Animal Models of Inflammatory Bowel Disease

doi:10.1016/B978-0-12-394596-9.00009-3

Progress in Molecular Biology and Translational Science

Volume 105, 2012, Pages 263-320

https://doi.org/10.1016/B978-0-12-394596-9.00009-3 Get rights and content

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is medicated by genetic, immune, and environmental factors. At least 66 different kinds of animal models have been established to study IBD, which are classified primarily into chemically induced, cell-transfer, congenial mutant, and genetically engineered models. These IBD models have provided significant contributions to not only dissect the mechanism but also develop novel therapeutic strategies for IBD. In addition, recent advances on genetically engineered techniques such as cell-specific and inducible knockout as well as knockin mouse systems have brought novel concepts on IBD pathogenesis to the fore. Further, mouse models, which lack some IBD susceptibility genes, have suggested more complicated mechanism of IBD than previously predicted. This chapter summarizes the distinct feature of each murine IBD model and discusses the previous and current lessons from the IBD models.

Section snippets

Classification of Murine IBD Models

As shown in Fig. 1, IBD models are classified into five major groups: chemically induced model, cell-transfer model, spontaneous model, congenital (spontaneous gene mutation) model, and genetically engineered model. In addition, recent advances on genetic engineering technology have prompted us to further classify the genetically engineered model into six subgroups (Fig. 1). Conventional Tg or KO model groups are mice that are genetically engineered to continuously overexpress or lack the gene

IL-10 KO Mice

IL-10 is a well-known regulatory cytokine and represents a key IBD (both UC and CD) susceptibility gene.16, 17, 18, 19, 20 IL-10 KO mice, which are genetically engineered to lack IL-10 gene, spontaneously develop colitis after 3 months of age.¹¹ C3H and Balb/c backgrounds are more susceptible to this colitis as compared to C57BL/6 background. Enteric microbiota plays the major role in this colitis. Indeed, many studies in the microbiology field such as probiotics have been done using IL-10 KO

IL-2 KO Mice

IL-2 is a critical cytokine that is necessary for T-cell homeostasis. IL-2 suppresses excessive T-cell responses by inducing activation-induced cell death (AICD) and elicits the function of CD4⁺ Foxp3⁺ Treg. Importantly, IL-2RA (IL-2 receptor α) is a potential CD susceptibility gene and IL-2 gene is located within an IBD susceptibility locus.16, 17, 18, 19, 20

IL-2 KO mice spontaneously develop a systemic autoimmune disease characterized by colitis, gastritis, hepatitis, pneumonia, pancreatitis,

TCRα KO Mice

TCR, which is composed of TCRα and TCRβ chains, is required for the recognition of antigens for consequent activation of T cell-mediated adaptive immune responses. Interestingly, deletion of TCRα chains induces the spontaneous development of colitis.¹² Approximately 60% of TCRα KO mice develop Th2-mediated colitis at 6 months of age, and the inflammation is restricted primarily to the mucosa. C57BL/6 background is more susceptible to this colitis as compared to Balb/c and C3H/HeJ backgrounds.¹²

TGFβ KO Mice

Transforming growth factor (TGF)β1 is a multifunctional growth factor involved in developmental, physiological, and immune regulatory processes. TGFβ1 KO mice develop necrotic inflammation in multiple organs including intestine and they are only able to survive only until 3–4 weeks of age.⁷²

The early death hampered investigators to closely examine the inflammatory mechanism of TGFβ1 KO mice. To overcome this problem, conditional TGFβ1 KO mouse strains have been developed. One of the conditional

TAK1 KO Mice

TGFβ-activated kinase 1 (TAK1), which is activated by TLRs, IL-1, and NOD2, is an essential intermediate for the consequent activation of AP1 and NFκB1 in innate immune signaling pathways. Epithelial cell-specific deletion of TAK1 (under control of villin promoter) causes very severe epithelial damage characterized by increased apoptosis in the small intestine by 3 days of age.⁷⁷ In addition, inducible epithelial-specific TAK1 KO mice exhibit the intestinal epithelial damage within 3 days after

WASP KO Mice

Wiskott–Aldrich syndrome protein (WASP) is a key organizer involved in the remodeling of actin cytoskeleton to regulate cell movement, cell signaling, and cell division. Mice deficient in WASP develop colitis from 4 months of age, and 100% penetration of colitis is observed at 6 months of age.⁷⁸ This colitis is characterized by elevated expressions of IL-4 and IL-13 and decreased expression of IL-6. Adoptive cell transfer experiments indicate the requirement of IL-4-expressing CD4⁺ T cells in the

P110δ Mutant Mice

Phosphatidyl inositol 3-kinase (PI3K) is a family of p85/p110 heterodimeric lipid kinases that generate second messenger signals downstream of tyrosine kinases activated by antigen receptors. A PI3K p100 subunit, p110δ is expressed predominantly in leukocytes. Mice, which are genetically engineered to carry a point mutation in the P110δ gene locus at position 910 (D > A), spontaneously develop mild, focal inflammation restricted to the rectum and cecum.⁸¹ The development of colitis may be

PDK1 KO Mice

Phosphoinositide-dependent kinase 1 (PDK1), a pleckstrin-homology domain containing protein kinase, is a key downstream effector of PI3K pathway. T-cell-specific deletion (under a control of CD4 promoter) of PDK1 induces spontaneous development of colitis at 8 weeks of age.⁸⁴ This colitis is associated with the upregulation of colonic expressions of IL-17A, IL-23p19, and TNF-α. Interestingly, CD8α⁺ TCRγδ T cells, which produce IL-17A, are dramatically increased in the intraepithelial compartment

Cbl-b KO Mice

Cbl-b belongs to a family of Casitas B-lineage lymphoma (Cbl) proteins consisting of c-Cbl, Cbl-b, and Cbl-3; which function as E3 ubiquitin ligases and molecular adaptor to promote ubiquitin conjugation to the p85 regulatory subunit of PI3K. Cbl-b acts as a negative regulator of T-cell activation. Cbl-b KO mice spontaneously develop massive infiltration of activated T cells and B cells in multiple organs from 3 months of age, including the intestine, salivary glands, pancreas, liver, lung,

Blimp-1 KO Mice

B lymphocyte-induced maturation protein-1 (Blimp-1) is a zinc finger-containing transcriptional repressor that is necessary for the terminal differentiation of B cells into antibody-secreting plasma cells. In addition to B cells, Blimp-1 is expressed by several different cell lineages, including memory, but not naïve, T cells, myeloid lineage cells, and epithelial cells. Interestingly, T-cell-specific depletion of Blimp-1 (under control of Lck promoter) induces the spontaneous development of

A20 KO Mice

A20 is an ubiquitin-editing enzyme that is necessary for the termination of NFκB1 activation after stimulation with TNF or TLRLs. A20 KO mice develop inflammation in multiple organs such as liver, kidney, intestine, and joints at 3–6 weeks of age.⁸⁷ The colitis is independent of T and B cells as indicated by the development of inflammation in RAG1-deficient A20 double KO mice. Although A20 is critical for restricting TNF-induced NFκB1 signaling, both TNF-α and TNFR1 are dispensable for the

SHIP KO Mice

The Src homology 2 (SH2)-containing inositol-5 phosphatase (SHIP) is activated in response to various growth factors as well as TCR and BCR ligations. SHIP gene is located within an IBD association locus 2q37. Ninety-four percent of SHIP KO mice develop transmural, segmental ileitis at 6–8 weeks of age.⁸⁹ Granulomas are detectable in 28% of mice. Interestingly, inducible deletion of SHIP during adult life by administration of polyI/C also results in the spontaneous development of ileitis within

Gαi2 KO Mice

G-protein is a family of GTP-binding proteins that are involved in a wide variety of transmembrane signaling systems. 100% of Gαi2 KO mice on 129/sv background develop a lethal, diffuse colitis at 16–20 weeks of age, and adenocarcinoma is observed in 30% of them.⁹⁰ In contrast, Gαi2 KO mice on C57BL/6 background are relatively resistant to the colitis development. The colitis in 129/sv background is characterized by Th1, but not Th2, response and by reduction of B-cell subsets, including

TNF(ARE) Mice

A regulatory sequence, which consists of adenosine–uracil multimers (AU-rich elements, ARE), is located in the 3′-untranslated region (3′-UTR) of transcripts encoding cytokines. ARE is responsible for the mRNA destabilization and translational silencing. Deletion of a 69 bp-nucleotide encompassing the TNF-ARE enhances the stabilization of TNF-α expressions and induces the spontaneous development of intestinal inflammation between 2 and 4 weeks of age.⁹³ The inflammation is localized primarily to

LIGHT Tg Mice

A member of TNF super family LIGHT (TNFSF14), which is expressed by activated T cells, serves as a key component of the communication system that controls the response of T cells. LIGHT interacts with two cell-surface receptors, herpes virus entry mediator (HVEM), and lymphotixin (LT) β receptor, and the interaction is inhibited by soluble decoy receptor 3. T-cell-specific overexpressions (under a control of CD2 promoter) of human LIGHT induce the spontaneous development of hepatitis and small

TNFSF15 Tg Mice

TNFSF15 (also known as TL1A) is a member of the TNF super family that binds to death domain receptor 3 (DR3, TNFRSF25). TNFSF15 has been identified as an association gene of both CD and UC.16, 17, 18, 19, 20 TNFSF15, which is produced primarily by lamina propria (LP) macrophages in CD patients, promotes the production of IFN-γ and IL-17 by the LP CD4⁺ T cells.⁹⁹ In addition, the pathogenic role of TNFSF15 in colitis and its ability to enhance both Th1 and Th17 responses have been demonstrated

IL-7 Tg Mice

IL-7 is essentially involved in T-cell homeostasis at various developmental stages. This cytokine is required for the development of mature T cells in the thymus and also prompts the survival of naïve and memory T cells in the periphery. IL-7 has been identified as a candidate gene associated with UC.¹⁶ IL-7 Tg mice spontaneously develop colitis between 4 and 12 weeks of age depending on the copy number of transgenes.¹⁰² Increase in IL-7 receptor expressions on mucosal lymphocytes is associated

IL-15 Tg Mice

IL-2 and IL-15 bind to their heterotrimeric receptors that have two receptor subunits in common, but these two cytokines have contrasting roles in adaptive immune responses. IL-2 induces AICD to eliminate potentially self-reactive T cells, whereas IL-15 may play a crucial role for the maintenance of memory T-cell responses particularly to invading pathogens. Interestingly, overexpressions of IL-15 in the thymus and intestinal epithelial cells under a control of T3^b promoter induce the

CD40L Tg Mice

CD40 ligand (CD40L, also known as gp39 or CD154) on T cells interacts with CD40 expressed on the potentially or professional antigen-presenting cells (APCs) such as B cells, dendritic cells, and macrophages. This interaction provides bidirectional costimulatory signals to both T cells and APCs to activate humoral as well as cell-mediated immune responses. T-cell-specific overexpressions of CD40L (under a control of Lck promoter) induce the development of lethal, transmural, granulomatous

Soluble B7.2 Tg Mice

B7.2 (also known as CD86) is a costimulatory molecule expressed by APCs, which interacts with CD28 for T-cell activation and survival and with CTLA4 for immune regulation. Soluble B7.2 Ig Fc fusion protein, which is artificially generated, interacts with both CD28 and CTLA4. Interestingly, Tg mice, which are genetically engineered to express soluble B7.2 Ig Fc under the control of a liver-specific promoter, develop transmural colitis with extensive inflammatory-cell infiltration at 8–10 weeks of

Integrin αV KO Mice

Integrins are dimeric cell-surface receptors composed of α and β subunits. Integrin αV is the most promiscuous α subunit, associated with β1, β3, β5, β6, and β8 and participating in many cellular processes such as cell adhesion and cell survival. Specific deletion of αV in endothelial and hematopoietic cells (under control of tie 2 promoter) elicits multiorgans inflammation from 14 weeks of age.¹¹³ The organs affected include the colon, cecum, peritoneum, liver, nasal cavity, and respiratory

Integrin β8 KO Mice

Integrin β8 is associated with integrin αV subunit to form αVβ8 that is capable of activating TGFβ. Mice lacking αV die before or shortly after birth from defects in brain vascular development. In contrast, mice with specific deletion of β8 in both CD4⁺ T cells and dendritic cells (under control of Vav1 promoter) survive and begin to develop a progressive wasting disorder from 4 to 5 months of age.¹¹⁴ All mice then develop colitis by 10 months of age. Interestingly, mice with deletion of β8 only

STAT4 Tg Mice

Signal transducer and activator of transcription (STAT)4 is a transcription factor that promotes Th1 development. Mice, which are genetically engineered to overexpress STAT4 when cytomegaro virus (CMV) promoter is activated, develop transmural colitis within 7–14 days after immunization with DNP-KLH/CFA for activation of CMV promoter.¹¹⁵ The colonic CD4⁺ T cells produce TNF-α and IFN-γ but not IL-4. Adoptive transfer of CD4⁺ T cells from the inflamed colon of STAT4 Tg mice induces colitis in

STAT3 KO Mice

STAT3 is a master transcriptional factor involved in a broad spectrum of adaptive and innate immune functions such as Th17 differentiation and epithelial regeneration. STAT3 is highlighted by recent human genome-wide association studies that identify STAT3 as a susceptibility gene of both CD and UC.16, 17, 18, 19, 20 Alternatively, it is becoming increasingly apparent from IBD models that function of STAT3 in IBD is much more complicated than previously predicted. For example, absence of STAT3

SOCS1 Tg Mice

Several cytokines activate JAK and STATs signaling pathway, which is in turn suppressed by suppressor of cytokine signaling (SOCS) protein that is characterized by the presence of a SH2 domain and a SOCS box. Approximately 40% of T-cell-specific SOCS1 Tg mice (under control of Lck promoter) develop colitis after 15 weeks of age when they are kept under conventional conditions.¹²³ Interestingly, the SOCS1 Tg mice do not develop colitis under specific pathogen-free condition. This colitis is

Gp130 KI Mice

IL-6 activates various cell types carrying the membrane-bound IL-6R/gp130 heterodimer receptors (classical IL-6 signaling) as well as IL-6R⁻ gp130⁺ cells via the soluble IL-6R (IL-6 trans-signaling). The gp130 KI mice, which carry a truncation mutation within gp130 gene that deletes all STAT3-binding sites, spontaneously develop ulceration in the gastric pylorus and the anorectal region at 4 months of age when maintained under specific pathogen-free condition.¹²⁴ Approximately 40% of gp130 KI

NFκB1 KO Mice

Canonical NFκB (NFκB1) pathway is activated by tri-complex of IκB kinase (IKK)1, IKK2, and NEMO (also called IKKγ). Inhibition of NFκB1 has been shown to suppress T-cell-mediated colitis such as TNBS colitis.¹²⁵ In contrast, mice with specific deletion of NEMO in epithelial cells spontaneously develop colitis at 6 weeks of age.¹²⁶ This colitis, which is associated with extensive epithelial cell apoptosis and downregulation of β-defensin 3 expressions, fully depends on MyD88 and TNFR1 as

Runx3 KO Mice

Runx3, which is expressed by CD4/CD8 double negative and single positive thymocytes and peripheral DCs, functions as context-dependent transcription factor involved in neurogenesis, thymopoiesis, and dendritic cell maturation. 100% of Runx3 KO mice develop colitis spontaneously by 4 weeks of age and the inflammation is expanded to the small intestine in 20% of them.¹²⁹ The colitis is characterized by the enhancement of both Th1 and Th2 (IL-4 not IL-5) responses and by decrease in IL-18

TLR5 KO Mice

Toll-like receptors (TLRs) are pattern recognition receptors that selectively recognize different microbial products. KO mouse strains, which are engineered to lack individual TLRs (TLR2, TLR4, TLR5, TLR7, and TLR9), have already been generated. Among them, only TLR5 KO mice have been shown to develop colitis spontaneously.¹³¹ Approximately 30% of TLR5 KO mice may develop colitis characterized by rectal prolapse, bleeding, and body weight loss at 8–12 weeks of age. The inflammation is primarily

Enteric Glia KO

Tg mice, which are genetically engineered to express herpes simplex virus thymidine kinase under control of glial fibrillary acidic protein (GFAP), ablate GFAP-positive glial cells in the small intestine after administration of an antiviral agent ganciclovir for 14–17 days. Interestingly, the ablation of enteric glial cells induces fulminating and fatal ileitis characterized by necrosis, severe inflammation, and hemorrhage.¹³⁵ The enteric glia KO mice exhibit intestinal epithelial barrier

XBP1 KO Mice

X-box-binding protein (XBP1) plays a critical role in unfolded protein response that is a primitive cellular pathway that is engaged in response to endoplasmic reticulum stress. Although the function of XBP1 to induce the terminal differentiation of B cells into plasma cells has been well known, the critical role of XBP1 in epithelial cell function is clearly highlighted by the fact that specific deletion of XBP1 in intestinal epithelial cells (under control of villin promoter) leads to the

Atg5 KO Mice

Autophagy is a cellular pathway involved in protein and organelle degradation. Although autophagy was thought to be a primary response to starvation, recently accumulating data indicate that it exerts diverse physiological functions ranging from microbial infections to MHC class II-dependent antigen presentation.¹³⁸ Importance of autophagy process in IBD is highlighted by the identification of autophagy-related gene (Atg) 16L1 and IRGM, a gene essential for autophagy, as major susceptibility

mK8 KO Mice

Majority of single-layered epithelial cells express keratin 8 (mK8). K8-targeted mutation in mice on C57BL/129 background causes embryonic lethality (94% penetration). In contrast, K8-deficient mice on FVB/N background survive and develop colorectal, but not small intestinal, hyperplasia with rectal prolapse at 9 weeks of age.¹⁴² The elongation of epithelial crypt is accompanied with inflammatory-cell infiltration extended to the submucosa. Of note, K8 deficiency confers resistance to colonocyte

N-Cadherin Mutant Mice

N-cadherin is a transmembrane glycoprotein that mediates homophilic adhesive interactions between cells. Chimeric mice, which are generated from ES cells to carry dominant negative mutation of N-cadherin and express it only in small intestinal epithelial cells (under the control of a Fabp promoter), exhibit loss of endogenous E-cadherin that is localized to basolateral surfaces and apical junction complexes of epithelial cells. The N-cadherin mutant mice develop transmural inflammation in the

Mdr1a KO Mice

Multiple drug resistance (Mdr) 1 belongs to a family of transporters known as ATP-binding cassette transporters, which are characterized by the ability to pump small amphiphilic and hydrophobic molecules across membranes in an ATP-dependent manner. Mdr1a is expressed by epithelial cells, some T cell subsets, hematopoietic cells, and blood–brain barrier cells. Interestingly, 20–25% of Mdr1a KO mice on FVB background develop a continuous colitis with significant increase in serum Ig levels by 1

GPX KO Mice

Glutathione peroxidases (GPX) are selenium-dependent hydroperoxidase-reducing enzymes that contribute in reducing H₂O₂ and fatty acid hydroperoxides. Mice deficient for both, but not either, GPX1 and GPX2 spontaneously develop perianal ulceration, diarrhea, and hypothermia at 14 days of age.¹⁴⁸ Histologically recognized inflammation in the colon and ileum can be detected at 24 days of age. Approximately 40% of GPX1 × GPX2 double KO mice die between 20 and 36 days after birth. One hundred and

Muc2 KO Mice

There is a layer of mucus covering the surface of intestinal tract, which serves as a lubricant and a physiological barrier between luminal contents and mucosal surface. Mucins, which are a major component of intestinal mucus, are heavily O-glycosylated protein that are classified into two groups—secreted (e.g., Muc2, 5, and 6) and membrane-bound (e.g., Muc1, 3, 4, 12, 13, and 17) mucins. UC, which is characterized by a thin mucus layer in association with goblet cell depletion, exhibits strong

C1galt1 KO Mice

Colonic mucus carries large numbers of O-glycan, which account for approximately 80% of the mass of mucus molecules. O-glycan synthesis is initiated from a primary core structure termed Tn antigen, which is formed by a glycosylation enzyme termed core 1β1,3-galactosyltransferase (C1galt1). After establishment of the core formation, sequential addition of saccharides is induced by other enzymes to elongate the O-glycan. Interestingly, epithelial cell-specific deletion of C1galt1 induces

NFATc2/RAG DKO Mice

The nuclear factor of activated T cells (NFAT)c 2 is an immune-specific calcium-regulated NFTA family member that plays redundant function in gene regulation. NFATc1 and NFATc2 together are the most important NFAT isoforms in T-cell differentiation. NFATc2 KO mice do not develop colitis, but double KO mice deficient in both NFATc2 and RAG2 (lacking T and B cells) spontaneously develop colitis with rectal prolapse at 15 weeks of age.¹⁵⁶ Adoptive transfer of B cells, but not T cells, from WT mice

T-bet/RAG DKO Mice

T-bet is a T-box transcriptional factor involved in the differentiation of Th1 T cells. Inhibition of T-bet in CD4⁺ T cells contributes to the improvement of T-cell-mediated colitis in CD45RB model.¹⁵⁷ In contrast, although T-bet KO mice do not develop colitis, T-bet-deficient RAG2 double KO mice, which lack both T and B cells, spontaneously develop colitis from 4 weeks of age.²¹ This colitis is characterized by continuous area of inflammation expanded from distal part of colon (homologue of

Anti-CD40mAb Model

Cognate interaction of T and B cells through CD154 (T cells) and CD40 (B cells) is implicated in the activation of adaptive immune responses. Interestingly, administration of agonistic CD40 mAbs induces acute colitis in RAG1 KO mice lacking T and B cells but not in WT mice.¹⁶⁰ The CD40mAb-treated RAG1 KO mice develop colitis within 4 days, and the colitis is observed until 3 weeks after injection. Unlike chronic colitis models, the colitis can be induced in germ-free environment and it is

C3H/HeJBir Mice

C3H/HeJBir mice are a substrain of mice, which was generated by a program of selected breeding of C3H/HeJ mice. C3H/HeJBir mice develop inflammation mainly in the cecum and right colon at 3–6 weeks of age, and the inflammation resolves spontaneously by 12 weeks of age.¹⁶² A gene locus on chromosome 3, termed CdCs1, seems to make this mouse substrain susceptible to colitis.¹⁶³ Bacterial antigen-stimulated CD4⁺ T cells from C3H/HeJBir mice have the ability to elicit the development of colitis in

SAMP1/Yit Model

SAMP1 mouse strain is one of senescence-prone strains derived from 24 generations of siblings from a litter of AKR/J mice. SAMP1 mice show early signs of senescence such as amyloidosis, alopecia, and osteoporosis. There are two substrains of SAMP1 mice, termed SAMP1/Yit and SAMP1/YitFc. These substrains develop discontinuous, transmural inflammatory lesions in the terminal ileum with 100% penetrance by 30 weeks of age.165, 166 Unlike colitis models, enteric bacteria are required for the

CD45RB Model

Adoptive transfer of naïve CD4⁺ T cells (CD4⁺CD45RB^high T cells) from the spleen of WT mice induces transmural colitis in immune-deficient recipients at 6–8 weeks after cell transfer. The colitis cannot be induced when mixture of naïve and memory CD4⁺ T cells (Treg) are used as donor cells. This model system, which was initially developed by Dr. Powrie,⁷ has not only provided significant contributions for dissecting the fundamental mechanism of CD but also made a major breakthrough by bringing

Human CD3ε Model

Overexpression of human CD3ε26 disrupts the normal thymic selection in mice. Transplantation of T cell-depleted bone marrow cells from WT mice induces the development of colitis in the CD3ε Tg mice at 5–8 weeks after transplantation, and this colitis can be inhibited by preimplantation of WT thymi under the recipient kidney capsule.²⁰² Both TCRαβ T cells and TCRγδ T cells mediate this colitis,²⁰³ and enteric bacteria are required for eliciting the pathogenic ability of these T cells,

CD8-Transfer Models

Adoptive transfer of heat shock protein (hsp) 60-reactive CD8⁺ T cell clones, which coexpress Vβ8.1 and Vα8 and possess Fas-dependent cytolytic activity, induces inflammation in the small intestine of recipient TCRβ KO mice.²⁰⁸ This ileitis occurs in the absence of enteric bacteria.

Adoptive transfer of ovalbumin (OVA)-specific CD8⁺ T cells cannot induce inflammation in the recipient mice engineered to express the exogenous antigen OVA in the intestinal epithelial cells. However, infection with

ECOVA Model

SCID mice reconstituted with CD4⁺ T cells from Tg mice bearing chicken OVA-specific TCR do not develop inflammation. Alternatively, preinoculation of Escherichia coli engineered to express OVA allows OVA-specific CD4⁺ T cells to induce transmural colitis in the recipient SCID mice within 12–20 days after CD4⁺ T-cell transfer.211, 212 A technical impediment confronted at the outset of this system is the difficulty in the development of laboratory E. coli that could stably express OVA in the

TNBS Model

Acute colitis in rats, mice, rabbits, and pig can be induced by an enema containing a contact-sensitizing allergen, trinitrobenzene sulfonic acid (TNBS), in 50% ethanol solution.²¹⁴ The TNBS initially causes acute discrete foci of necrosis and inflammation, and this change is believed to be followed by immune responses to “hapten-modified self-antigen.”⁴ In mice, TNBS colitis is highly dependent on the strains. SJL/J, C3HeJ, and Balb/c are susceptible strains, whereas C57BL/6 and DBA/2 are

Oxazolone Model

Oxazolone (4-ethoxylmethylene-2-phenyloxazol-5-one) is a classical haptenating agent that has historically been used for studying delayed-type hypersensitive responses in skin. An intrarectal administration of high dose (6 mg/mouse) of oxazolone resolved in ethanol induces rapid onset of inflammation in the distal part of colon in an autoimmune prone mouse strain SJL/J by 2 days after administration.²³⁰ This colitis is characterized by hemorrhagic inflammation and severe submucosal edema, and it

DSS Model

Dextran sulfate sodium (DSS) is polymer of sulfated polysaccharide. Continuous administration of 1–5% DSS in drinking water induces acute intestinal injury characterized by bloody diarrhea, ulcerations, intestinal inflammation, body weight loss, and shortening of colon length. This injury seems to be induced by direct hyperosmotic damage to epithelial cells²³⁷, and it can be induced in immune-deficient mice that lack T and B cells.²³⁸ C3H/HeJ mice are highly susceptible to this injury model as

Conclusion

There are currently many murine IBD models available to use. As proposed in Table VIII, each model has specific advantage(s) over other models. For example, a series of meritorious information to understand the adaptive immune mechanism involved in the pathogenesis of IBD have been brought from CD45RB model. TNBS model has provided significant impact on developing anti-IL-12p40 therapy that is currently applying to human CD. IL-10 KO model has provided significant contributions to the

Acknowledgments

We greatly thank Cindy W. Lau for her excellent editorial help and NIH (RO1AI081807, RC1DK086242), Crohn's and colitis foundation of America, and Broad Foundation for supporting our projects.

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T Cell Repertoire Homogeneity and Blood-Gut Overlap in Patients With Inflammatory Bowel Disease
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Inflammatory bowel disease (IBD) causes a marked increase in the number of T cells in the intestinal mucosa. Debate exists about whether these excess cells arise from local clonal proliferation or recruitment from the periphery.
CD8+ T cells were sorted from colon biopsy specimens and blood for T-cell receptor (TCR) β-chain sequencing. Biopsy specimens from inflamed or uninflamed colon from ulcerative colitis or Crohn’s disease cohorts were compared with colon biopsy specimens from people without IBD, as well as with autologous blood α4β7+, α4β7- effector/memory, terminal effector/memory CD45RA⁺ T cell, and mucosal-associated invariant T-cell CD8 subpopulations.
CD8 TCR diversity in mucosa and blood did not correlate with inflammation. Repertoire overlap between any 2 distinct locations of a given person’s colon was consistently high, although often lower between inflamed and uninflamed sites. CD8 TCR repertoires overlapped between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells. Inflamed tissue consistently overlapped more than uninflamed tissue with each blood subpopulation.
CD8 T-cell clones are spread homogenously throughout the length of the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar TCR diversity in both argues against local clonal expansion being the main source of excess cytotoxic T cells in inflamed mucosa. Rather, the increased TCR overlap observed between blood and inflamed mucosa supports the significance of T-cell trafficking in IBD pathogenesis, particularly concerning α4β7+ T-cell populations.
Anti-inflammatory effects of dietary β-Casein peptides and its peptide QEPVL in a DSS-induced inflammatory bowel disease mouse model
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β-Casein (β-CN) can be a good source of bioactive peptides in milk. It has several beneficial bioactive components that have anti-inflammatory and immunomodulatory properties. However, it is still unclear which peptides offer the strongest anti-inflammatory properties. The purpose of this research is to contrast the anti-inflammatory activity to alleviate inflammatory bowel disease (IBD) symptoms of β-CN hydrolyzed peptide (BP) and Gln-Glu-Pro-Val-Leu (QEPVL) peptide from β-CN (QP). Currently, we used a dextran sodium sulfate (DSS)-induced inflammatory bowel disease mouse model to assess the anti-inflammatory activity of the dietary β-CN peptides and its peptide QEPVL. The results showed that BP and QP groups had anti-inflammatory effect on the recovery of mice with ulcerative colitis caused by DSS. Compared with the QP group, the BP group can better alleviate the pathological characteristics of mice and suppress the production of inflammatory cytokines and genes associated with the NLRP3/NF-κB signaling pathway. In addition, the BP group improved microbial biodiversity, especially for the level of intestinal microbiota, by enriching the abundance of Erysipelotrichaceae in Firmicutes. These results enhance our understanding of the differential anti-inflammatory effects between β-Casein peptides and its characteristic peptide QEPVL. And how they can alleviate intestinal inflammation by regulating intestinal microbiota.
Chitosan-gentamicin conjugate attenuates heat stress-induced intestinal barrier injury via the TLR4/STAT6/MYLK signaling pathway: In vitro and in vivo studies
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Heat stress (HS) has a negative impact on animal health. A modified chitosan-gentamicin conjugate (CS-GT) was prepared to investigate its potential protective effects and mechanism of action on heat stress-induced intestinal mucosa injury in IPEC-J2 cells and mouse 3D intestinal organs in a mouse model. CS-GT significantly (P < 0.01) reversed the decline in transmembrane resistance and increased the FITC-dextran permeability of the IPEC-J2 monolayer fusion epithelium caused by heat stress. Heat stress decreased the expression of the tight binding proteins occludin, claudin1, and claudin2. However, pretreatment with CS-GT significantly increased (P < 0.01) the expression of these tight binding proteins. Mechanistically, CS-GT inhibited the activation of the TLR4/STAT6/MYLK signaling pathway induced by heat stress. Molecular docking showed that CS-GT can bind effectively with TLR4. In conclusion, CS-GT alleviates heat stress-induced intestinal mucosal damage both in vitro and in vivo. This effect is mediated, at least partly, by the inhibition of the TLR4/STAT6/MYLK signaling pathway and upregulation of tight junction proteins. These findings suggest that CS-GT may have therapeutic potential in the prevention and treatment of heat stress-related intestinal injury.
Chemically-induced trout model of acute intestinal inflammation using TNBS
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Chemically-induced models of intestinal inflammation are a useful tool for the study of immune responses and inflammation. Although well established in mammals, application of these models is currently limited in teleosts. Based on a variety of factors, including genetic diversity, known toxicological sensitivity, and economic importance, we propose salmonids as a model family of fishes for studying intestinal inflammation. We present a rainbow trout model of chemically-induced intestinal inflammation using 2,4,6-trinitrobenzene sulfonic acid (TNBS), assessed through histological analysis of primary and secondary intestinal folding, enterocyte morphology, goblet cell size and frequency, tissue layer thickness, and immune cell infiltration. Twenty-four hours after treatment with one of three concentrations of TNBS, trout developed classic signs of intestinal inflammation, including notably increased thickness of primary and secondary folds, and increased immune cell infiltration as compared to controls. This study provides a simple, reproducible model of rapid TNBS-induction of moderate intestinal inflammation.
Thymopentin ameliorates experimental colitis via inhibiting neutrophil extracellular traps
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The long-term prognosis of Crohn’s disease (CD) remains unsatisfactory. Therefore, we assessed the therapeutic effect of thymopentin (TP5) in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which mimics CD, and analyzed its impact on neutrophil extracellular traps (NETs).
NET markers, including myeloperoxidase (MPO), neutrophil elastase (NE), citrullinated histone H3 (CitH3), peptidyl arginine deiminase IV (PAD4), and double-stranded DNA (dsDNA) were assessed by immunostaining and enzyme-linked immunosorbent assay. NET formation was evaluated in vitro. Neoseptin 3, a specific NET agonist, was used to reverse the effect of TP5 on TNBS-induced colitis. The action mechanism of TP5 was investigated using RNA-seq.
TP5 ameliorated weight loss (P < 0.001), disease activity index (DAI) (P = 0.05), colon shrinkage (P = 0.04), and elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and neutrophils in the TNBS group. The TNBS group exhibited increased MPO, NE, CitH3, PAD4, dsDNA and MPO-DNA levels (all P < 0.001), which decreased after TP5 administration (P = 0.01, P < 0.001, P < 0.001, P < 0.001, P = 0.02, and P = 0.02 respectively). Tissue CitH3 levels were positively correlated with DAI and TNF-α levels (P < 0.05). Furthermore, phorbol 12-myristate 13-acetate-stimulated NET formation increased by 1.8-, 2.8-, and 2.3-fold in vitro in the control, TNBS + saline, and TNBS + TP5 groups, respectively. Neoseptin 3 significantly reversed the effect of TP5. RNA-seq revealed potential pathways underlying the effect of TP5.
TP5 effectively ameliorated colitis by suppressing NETs in the experimental CD model.
Vitamin D, microbiota, and inflammatory bowel disease
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Inflammatory bowel disease (IBD) is a chronic intestinal inflammation that occurs because of uncontrolled immune responses to commensal microbiota in the gut and is estimated to affect over 6.8 million people globally. The composition of the gut microbiota and vitamin D status have been shown to impact IBD susceptibility. Patients with IBD have dysbiosis of the microbiome. Vitamin D is an important regulator of the immune system, and patients with IBD are frequently vitamin D deficient. Vitamin D interventions were able to resolve dysbiosis of the gut microbiota, induce regulatory T cells that suppress colitis, and reestablish immune homeostasis. There is no cure for IBD. Immunosuppressive drugs are used to suppress the intestinal inflammation in patients with IBD, but these drugs are extremely expensive and increase the risk of infection and cancer. Vitamin D supplementation could be a safe and effective adjunct to the therapies available to treat or prevent IBD.

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Progress in Molecular Biology and Translational Science

Animal Models of Inflammatory Bowel Disease

Section snippets

Classification of Murine IBD Models

IL-10 KO Mice

IL-2 KO Mice

TCRα KO Mice

TGFβ KO Mice

TAK1 KO Mice

WASP KO Mice

P110δ Mutant Mice

PDK1 KO Mice

Cbl-b KO Mice

Blimp-1 KO Mice

A20 KO Mice

SHIP KO Mice

Gαi2 KO Mice

TNF(ARE) Mice

LIGHT Tg Mice

TNFSF15 Tg Mice

IL-7 Tg Mice

IL-15 Tg Mice

CD40L Tg Mice

Soluble B7.2 Tg Mice

Integrin αV KO Mice

Integrin β8 KO Mice

STAT4 Tg Mice

STAT3 KO Mice

SOCS1 Tg Mice

Gp130 KI Mice

NFκB1 KO Mice

Runx3 KO Mice

TLR5 KO Mice

Enteric Glia KO

XBP1 KO Mice

Atg5 KO Mice

mK8 KO Mice

N-Cadherin Mutant Mice

Mdr1a KO Mice

GPX KO Mice

Muc2 KO Mice

C1galt1 KO Mice

NFATc2/RAG DKO Mice

T-bet/RAG DKO Mice

Anti-CD40mAb Model

C3H/HeJBir Mice

SAMP1/Yit Model

CD45RB Model

Human CD3ε Model

CD8-Transfer Models

ECOVA Model

TNBS Model

Oxazolone Model

DSS Model

Conclusion

Acknowledgments

Unravelling the pathogenesis of inflammatory bowel disease

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Inflammatory bowel disease

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The production of an experimental ulcerative colitis in rabbits

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