Species-specific differences in gastrointestinal anatomy and physiology
Since IBD affects nutrient absorption, immunity, microbiome, and mucosal healing in different regions of the GI tract, these physiological and anatomical differences have major implications for the ability of model organisms to faithfully recapitulate IBD.For instance, segmental contractions in the rodent colon differ from the peristaltic waves observed in humans, impacting how external triggering factors interact with the gut mucosa and the gut microbiome.
Species-specific differences in gut microbiome
Inter-species differences in GI microbiome have a major impact on the activity of drug-metabolizing enzymes, on intestinal pH, on gut inflammation, and on integrity of the gut barrier, thereby affecting predictive value of animal models of IBD. Analyses of the microbiota at lower taxonomy level, have shed light on previously unknown species-specific differences in GI microbiome composition, quantity, and function, rendering model organisms inappropriate for studying the effect of the human gut microbiota on UC and CD.
Species-specific differences in stress response capacity
Inter-species differences in organisms' ability to detect, respond to, and adapt to stressors negatively affect predictivity of animal research, and notably in studies that investigate the role of environmental triggers in IBD pathogenesis. For example, in contrast to mouse pregnane X receptor (PXR), rifampicin and SR12813 are potent agonists for human PXR, leading to induction of P450 enzymes followed by increased metabolism and clearance of co-administered drugs.
Species-specific differences in mucins
In IBD, defects in mucin production and function can lead to a compromised barrier, exacerbating inflammation and disease progression. Crucially, there are major species-specific differences in mucins' composition, glycosylation patterns, expression levels, and functional roles that are likely to affect the fidelity of disease pathophysiology.
Species-specific differences in immune system
Innate and adaptive immunity responses play a crucial role in the pathogenesis of IBD. Extensive differences between humans and mice were demonstrated in the structure of innate and adaptive immunity, as well as in transcriptional regulation, chromatin state and higher order chromatin organization.
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Face validity - How well do animal models replicate the human disease phenotype?
No single animal model, may it be rodent, dog, pig, or non-human primate, faithfully recapitulates the clinical and histopathological characteristics of IBD.
Chemically-induced animal models - Dextran Sodium Sulfate (DSS) directly damages the epithelial barrier of the colon, leading to UC-like symptoms of colonic inflammation with granuloma, bleeding, diarrhea, and weight loss. 2,4,6-Trinitrobenzene Sulfonic Acid (TNBS) induces transmural inflammation characteristic of CD, with corresponding symptoms of severe diarrhea, weight loss, and rectal prolapse. A major limitations of this method is the difficulty in producing irreversible IBD-like phenotypes in vivo.
Adoptive T cell transfer animal models - Transferring naïve Treg-depleted CD4+CD45RBhigh T cells from wild-type mice into Rag-KO or SCID immunodeficient mice, induces chronic colonic inflammation characteristic of UC but does not recapitulate transmural inflammation, intestinal fibrosis and strictures characteristic of CD.
Genetically-engineered animal models - Several dozen genetic knock-out (KO) mouse strains, were engineered to induce colitis/ileitis with variable success. For example, the IL-10 KO mouse only partially mimics the IBD phenotype since no weight loss was observed and the colitis development was highly variable.
Spontaneous animal models - The SAMP1/YitFc mouse strain, obtained by selective inbreeding, develops ileitis spontaneously but does not display colitis. Mice that overexpress tumor necrosis factor show CD-like chronic ileitis and granuloma formation, but without strictures and fistulas.
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Construct validity - How well do the mechanisms of disease induction in animals reflect the currently understood etiology of the human disease?
Not only is there no evidence supporting the relevance of animal models to human inflammatory bowel diseases but existing research suggests the opposite. The polygenic and multifactorial nature of UC and CD cannot be captured in animal models. Pathways that underly development of natural human IBD are thus likely to diverge from pathways triggered experimentally in animals.
Chemically-induced animal models - In real-world scenarios, DSS and TNBS are not ingested by IBD patients. In humans, IBD does not occur following a single acute exposure or a repeated exposure to a toxicant. In addition, DSS and TNBS compounds induce acute inflammation, while human IBD is characterized by a chronic, relapsing-remitting pattern.
Genetically-engineered animal models - Typically, genetically engineered IBD animal models were generated without evidence that experimentally targeted genes are in effect involved in IBD. Furthermore, genetic knock-out is frequently employed whereas complete loss of gene function is rarely observed in IBD patient populations.
Spontaneous animal models - Do not contain the genetic mutations identified in IBD patients. The lack of human-specific genetics, immune system, and microbiome makes such model unlikely to shed light on human-relevant mechanisms of IBD.
Adoptive T cell transfer animal models - Since the method of T cell transfer makes use of immunodeficient mice it does not recapitulate the complex interplay between the human immune system and other components that play a major role in IBD.
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Predictive validity - How well do animal models predict safety and efficacy of therapies in patients?
Unsurprisingly, given the poor face and construct validity of animal models of IBD, the overwhelming majority of treatments developed through animal research failed to produce benefits for patients. Currently there is no cure for IBD. Treatment strategies for induction and maintenance of remission in UC and CD focus on reducing the inflammatory response and altering the immune system's activity.
Monoclonal antibodies, such as infliximab, that target proinflammatory cytokine tumor necrosis factor-α (TNF-α), were introduced in the late 1990s to induce and maintain remission in CD. However, approximately one third of IBD patients are primary non-responders to anti-TNF-α induction therapy and another third go on to become secondary non-responders during TNF-α inhibitor maintenance therapy. In 2014, the chimeric anti-α4β7 integrin monoclonal antibody vedolizumab, was approved by the FDA for treatment of UC and CD patients who exhibited an unsatisfactory response to anti-TNF-α biologics and immunomodulators. More recently approved therapeutics include new small molecule drugs, such as Janus kinase inhibitor (JAK) upadacitinib, that is not recommended for use in pregnancy. In 2025, it is the humanized IgG4 monoclonal antibody mirikizumab-mkrz, that was approved by the FDA for treatment of UC and CD, despite potentially severe and life-threating side effects.
To date, there are no therapeutic interventions available that promote the restoration of integrity and function of intestinal epithelial cells. More than half of patients with CD develop strictiring complications over their lifetime, and yet, therapies against this complex pathology are missing.
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Ethical validity - How well do animal experiments align with human ethical principles?
Preclinical - Animal research is unethical in essence by human standards, since it involves physical constraint, psychological suffering and deprivation of freedom, social interactions, natural environment, and life purpose. In addition to this baseline, experiments inflict severe clinical harm in animals.
Clinical - Statistics consistently show that clinical success rates of drugs developed and tested in animals is very low, raising the question of whether it is ethical to put the health of patients at risk.
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Intrinsic validity - How well do animal models capture the clinical heterogeneity of the human disease?
Animal models of inflammatory bowel diseases do not recapitulate the inter-individual heterogeneity in clinical features, pathophysiology, and responses to treatment.
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Extrinsic validity - How well does animal experimentation generate reliable and reproducible outcomes?
In spite of significant investment in dissemination, various incentives and training of animal researchers, the ARRIVE - Animal Research: Reporting of In Vivo Experiments - guidelines remain poorly implemented and the majority of animal experiments irreproducible. While in vitro methods are not immune to issues of reproducibility, the moral weight of irreproducible animal studies is not the same.
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Key takeaways
Inflammatory bowel diseases [IBD], ulcerative colitis (UC) and Crohn’s disease (CD), are autoimmune disorders of the gastrointestinal system posing a significant personal and economic burden. Complications arising from IBD can lead to significant morbidity and mortality, requiring early diagnosis, careful monitoring and effective treatment.
In vivo modelling fails to recapitulate the underlying mechanisms and clinical features of IBD, all while producing severe clinical signs in animals. For a very long time - and still today - the path to developing safe and effective therapies for IBD has been fraught with clinical failures, due to inter-species differences in gastrointestinal physiology, microbiome, metabolism, gene expression and immune system. Currently there is no cure for UC and CD, and the existing treatment options show a variable efficacy, underscoring the need for a personalized approach.
Human-based tools are needed to elucidate heterogenous disease mechanisms, identify new therapeutic targets and adjust treatments to patient subtypes.
How is Human-Based In Vitro the Answer to Advance Biomedical Research into Inflammatory Bowel Diseases
The following section explores how researchers can leverage advanced in vitro technologies to improve the understanding of disease mechanisms and develop new treatments for inflammatory bowel diseases. The list of over 20 examples and suggestions includes capturing the inter-individual differences in pathophysiology, investigating pathogenic-beneficial inter-microbial dynamics, identifying the drivers of epithelial barrier dysfunction, improving prediction of drug bioavailability, and testing the efficacy of personalized medicine in patient-specific 3D GI tissues, organoids, microfluidic systems and biofabricated platforms.
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