Nonspecific ulcerative colitis - Pathogenesis

The main pathogenetic factors of nonspecific ulcerative colitis are:

• intestinal dysbacteriosis - a violation of the normal composition of microflora in the large intestine, which has a local toxic and allergenic effect, and also contributes to the development of non-immune inflammation of the large intestine;
• violation of neurohumoral regulation of intestinal function caused by dysfunction of the autonomic and gastrointestinal endocrine systems;
• significant increase in the permeability of the colon mucosa for protein molecules and bacterial antigens;
• damage to the intestinal wall and the formation of autoantigens with subsequent formation of autoantibodies to the intestinal wall. Antigens of some strains of E. Coli induce the synthesis of antibodies to the tissue of the large intestine;
• the formation of immune complexes localized in the wall of the colon, with the development of immune inflammation in it;
• development of extraintestinal manifestations of the disease due to multifaceted autoimmune pathology.

Although the pathogenesis of ulcerative colitis is often described alongside Crohn's disease in the existing literature, there are important differences. Colonic epithelial cells (colonocytes), mucosal barrier defects, and epithelial barrier defects play an important role in the pathogenesis of ulcerative colitis. Expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), a negative regulator of NF-κB-dependent inflammation, is reduced in colonocytes of patients with ulcerative colitis, suggesting a causal relationship. [ 1 ], [ 2 ] Existing PPAR-γ agonists are limited by cardiac and metabolic toxicity. However, new 5-aminosalicylic acid (5-ASA) analogs with greater PPAR-γ agonist activity are currently under development. [ 3 ] Autoantibodies against colonocyte-associated tropomyosins have been described in ulcerative colitis, [ 4 ] but convincing evidence classifying ulcerative colitis as an autoantibody-mediated disease is lacking. Colonocyte-associated defects in XBP1, a key component of the endoplasmic reticulum stress response pathway, have been reported in ulcerative colitis. [ 5 ] [ 6 ]

The notion that barrier function defects are major factors in disease development is supported by the fact that patients with active ulcerative colitis have depleted colonic goblet cells and a permeable mucosal barrier.[ 7 ]

Dysbiosis has been observed in patients with ulcerative colitis, although to a lesser extent than in patients with Crohn's disease.[ 8 ] Decreased biodiversity with a lower proportion of Firmicutes and an increase in Gammaproteobacteria and Enterobacteriaceae has been reported in patients with ulcerative colitis.[ 9 ] In addition, patients with this disease have increased levels of sulfite-reducing Deltaproteobacteria in the colon.[ 10 ] However, it is unclear whether dysbiosis is a cause or a consequence of mucosal inflammation.

Innate lymphoid cells (ILCs) may play a central role in the pathogenesis of inflammatory bowel disease. ILC3s are major mediators of chronic intestinal inflammation.[ 11 ] Furthermore, ILCs isolated from patients with active ulcerative colitis exhibit increased gene expression of key ILC3 cytokines (IL17A and IL22), transcription factors (RORC and AHR), and cytokine receptors (including IL23R).[ 12 ] The possibility that ILCs may be drivers of disease pathogenesis has led to a number of potential novel therapeutic targets.

Current evidence suggests that both innate and adaptive cellular immunity are key to disease pathogenesis. Previous evidence suggests that ulcerative colitis is a modified T helper 2 (Th2) disease, while Crohn's disease is caused by Th1. In support, colonic lamina propria cells from patients with ulcerative colitis were found to contain Th2-polarized T cells that produce interleukin-5 (IL-5). [ 13 ]

Pathomorphology

In nonspecific ulcerative colitis, a pronounced inflammatory process develops in the mucous membrane of the colon. Progressive destruction of the epithelium and the fusion of inflammatory infiltrates cause the development of ulcers of the mucous membrane.

In 70-80% of patients, a characteristic sign of nonspecific ulcerative colitis develops - microabscesses of the colon crypts. In chronic cases, dysplasia of the intestinal epithelium and fibrosis of the intestinal wall are observed.

The most common lesions in nonspecific ulcerative colitis are the distal colon and rectum, with the latter being involved in the pathological process in almost 100% of cases. Pancolitis develops in 25% of patients.

[ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ], [ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ], [ 25 ]