Crohn’s Disease: Causes

Pathogenesis (disease development)

To date, it is not clear what causes Crohn’s disease. Genetic, familial, infectious, and immunologic causes are discussed. What is certain is a dysbalance of pro- and anti-inflammatory messenger substances. Among the proinflammatory (inflammation-promoting) cytokines, tumor necrosis factor (TNF) plays a key role.

Etiology (causes)

Biographic Causes

  • Genetic burden
    • Familial clustering – first-degree relatives with affected individuals have a 5- to 20-fold increased risk of developing inflammatory bowel disease. Numerous studies have identified a variety of genes that may play a role in the occurrence of Crohn’s disease; these genes are subject to mutation and are involved in the regulation of the immune system of the intestinal mucosaGenetic predisposition – disorder or dysfunction of the immune system of the intestinal mucosa with chronic inflammatory response – immune and inflammatory mediators, such as cytokines, prostaglandins, and leukotrienes, have been detected in increased concentrations in tissues of Crohn’s patients. Patients whose colon is affected by the disease have fewer copies of the gene responsible for so-called beta defensin-2 – an endogenous peptide antibiotic – according to an international study. Defensins are peptides composed of only about 30 protein building blocks and act like the body’s own antibiotics, protecting mucous membranes from bacterial attack. Patients with colon involvement from Crohn’s disease have low levels of beta-defensins in their mucous membranes.
      • Genetic risk dependent on gene polymorphisms:
        • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
          • Genes: ATG16L1, BSN, IBD5, CDKAL1, IL23R, NOD2, PTPN2.
          • SNP: rs2066844 in the NOD2 gene.
            • Allele constellation: CT (3.0-fold).
            • Allele constellation: TT (35.0-fold)
          • SNP: rs2066845 in the gene NOD2
            • Allele constellation: CG (3.0-fold).
            • Allele constellation: CC (35.0-fold)
          • SNP: rs2066847 in the gene NOD2
            • Allele constellation: DI (3.0-fold).
            • Allele constellation: II (35.0-fold)
          • SNP: rs17234657 in an intergenic region.
            • Allele constellation: GT (1.54-fold).
            • Allele constellation: GG (2.32-fold)
          • SNP: rs6596075 in the gene IBD5
            • Allele constellation: CG (1.5-fold).
            • Allele constellation: CC (2.0-fold)
          • SNP: rs2542151 in the gene PTPN2
            • Allele constellation: GT (1.3-fold).
            • Allele constellation: GG (2.0-fold)
          • SNP: rs6908425 in the gene CDKAL1
            • Allele constellation: CT (1.63-fold).
            • Allele constellation: CC (1.95-fold)
          • SNP: rs1000113 in an intergenic region.
            • Allele constellation: CT (1.5-fold).
            • Allele constellation: TT (1.9-fold)
          • SNP: rs17221417 in the gene NOD2
            • Allele constellation: CG (1.3-fold).
            • Allele constellation: GG (1.9-fold)
          • SNP: rs11805303 in the gene IL23R
            • Allele constellation: CT (1.4-fold).
            • Allele constellation: TT (1.8-fold)
          • SNP: rs10210302 in the gene ATG16L1
            • Allele constellation: CT (1.2-fold).
            • Allele constellation: TT (1.8-fold)
          • SNP: rs9858542 in the gene BSN
            • Allele constellation: AG (1.1-fold).
            • Allele constellation: AA (1.8-fold)
          • SNP: rs12037606 in an intergenic region.
            • Allele constellation: AG (1.22-fold).
            • Allele constellation: AA (1.52-fold)
          • SNP: rs6601764 in an intergenic region.
            • Allele constellation: CT (1.16-fold).
            • Allele constellation: CC (1.52-fold)
          • SNP: rs7753394 in an intergenic region.
            • Allele constellation: CT (1.2-fold).
            • Allele constellation: CC (1.5-fold)
          • SNP: rs9469220 in an intergenic region.
            • Allele constellation: AG (1.1-fold).
            • Allele constellation: AA (1.5-fold)
          • SNP: rs7807268 in an intergenic region.
            • Allele constellation: CG (1.3-fold).
            • Allele constellation: CC (1.4-fold)
          • SNP: rs11209026 in the gene IL23R
            • Allele constellation: AG (0.14-fold).
            • Allele constellation: AA (< 0.14-fold)
  • Delivery by caesarean section (cesarean section; risk increase for inflammatory bowel disease 20%).
  • Skin type – fair-skinned people are affected twice as often as dark-skinned people.
  • Breastfeeding time – the longer the mother breastfeeds, the lower the risk of the child getting the disease

Behavioral causes

  • Nutrition
    • Food components, especially increased use of refined carbohydrates – white sugar, white flour products.
    • Low consumption of fiber
    • High consumption of chemically processed edible fats
    • Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
  • Consumption of stimulants
    • Tobacco (smoking) – major risk factor for manifestation (smokers have 2 times higher risk of disease) and for complicated courses.
    • Furthermore, children of mothers who smoked during pregnancy have twice the risk of disease compared with children of non-smoking mothers
  • Psycho-social situation
    • Conflict situations
    • Stress – can lead to the occurrence of new relapses
  • Hygiene situation – regular contact with stabled animals or their excreta in the first year of life is statistically associated with a halving of the risk of developing Crohn’s disease by the age of 18 (hypothesis: lack of confrontation with parasites and microbial toxins increases the risk of “misprogramming” the immune system, leading to autoimmune diseases)

Medication

  • Repeated and early use of antibiotics, especially those with a broad spectrum of activity.
  • Taking non-steroidal anti-inflammatory drugs (NSAIDs).
  • TNF blockers (biologics that neutralize tumor necrosis factor alpha): etanercept: adjusted hazard ratio of 2.0 (95% confidence interval 1.4 to 2.8); no increased risk was detectable for infliximab and adalimumab.

Environmental exposure – intoxications (poisonings).

Other causes

  • Barrier disorder – another hypothesis is that there may be a barrier disorder between the intestinal lumen and the organism in some Crohn’s disease patients. This allows intestinal bacteria to invade the intestinal wall and cause inflammation (gastrointestinal infections), further damaging the intestinal wall.
  • Cytokines are produced by all cells in the intestinal wall, act on the mucosal immune system, and – by promoting inflammatory processes – are significantly involved in clinical symptoms, such as fibrosis development, edema, fever, weight loss, as well as underweight. Cytokines activate neutrophil granulocytes, which subsequently migrate from the capillary region and enter the intestinal wall in high numbers. There they release increased eicosanoids (inflammatory mediators), damage the intestinal mucosa and increase the risk of infection.