Crohn's disease is a chronic inflammatory condition of the gastrointestinal (GI) tract, categorized under inflammatory bowel diseases (IBD). It is characterized by a relapsing and remitting pattern of inflammation that can affect any part of the GI tract, from the oral cavity to the anus, though it most commonly involves the terminal ileum and colon. The pathogenesis of Crohn’s disease is multifactorial, involving complex interactions between genetic susceptibility, immune dysregulation, environmental triggers, and microbial factors.

Pathogenesis and Mechanisms:

In Crohn’s disease, an abnormal immune response to intestinal microbiota occurs in genetically predisposed individuals. Genetic mutations, such as those in the NOD2/CARD15 gene, lead to impaired recognition of bacterial components --> altered mucosal immune response. Dysregulation of innate and adaptive immune pathways --> ↑ production of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-12/23) and recruitment of immune cells like T-helper 1 (Th1) and Th17 cells --> chronic intestinal inflammation.

The imbalance between pro-inflammatory (e.g., TNF-α, IFN-γ) and anti-inflammatory mediators (e.g., IL-10) --> ↑ NF-κB activation --> transcription of inflammatory genes --> ↑ cytokine release, immune cell infiltration, and epithelial barrier dysfunction. Dysbiosis of the gut microbiome --> ↑ pathogenic bacteria, ↓ beneficial commensals, further perpetuating the inflammatory cycle. Mucosal damage leads to transmural inflammation --> ulcerations, fistulas, and strictures.

Treatment Approaches:

Treatment of Crohn’s disease aims to induce and maintain remission, reduce inflammation, manage symptoms, and prevent complications. The therapeutic strategy often involves a combination of pharmacological, nutritional, and surgical interventions tailored to disease severity and location.

Pharmacological Management:

1. Anti-inflammatory Agents: 5-ASA compounds are used for mild disease; however, their efficacy in Crohn's is limited. Corticosteroids (e.g., prednisone) act by binding to glucocorticoid receptors --> ↓ pro-inflammatory gene expression through inhibition of NF-κB and AP-1 pathways but are not suitable for long-term use due to side effects.

2. Immunomodulators: Azathioprine and 6-mercaptopurine --> purine synthesis inhibition --> ↓ lymphocyte proliferation. Methotrexate inhibits dihydrofolate reductase --> ↓ thymidine and purine synthesis, suppressing immune cell proliferation. These agents are used to maintain remission and as steroid-sparing therapies.

3. Biologics: TNF-α inhibitors (e.g., infliximab, adalimumab) directly bind to TNF-α --> ↓ TNF-α mediated signaling, blocking downstream pathways like JAK/STAT and MAPK --> ↓ cytokine production, immune cell activation, and epithelial apoptosis. Anti-integrin agents (e.g., vedolizumab) inhibit lymphocyte trafficking to the gut, while IL-12/23 inhibitors (e.g., ustekinumab) disrupt Th1/Th17 mediated inflammation.

4. Antibiotics: Used for complications like abscesses or fistulas, metronidazole, and ciprofloxacin --> ↓ bacterial load, modulating gut microbiota and reducing secondary inflammation.

Nutritional Therapy and Surgery:

Nutritional interventions, including exclusive enteral nutrition (EEN), serve as first-line therapy in pediatric patients and adjuncts in adults, promoting mucosal healing by modulating gut microbiota and ↓ antigen exposure. Surgery is reserved for refractory disease or complications (e.g., obstruction, perforation), with resections often followed by biologic therapy to prevent recurrence.

Curcumin (from Turmeric)

• Curcumin is one of the most potent natural inhibitors of TNF-alpha. It modulates multiple signaling pathways, including NF-κB, a major regulator of TNF-alpha production.

Epigallocatechin Gallate (EGCG) (from Green Tea)  ***MATCHA TEA ***

• EGCG is a powerful catechin with strong inhibitory effects on TNF-alpha and related pro-inflammatory cytokines. It also suppresses the activation of NF-κB.

Resveratrol (from Grapes, Red Wine)

• Resveratrol inhibits TNF-alpha production through its anti-inflammatory and antioxidant effects. It downregulates inflammatory pathways, including NF-κB and STAT3.

Quercetin (found in Apples, Onions)

• Quercetin is a flavonoid that reduces TNF-alpha levels by inhibiting NF-κB and other inflammatory mediators, making it an effective anti-inflammatory agent.

Boswellic Acids (from Frankincense)

• Boswellic acids exhibit strong anti-inflammatory effects, including TNF-alpha inhibition. They work by blocking 5-lipoxygenase, which indirectly suppresses TNF-alpha.

Apigenin (from Chamomile, Parsley)

• Apigenin reduces TNF-alpha production through its inhibitory effects on the NF-κB pathway and other inflammatory cytokines.

Berberine (from Goldenseal, Barberry)

• Berberine decreases TNF-alpha levels and modulates inflammatory responses through the AMPK and NF-κB pathways.

Gingerol (from Ginger)

• Gingerol exhibits moderate TNF-alpha inhibition by blocking inflammatory pathways, including COX-2 and NF-κB.

Sulforaphane (from Broccoli, Brussels Sprouts)

• Sulforaphane reduces TNF-alpha production via its antioxidant and anti-inflammatory effects, particularly through modulation of Nrf2 and NF-κB.

Capsaicin (from Chili Peppers)

• Capsaicin has moderate effects on reducing TNF-alpha, primarily by inhibiting inflammatory signaling pathways.

Treatments and treatment categories for Crohn's disease: 

1. Anti-inflammatory Medications: Reduce inflammation in the gut |Examples: Corticosteroids (e.g., prednisone) are used short-term to control inflammation.

2. Immune System Suppressors (Immunomodulators): Purpose: Suppress or weaken the immune system to reduce inflammation.

• Examples: Azathioprine, 6-Mercaptopurine (6-MP), and Methotrexate.

3. Biologic Therapies (Biologics): Target specific parts of the immune system that trigger inflammation.

• Examples 

  • TNF-α inhibitors (e.g., Infliximab, Adalimumab) that block proteins causing inflammation.

  • Anti-integrin agents (e.g., Vedolizumab) that prevent immune cells from moving into the gut.

4. Antibiotics: Treat infections and reduce harmful bacteria in the gut.

• Examples:

  • Metronidazole and Ciprofloxacin, often used for complications like abscesses or fistulas.

5. Nutritional Therapy:

• Purpose: Use special diets to reduce symptoms, provide nutrition, and promote healing.

• Examples:

  • Exclusive enteral nutrition (liquid diets) used especially in children.

6. Surgery:

• Purpose: Remove damaged sections of the digestive tract or treat complications when medications are not enough.

• Examples:

  • Bowel resection (removing a part of the intestine), drainage of abscesses, or opening blocked areas.

Treatments and treatment categories for Crohn's disease: 

1. Anti-inflammatory Medications: Reduce inflammation in the gut |Examples: Corticosteroids (e.g., prednisone) are used short-term to control inflammation.

2. Immune System Suppressors (Immunomodulators): Purpose: Suppress or weaken the immune system to reduce inflammation.

• Examples: Azathioprine, 6-Mercaptopurine (6-MP), and Methotrexate.

3. Biologic Therapies (Biologics): Target specific parts of the immune system that trigger inflammation.

• Examples 

  • TNF-α inhibitors (e.g., Infliximab, Adalimumab) that block proteins causing inflammation.

  • Anti-integrin agents (e.g., Vedolizumab) that prevent immune cells from moving into the gut.

4. Antibiotics: Treat infections and reduce harmful bacteria in the gut.

• Examples:

  • Metronidazole and Ciprofloxacin, often used for complications like abscesses or fistulas.

5. Nutritional Therapy:

• Purpose: Use special diets to reduce symptoms, provide nutrition, and promote healing.

• Examples:

  • Exclusive enteral nutrition (liquid diets) used especially in children.

6. Surgery:

• Purpose: Remove damaged sections of the digestive tract or treat complications when medications are not enough.

• Examples:

  • Bowel resection (removing a part of the intestine), drainage of abscesses, or opening blocked areas.