May 19th each year marks World Inflammatory Bowel Disease (IBD) Day. IBD is a heterogeneous groupof diseases characterized primarily by chronic, relapsing intestinal inflammation, encompassing Crohn's disease (CD) and Ulcerative Colitis (UC). It differs fundamentally from common irritable bowel syndrome or infectious diarrhea: it is a non-self-healing, lifelong condition where the immune system attacks the body's own intestinal tissues, frequently complicated by intestinal perforation, strictures, and colorectal neoplasia.
 

Statistics reveal significant regional disparities in the incidenceof UC and CD: the highest rates are observed in North America (19.2/100,000 for UC; 20.2/100,000 for CD), Asia (6.3/100,000 for UC; 5.0/100,000 for CD), and Europe (24.3/100,000 for UC; 12.7/100,000 for CD).
 

Pathogenesis
 

The pathogenesisof IBD is not attributableto a single factor but results from the combined effects of multiple mechanisms, including intestinal mucosal immune dysregulation, gut barrier impairment, microbiota dysbiosis, and redox imbalance (ROS homeostasis).
 

Image source: Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives
 

Intestinal Mucosal Immune Dysregulation
 

The essenceof intestinal mucosal immune dysregulation is a vicious cycle formed by excessive innate immune activation and adaptive immune imbalance. At the molecular level, hyperactivation of the TLR2/4-mediated NF-κB pathway serves as the starting pointfor the inflammatory outbreak, driving the massive releaseof pro-inflammatory cytokines like TNF-α and IL-1β, which directly exacerbate tissue damage. Concurrently, the intestinal hypoxic microenvironment and redox imbalance create a "double hit": While Hypoxia-Inducible Factor HIF-1α attempts to upregulate barrier-protective genes, HIF-2α promotes epithelial inflammation and proliferation, potentially increasing carcinogenic risk. Abnormal activationof NADPH oxidases (NOX1/2) and Dual Oxidases (DUOX2) leads to excessive ROS production. While physiologically intended for bacterial defense, this excess ROS damages epithelial DNA and proteins, accelerating disease progression.
 

At the cellular level, NK cells and γδ T cells undergo metabolic reprogramming—mitochondrial dysfunction and mTORC1 inhibition lead them to secrete large amounts of IL-17 and TNF-α, while simultaneously losing their cytotoxic and pathogen-clearing capabilities. This results in persistent inflammation that is difficult to repair.
 

Intestinal Mucosal Adaptive Immune Dysregulation
 

Research indicates that adaptive immune responses play a crucial role in the pathogenesis and progressionof IBD. The imbalance in T cell subset lineage constitutes the core pathology: the excessive expansionof Th1/Th17 effector cells and the impaired functionof Regulatory T cells (Tregs) disrupt critical immune homeostasis. This imbalance leads to the massive releaseof pro-inflammatory cytokines (TNF-α, IFN-γ, IL-17), while anti-inflammatory mediators (e.g., IL-10) are relatively scarce, forming a self-amplifying inflammatory cascade.
 

Beyond classic CD4+ T cells, the pathological roleof B cells is becoming increasingly prominent. Aberrant B cell activation and elevated BAFF levels in the mucosa not only drive local antibody responses but also recruit cells to the colon via axes like CCR8-CCL1, exacerbating inflammation through enhanced differentiation.
 

Intestinal Barrier Injury
 

Intestinal Epithelial Cells (IECs) form the frontline defenseof the gut barrier. Barrier dysfunction is a core driverof IBD onset and progression, with the pathological essence lying in the combined effectof epithelial junctional defects and Endoplasmic Reticulum Stress (ERS). Abnormal expressionof tight junction proteins (e.g., Claudin family, Occludin) and a "leaky phenotype" mediated by Claudin-2 often precede clinical inflammation, suggesting their pivotal role in disease initiation. Simultaneously, ERS and mitochondrial dysfunction disrupt intracellular homeostasis.叠加 with the exacerbationof epithelial damage by pro-inflammatory cytokines like TNF-α/IFN-γ via MLCK/MLC and JAK/STAT pathways, while protective mechanisms like IL-22 are relatively deficient. This structural breakdown and imbalanced immune microenvironment leadto the collapseof epithelial injury-repair homeostasis, ultimately driving the sustained progressionof chronic inflammation.
 

Gut Microbiota Dysbiosis
 

The signatureof gut microbiota dysbiosis is characterized by the depletionof butyrate-producing bacteria and the enrichmentof pathogenic bacteria. This dysbiosis not only weakens the epithelial barrier due to Short-Chain Fatty Acid (SCFA) deficiency but also drives aberrant immune responses like Th17 polarization, breaking immune homeostasis. Concurrently, pathogens can directly disrupt tight junctions, while probiotics exert protective effects via metabolites and immunomodulation. Thus, the bidirectional imbalance between microbiota structure changes and host barrier-immune interactions forms the pathological cornerstoneof chronic IBD progression.
 

Redox Homeostasis Imbalance (ROS)
 

The dynamic imbalanceof Reactive Oxygen Species (ROS) involves mitochondrial sources, NADPH oxidases, and myeloid cell-derived ROS bursts. Under physiological conditions, moderate ROS participate in immune defense and epithelial homeostasis maintenance. However, under pathological conditions, excessive ROS not only directly cause epithelial barrier disruption and mucosal injury but also exacerbate immune dysregulation by regulating Th1/Th17 polarization and macrophage phenotype switching. Furthermore, ROS-driven ferroptosis and lipid peroxidation further amplify inflammatory cascades and negatively interact with the gut microecology, jointly promoting the chronicification and fibrotic processesof IBD.
 

Image source: Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives
 

Common Mouse Models
 

IL-10 ⁻/⁻ Mice:​ Due to the lackof the key anti-inflammatory cytokine IL-10, these mice spontaneously develop chronic colitis in SPF environments. They serve as a standard model for studying the breachof immune tolerance and microbe-host interactions.
 

TCRα ⁻/⁻ Mice:​ T cell receptor deficiency leads to immune dysregulation characterized by a Th2-biased immune response, often accompanied by autoantibodies. They are primarily usedto model the pathological mechanismsof Ulcerative Colitis (UC).
 

Mdr1a ⁻/⁻ Mice:​ Multidrug resistance gene deficiency results in epithelial barrier defects. Under microbial stimulation, they are prone to developing Th1/Th17-type colitis and are frequently usedto assess the roleof barrier function in IBD initiation.
 

Supporting Gene Therapy
 

Gene therapy offers hope for common diseases, but its development and validation rely heavily on animal model support. MingCeler Biotech, leveraging its self-developed TurboMice™ technology, has developed multiple disease mouse models. TurboMice™ technology overcomes the technical challengesof long mouse model generation cycles and low success rates for complex models, enabling editing at almost any target gene locus. Complete homozygous gene-edited mouse models can be prepared directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech​ can customize various IBD mouse models accordingto client needs, such as IL-10 ⁻/⁻ mice, TCRα ⁻/⁻ mice, and Mdr1a ⁻/⁻ mice. Inquiries are welcome.
 

References:

1.Yang X, Guo H, Zou M. Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives. Mol Biomed. 2026 Jan 7;7(1):2. doi: 10.1186/s43556-025-00395-z. PMID: 41495287; PMCID: PMC12775382.

Zhang J, Wu D. Research progress on the pathogenesis of inflammatory bowel disease [J]. Bioprocess, 2024, 14(4):225-234. DOI: 10.12677/bp.2024.144028