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Inflammatory Bowel Disease (IBD): Types, Subtypes & Pathophysiology

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1. Types and Subtypes of IBD

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A. Crohn's Disease (CD)

• B1 - Non-stricturing, non-penetrating (inflammatory): most common at diagnosis
• B2 - Stricturing: luminal narrowing from fibrosis, risk of obstruction
• B3 - Penetrating (fistulizing): deep fissures form fistulas (enteroenteric, enterovesical, perianal), abscesses, and perforation

• A1: <16 years
• A2: 17-40 years
• A3: >40 years

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B. Ulcerative Colitis (UC)

• Mild: <4 stools/day, minimal systemic signs, no anemia
• Moderate: 4-6 stools/day, mild systemic signs
• Severe (Truelove-Witts): >6 bloody stools/day with systemic toxicity (fever, tachycardia, anemia, elevated ESR/CRP)
• Fulminant: >10 bloody stools/day, continuous bleeding, abdominal tenderness - risk of toxic megacolon

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C. IBD-Unclassified (IBDU) / Indeterminate Colitis

• Used when colonoscopic or histological findings do not clearly distinguish CD from UC, particularly in colonic disease
• Accounts for ~5-10% of IBD cases
• May be reclassified after further evaluation or resection specimen review

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Comparison: CD vs. UC at a Glance

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2. Pathophysiology of IBD

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A. Genetic Susceptibility

• Over 200 IBD-associated risk alleles have been identified; together they account for <20% of disease risk in CD and even less in UC - confirming IBD is a polygenic disorder
• NOD2 (chromosome 16): the most strongly associated gene with Crohn's disease. NOD2 encodes an intracellular sensor of muramyl dipeptide (MDP), a bacterial cell wall peptidoglycan. Three common polymorphisms (Arg702Trp, Gly908Arg, Leu1007fsX1008) are present in ~30% of CD patients in European populations but only ~5% of healthy individuals. NOD2 activation triggers NF-kB and MAPK signaling, producing TNF-α and IL-1β. Loss-of-function mutations impair bacterial clearance.
• ATG16L1: involved in autophagosome formation. The T300A mutation leads to abnormal Paneth cell granule formation and defective secretion of antimicrobial defensins.
• PTPN22: increases CD risk but is protective in UC - one of few genes differentially associated with the two diseases
• Genes at IL10/IL10RA/IL10RB loci: loss-of-function mutations here cause monogenic IBD (very-early-onset infantile colitis)
• IBD risk alleles overlap significantly with type 1 diabetes, ankylosing spondylitis, and psoriasis - reflecting shared immune mechanisms

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B. Intestinal Epithelial Barrier Dysfunction

• Intercellular tight junctions and adherens junctions
• Mucus layer produced by goblet cells
• Antimicrobial peptides secreted by Paneth cells (defensins, lysozyme)
• Immune regulation by intestinal epithelial cells (IEC)

• IBD risk genes CDH1, HNF4A, GNA12, MUC19, ITLN1 all affect barrier integrity. For example, CDH1 polymorphisms produce a truncated E-cadherin → defective goblet cell and Paneth cell maturation → reduced clearance of pathogenic bacteria.
• PTPN2 and GNA12 maintain tight junction integrity; PTPN2-deficient mice develop colitis.
• NOD2 and ATG16L1 mutations → Paneth cell defects → reduced defensin secretion → impaired bacterial clearance
• Endoplasmic reticulum (ER) stress: XBP1 deletion causes spontaneous colitis; disruption of the unfolded protein response (UPR) increases susceptibility. This is particularly relevant to the secretory burden on Paneth cells and goblet cells.
• Even healthy first-degree relatives of CD patients show increased intestinal permeability - indicating barrier defects may be a primary predisposing factor, not just a consequence of inflammation.

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C. Gut Microbiome and Dysbiosis

• The gut microbiome (bacteria, fungi, viruses) normally exists in homeostasis with the host immune system
• Patients with IBD consistently show dysbiosis - shifts in microbial populations and reduced species diversity
• Altered microbial metabolites (short-chain fatty acids, bile acids, tryptophan metabolites) affect immune and epithelial function
• The "hygiene hypothesis": improved sanitation and food storage have altered microbial exposures during early life, impairing development of regulatory immune processes - this may explain the rising IBD incidence in historically low-prevalence regions (Africa, South America, Asia)
• Dietary emulsifiers (polysorbate-80, carboxymethylcellulose) found in processed foods may disrupt the mucous barrier, contributing to dysbiosis and intestinal inflammation

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D. Innate Immune Dysregulation

• Dendritic cells and macrophages sense microbiota via pattern recognition receptors (PRRs) recognizing pathogen-associated molecular patterns (PAMPs)
• Bacterial antigens are presented via HLA class II molecules on dendritic cells, activating the innate immune response
• NOD2 variants, ATG16L1, CARD9, IL18RAP, and SLC11A1 polymorphisms all lead to a defective innate immune response to luminal antigens
• Defective bacterial killing by neutrophils and macrophages in CD paradoxically prolongs the inflammatory stimulus - the gut cannot clear the inciting organisms

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E. Adaptive Immune Dysregulation (T-Cell Polarization)

• Dominant Th1 response: dendritic cell-derived IL-12 → Th1 polarization → IFN-γ and TNF-α production → macrophage activation and granuloma formation
• Th17 response: dendritic cell-derived IL-23 → Th17 polarization → IL-17, IL-22, IL-21 → neutrophil recruitment and epithelial damage

• More prominent Th2 component: → IL-13 and IL-5 → epithelial barrier damage (IL-13 disrupts tight junctions)
• Th1/Th17 responses also occur

• In the steady state, tolerogenic DCs (CD103+) produce IL-10 and IL-27, expanding Tregs that suppress Th1/Th17
• In IBD, this regulatory circuit fails: Tregs are numerically reduced or functionally impaired → Th1/Th17 dominate → chronic inflammation perpetuates

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F. Autophagy Defects

• ATG16L1 and IRGM variants impair autophagosome formation
• Autophagy normally eliminates damaged organelles, clears reactive oxygen species, and kills intracellular pathogens
• In CD, the ATG16L1 Crohn-associated mutation accelerates protein degradation → impaired autophagy → structurally and functionally abnormal Paneth cell granules → reduced antimicrobial defensin secretion → persistent intracellular bacteria → sustained inflammation

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Summary: The Unified Pathophysiological Model

1. Genetic susceptibility (NOD2, ATG16L1, HLA, PTPN22, IL10, etc.) creates baseline vulnerability
2. Environmental triggers (diet, hygiene, antibiotics, smoking, stress) alter the gut microbiome → dysbiosis
3. Barrier dysfunction (leaky tight junctions, defective mucus, impaired Paneth cells) allows luminal antigens to translocate into the mucosa
4. Antigen exposure activates innate immune cells (dendritic cells, macrophages) via NOD2 and other PRRs
5. Ineffective bacterial clearance (defective autophagy) sustains the antigenic stimulus
6. Innate cells prime CD4+ T cells → predominantly Th1/Th17 polarization (with some Th2 in UC)
7. Proinflammatory cytokines (TNF-α, IFN-γ, IL-17, IL-12/23) drive transmural (CD) or mucosal (UC) inflammation
8. Regulatory T-cell failure prevents resolution → chronic relapsing inflammation
9. Chronic inflammation causes crypt destruction, fibrosis (CD), mucosal ulceration, and ultimately complications (strictures, fistulas in CD; toxic megacolon, dysplasia in UC)

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• Robbins, Cotran & Kumar Pathologic Basis of Disease - Pathogenesis section, Ch. 17
• Yamada's Textbook of Gastroenterology, 7th ed. - Ch. 62 (Intestinal epithelial barrier, immune response)
• Goldman-Cecil Medicine International Edition - Ch. 127 (Clinical characteristics table, UC/CD morphology)
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease - Ch. 115 (CD activity, disease patterns)