The specific pathogenesis underlining inflammatory bowel disease (IBD) is very complicated, and it is further more difficult to clearly explain the pathophysiology of 2 major forms of IBD, Crohn’s disease (CD) and ulcerative colitis (UC), and both disorders affect individuals throughout life. Despite every extensive effort, the interplay among genetic factors, immunological factors, environmental factors and intestinal microbes is still completely unrevealed. Animal models are indispensable to find out mechanistic details that will facilitate better preclinical setting to target specific components involved in the pathogenesis of IBD. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, not only IBD but also colon cancer, obesity, psoriasis as well as allergic disorders, in both human and animal models. Advanced technologies including cell-specific and inducible knockout systems, which are recently employed to mouse IBD models, have further enhanced the ability of developing new therapeutic strategies for IBD. Furthermore, data from these mouse models highlight the critical involvement of dysregulated immune responses and impaired colonic epithelial defense system in the pathogenesis of IBD. In this review, we will explain from the history of animal models of IBD to the recent reports of the latest compounds, therapeutic strategies, and approaches tested on IBD animal models.

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.

Chitinase 3-like 1 (also known as CHI3L1 or YKL-40) is a mammalian chitinase that has no enzymatic activity, but has the ability to bind to chitin, the polymer of N-acetylglucosamine (GlcNAc). Chitin is a component of fungi, crustaceans, arthropods including insects and mites, and parasites, but it is completely absent from mammals, including humans and mice. In general, chitin-containing organisms produce mammalian chitinases, such as CHI3L1, to protect the body from exogenous pathogens as well as hostile environments, and it was thought that it had a similar effect in mammals. However, recent studies have revealed that CHI3L1 plays a pathophysiological role by inducing anti-apoptotic activity in epithelial cells and macrophages. Under chronic inflammatory conditions such as inflammatory bowel disease and chronic obstructive pulmonary disease, many groups already confirmed that the expression of CHI3L1 is significantly induced on the apical side of epithelial cells, and activates many downstream pathways involved in inflammation and carcinogenesis. In this review article, we summarize the expression of CHI3L1 under chronic inflammatory conditions in various disorders and discuss the potential roles of CHI3L1 in those disorders on various cell types.

Background & Aims Signaling lymphocyte activation molecule (Slamf)1 is a co-stimulatory receptor on T cells and regulates cytokine production by macrophages and dendritic cells. Slamf1 regulates microbicidal mechanisms in macrophages, therefore we investigated whether the receptor affects development of colitis in mice. Methods We transferred CD45RB^hi CD4⁺ T cells into Rag^−/− or Slamf1^−/− Rag^−/− mice to induce colitis. We also induced colitis by injecting mice with an antibody that activates CD40. We determined the severity of enterocolitis based on disease activity index, histology scores, and levels of cytokine production, and assessed the effects of antibodies against Slamf1 on colitis induction. We quantified migration of monocytes and macrophage to inflamed tissues upon induction of colitis or thioglycollate-induced peritonitis and in response to tumor necrosis factor-α in an air-pouch model of leukocyte migration. Results Colitis was reduced in Slamf1^−/− Rag^−/− mice, compared with Rag^−/− mice, after transfer of CD45RB^hi CD4⁺ T cells or administration of the CD40 agonist. The numbers of monocytes and macrophages were reduced in inflamed tissues of Slamf1^−/− Rag^−/− mice, compared with Rag^−/− mice, after induction of colitis and other inflammatory disorders. An antibody that inhibited Slamf1 reduced the level of enterocolitis in Rag^−/− mice. Conclusions Slamf1 contributes to the development of colitis in mice. It appears to indirectly regulate the appearance of monocytes and macrophages in inflamed intestinal tissues. Antibodies that inhibit Slamf1 reduce colitis in mice, so human SLAMF1 might be a therapeutic target for inflammatory bowel disease.

Caffeine (1,3,7-trimethylxanthine, also abbreviated to CAF) is a natural chemical with stimulant effects and is commonly included in many drinks and foods, including coffee, tea, cola, energy drinks, cocoa, chocolates, and so on. Our group previously reported that oral administration of CAF efficiently suppressed the development of intestinal inflammation in a dextran sulfate sodium (DSS)-induced murine acute colitis model by suppressing the expression of chitinase 3-like 1, one of the mammalian chitinases without enzymatic activity. Chitinases are hydrolytic enzymes that break down chitin, a polymer of N-acetylglucosamine, and chitinase-like proteins have no enzymatic activity with preserving chitin-binding ability. CAF binds a cleft of the chitinase active site and plays a role as a pan-chitinase inhibitor. Although CAF showed an anti-inflammatory effect in the above model, oral administration of low-dose CAF with 10% sucrose showed potentially neoplastic effects in colonic epithelial cells in a DSS-induced murine chronic colitis model. In this review, we would like to discuss the pros and cons of coffee/CAF in colonic inflammation and neoplasia with an example of pathological finding.

Inflammatory bowel disease (IBD) is a dysregulated inflammatory condition induced by multiple factors. The etiology of IBD is largely unknown, and the disease progression and prognosis are variable and unpredictable with uncontrolled disease behavior. Monitoring the status of chronic colitis closely is challenging for physicians, because the assessment of disease activity and severity require invasive methods. Using laboratory biomarkers may provide a useful alternative to invasive methods in the diagnosis and management of IBD. Furthermore, patients with ulcerative colitis or Crohn’s disease are also at risk of developing cancer. Annual colonoscopies can help lower the risk for developing colorectal cancer. However, laboratory biomarkers may also be helpful as non-invasive indicators in predicting treatment responses, improving prognosis, and predicting possible tumors. This review addresses selected laboratory biomarkers (including ANCA, chitinase 3-like 1, S100A12/RAGE, calprotectin, and TNF/TNFR2), which are identified by utilizing two well-accepted animal models of colitis, dextran sodium sulfate-induced and T cell receptor alpha knockout colitis models. In addition to being useful for monitoring disease severity, these biomarkers are associated with therapeutic strategies. The factors may regulate the initiation and perpetuation of inflammatory factors in the gut.