Ulcerative colitis (UC) arises from a gene–environment interaction. In a genetically susceptible host, environmental exposures lead to a defective epithelial barrier, gut microbial dysbiosis, and a dysregulated mucosal immune response. Together these start and sustain continuous mucosal inflammation of the colon.^[1][2] There is no single causative agent. Genetics, barrier failure, dysbiosis, and immune dysregulation each contribute, but none is sufficient on its own.^[3] The adaptive immune response in UC is classically an atypical Th2 response driven by NKT cells through IL-13. This contrasts with the Th1 pattern of Crohn’s disease, and both diseases share a Th17/IL-23 axis.^[4][5] Each mechanistic node maps to an approved drug class: anti-TNF, anti-integrin, anti-IL-12/23 or IL-23, JAK inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators. This mapping is the main clinical value of understanding UC pathogenesis.^[1]

• Inflammation is confined to the mucosa. It begins in the rectum and extends proximally in a continuous pattern to a variable length of the colon.^[6]

UC is a multifactorial disorder with four interacting domains:^[1][2][7]

• Genetic susceptibility
  • Genome-wide association studies have identified more than 200 IBD risk loci. These loci are enriched for genes involved in intestinal barrier function and T-cell immunity.^[1][2]
  • Known risk variants explain only about 19–26% of IBD heritability.^[8]
  • Genotyping therefore does not predict disease onset or phenotype and has no routine clinical role.^[2]
• Environmental triggers
  • Smoking has a distinctive relationship with UC. Current smoking is associated with a lower risk, while former smokers and recent quitters have a higher risk.^[6]
  • Other modifiers include appendectomy, NSAIDs, antibiotics, enteric infections, and diet. Many of these act by reshaping the microbiome.^[2][6]
• Epithelial barrier dysfunction is an early and possibly primary event (see below).
• Immune dysregulation consists of aberrant innate and adaptive responses to luminal microbial antigens.

Barrier failure is detectable early in the disease. It is increasingly viewed as a primary driver rather than only a consequence of inflammation.^[7][6]

• Mucus layer defects: reduced mucin 2 (MUC2) synthesis and goblet cell depletion make the mucus barrier thinner and more permeable.^[7][6]
• Tight junction disruption: downregulation of occludin, claudins, and tricellulin increases paracellular permeability.^[7]
• Pre-clinical changes:
  • Foci of epithelial apoptosis appear before endoscopic disease.^[7]
  • Unaffected first-degree relatives show increased intestinal permeability.^[7]
• Epithelial stress pathways: two mechanisms link genetic and environmental hits to epithelial inflammation.^[7][6]
  • Reduced colonocyte PPAR-γ expression. PPAR-γ normally restrains NF-κB.
  • Unresolved endoplasmic reticulum stress, for example through the XBP1 pathway.
• Once the barrier fails, luminal microbial antigens reach immune cells in the lamina propria. This sets up a self-reinforcing cycle of inflammation and further barrier injury.^[7][9]

• Characteristic changes in the UC microbiome:^[6][8]
  • Reduced microbial diversity.
  • Depletion of commensals that produce short-chain fatty acids (SCFAs), such as Faecalibacterium prausnitzii.
  • Expansion of facultative pathobionts, including Escherichia coli and other Enterobacteriaceae and Proteobacteria.
• No single causative organism: no pathogen reproducibly causes UC. Disease reflects altered proportions of normally resident taxa and opportunistic pathobionts.^[3][8]
• Dysbiosis is both cause and consequence:^[10][9]
  • The inflamed mucosa is rich in oxygen and nitrate, which favors aerotolerant Proteobacteria and perpetuates inflammation.
  • The direction of causality remains unresolved.
• Functional consequences: loss of SCFAs (colonocyte fuel and inducers of regulatory T cells) and activation of toll-like receptor–NF-κB signaling amplify release of pro-inflammatory cytokines.^[6][10]

• After antigens cross the epithelium, dendritic cells, macrophages, and neutrophils are activated.^[2]
• A hallmark of UC is mucosal neutrophil accumulation with neutrophil extracellular traps (NETs). NETs amplify TNF and IL-1β signaling.^[2]
• Dendritic cells shift to a pro-inflammatory, less tolerogenic phenotype and induce fewer regulatory T cells.^[2]

• Atypical Th2 response: non-classic NKT cells produce IL-5 and IL-13.^[4][5]
  • IL-13 is directly cytotoxic to epithelial cells.
  • It induces apoptosis and disrupts tight junctions.
• Th9 cells: these PU.1⁺ cells are induced by epithelial IL-33 and produce IL-9.^[5][11]
  • They are more enriched in UC mucosa than in Crohn’s disease.
  • They impair epithelial proliferation and barrier function.
• Th17 cells: these RORγt⁺ cells are driven by IL-23 and produce IL-17, IL-21, and IL-22. They are present in both UC and Crohn’s disease.^[5][12]
• Effector:regulatory T-cell imbalance: impaired regulation by IL-10 and TGF-β sustains inflammation.^[4]
  • Loss-of-function mutations in IL-10 or its receptor cause severe early-onset colitis.
• T-cell plasticity: T cells can change phenotype, for example Th17 cells converting to Th1 cells or mixed FOXP3⁺IL-17⁺ cells appearing. Together with redundancy in the cytokine network, this helps explain why blocking a single cytokine often fails.^[13]

Adapted from Neurath 2017 and Neurath 2019.^[12][5]

Table sources: Gros 2023, Le Berre 2023, Neurath 2019.^[1][2][5]

Each agent blocks only one node of a redundant inflammatory network. As a result, only about 30–60% of patients respond to any given advanced therapy. This explains primary non-response and supports sequencing or combining mechanisms.^[1][13]