XIE Jing-ri, CHEN Shan-tao, LIU Zhi-wei

1. The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, China

2. Heilongjiang University of Traditional Chinese Medicine, Harbin 150006, China

Keywords:

ABSTRACT The incidence of ulcerative colitis is increasing year by year, yet the pathogenesis is still not clear. Many scholars have studied the genetic factors, environmental factors, intestinal microecological imbalance, intestinal mucosal barrier disorder, abnormal immune response and mitochondrial diseases, and abundant achievements have been made. In order to further understand the possible pathogenesis of ulcerative colitis, this paper reviews its research progress, in order to better guide clinical medication, and provide new ideas for further study of its pathogenesis.

1. Introduction

Ulcerative colitis (UC) is a common idiopathic inflammatory bowel disease in the world. Its pathogenesis is affected by many factors, including genetic susceptibility, epithelial barrier defect,immune response disorder and environmental factors[1]. In developed countries, the incidence rate is higher (＞0.3%), and the incidence rate of newly industrialized countries has increased rapidly (the annual percentage change increased by 14.9%)[2,3]. It is estimated that by 2025, the global prevalence rate will reach 30 million people[4]. The incidence rate of UC is age dependent, and the age distribution is bimodal. The first peak is between 15～30 years old and the second peak is between 50～70 years old[5,6]. UC patients have an increased risk of colorectal cancer. After 10 years of UC patients at increased risk of colorectal cancer and diagnosis was 2%, 20 years after diagnosis was 8%, 30 years after the diagnosis is 20%-30%[1]. UC seriously affects people's quality of life, and the academic achievements on its pathogenesis are changing with each passing day. The author has studied UC for many years, and now makes a review on its pathogenesis theory.

2. genetics

Genetics studies IBD from three aspects: genome wide association study (GWAS), whole genome sequencing and fine positioning. It is found that many gene loci are related to IBD, and a large part of them are common to UC and Crohn's disease (CD). The 1p36 and 12q15[7] gene loci were found by the majority of scholars through unremitting efforts; FCGR2A (rs1801274), 13q12 (rs17085007)and SLC26A3 (rs2108225)[8] were also identified; 20q13 (HNF4A),16q22 (CDH1, cdh3) and 7q31 (LAMB1)[9]; (IL17REL)[10] on 7q22 and 22q13; The genetic susceptibility sites such as 6q22.[11]have an effect on the occurrence and development of UC, and the subsequent reports have increased. At present, 260 susceptible sites have been identified to be related to IBD[12]. It has been found that 110 of 163 (67%) susceptibility sites are associated with UC and CD simultaneously[13]. UC shows obvious racial dependence on gene association among different races[14]. The region encoding human leukocyte antigen gene in chromosome 6 has obvious specificity in the pathogenesis of UC genetics[15,16]. New research found a false variant with 0.6% frequency in adenylate cyclase-7,which doubled the risk of ulcerative colitis[17], family genetic history of UC patients was 8% - 14%, and the risk of the disease in primary relatives was 4 times higher than that of ordinary people[18, 19]. The susceptibility changes of 15% and 19% were explained by using the immune chip (ichip) and estimated GWAS data, respectively. The intensive ichip region explained the 10% and 9% SNP heritability in the ichip and GWAS data[20]. It can be seen that the susceptible gene loci related to UC explain the possible pathogenesis of UC from genetics.

3. environmental factors

3.1. diet

Eating vegetables and fruits is negatively correlated with the risk of UC and CD[21]. Drinking a large amount of drinks may increase the risk of UC[22]. Alcohol can directly cause mucosal damage and increase bacterial translocation, which is the risk factor of UC[23]. Caffeine can delay colitis induced by sodium gluconate by lowering Chitosanase 3-like protein-1[24], and tea can reduce the risk of UC[22,25,26]. The risk of UC was significantly increased in meat consumers than in vegetarians, while the relationship between red meat and UC was more significant among meat consumers[27].The content of n-3 polyunsaturated fatty acids (n-3 PUFAs) in diet is favorable factors to UC process. The richer the n-3 PUFAs, the lower the risk of UC[28]. Omega-3 (a-linolenic acid) and omega-6(linoleic acid) are essential to ensure health. However, the body cannot manufacture it and must be obtained from the exogenous diet,However, excessive intake of omega-3 and omega-6 can increase the risk of UC[29]. The relationship between protein in diet and UC is delicate, and large amount of meat or fish is related to IBD risk in animal protein except eggs and dairy products[30]. H2S has antiinflammatory effect at low level, but it will damage intestinal mucosa as toxin when the concentration is high. The food rich in sulfur and sulfate reducing bacteria are related to the development of UC and the activity of disease. Although the metabolic environment in colon is affected by many factors, excessive intake of sulfur-containing food will damage the mucosal barrier of intestinal cavity[31,32,33].

3.2. smoking

Smoking can significantly increase the risk of lung cancer and affect the cardiorespiratory function[34], but it is surprising that smoking can improve the symptoms of UC in acute phase and reduce the incidence rate of[35]. Follow up studies have found that smoking may improve the symptoms of UC in the acute stage by increasing the perfusion of damaged blood vessels in the intestinal mucosa, but it will aggravate the symptoms in the remission stage of UC[36]. Smoking can prevent the occurrence of UC, shorten the course of disease and reduce the operation rate of colectomy[37]. The new study found that people with a history of smoking have a higher prevalence rate than those who have never smoked; The risk of UC among current smokers is significantly reduced. Among current smokers, the risk of UC development has nothing to do with lifetime cumulative smoking. As for the preventive effect of smoking on UC,it is only verified in male population[38]. Later, scholars found that there was a positive causal relationship between smoking age and the risk of UC[39]. Although smoking has protective factors for UC, the risk of smoking far exceeds any possible benefit. Therefore, doctors still recommend, encourage and help smoking UC patients to quit smoking.

3.3. appendix

History of appendectomy is a risk factor for UC[40], and appendectomy can increase the extraintestinal symptoms of UC[41].The lymphatic follicles of the appendix begin to develop and mature 5 days after birth. They are important immune organs to prevent intestinal microbial infection. The appendix provides a symbiotic biofilm to the intestine to fight against intestinal inflammatory factors and repair small damage in the intestinal cavity, so as to maintain the stability of the intestinal internal environment. At the same time, the appendix is also a necessary condition to maintain the diversification of extraintestinal mucosal immune tissue[42].Histological analysis showed that aging can cause fatty degeneration of appendiceal lymphoid tissue, and the patients with UC are more prone to fatty degeneration of appendiceal lymphoid tissue. After the degeneration and inactivation of appendiceal lymphoid tissue,it will further aggravate the occurrence and development of UC[43].Through in-depth understanding of the intestinal flora and intestinal mucosal immune system, the appendix is considered to be a “moat” to maintain the steady state of intestinal flora. The normal intestinal flora provides rich nutrients for the body and protects the intestinal cavity from the damage of pathogenic bacteria[44]. It can be seen that the appendix can not only repair the inflammatory damage of intestinal cavity through lymphatic tissue, but also prevent the occurrence and development of UC by maintaining the diversity of intestinal microorganisms.

4. Intestinal Microecology

More and more studies have found that the imbalance of intestinal flora plays an important role in the pathogenesis of UC. The intestinal microbiota is a complex and rich ecosystem. The colon provides a rich nutritional environment for the microbiota and becomes the main settlement place of the intestinal microbiota[45].The intestinal microbiota provides energy and nutrients to the host through metabolites[46], Protect the host[47] and regulate the host's immune system[48]. Intestinal bacteria produce short chain fatty acids(SCFA) when digesting cellulose in chyme. SCFA can effectively resist the inflammatory response of UC[49]. At the same time,intestinal microflora can promote the secretion of epithelial cell repair factor interleukin-18, increase the integrity of epithelial cells,promote goblet cells to produce mucin, and further strengthen the tight junction between cells[50], Prevent the invasion of pathogenic bacteria. Intestinal microbiota is involved in the occurrence and development of UC by mediating a variety of related immune and inflammatory pathways. Intestinal epithelial barrier is the first line of defense against bacterial invasion. If the colonic epithelial barrier is damaged, the intestinal permeability will increase, which will lead to changes in host immune response[51]. The number of antigenpresenting cells increased and the homeostasis of T cells was out of balance, which further aggravated the inflammation. Imbalance of intestinal microecology causes T cell subsets to mediate nonspecific Th2 immune response, release interleukin-13 and damage intestinal epithelial cells[52]. At the same time, the mesenteric lymph node microbiota also plays an important role in the development of UC.There are obvious differences between the mesenteric lymph node microbiota of UC and CD, which is helpful for the differential diagnosis of UC[53]. Although the pathogenesis of UC has not been fully understood, the imbalance of intestinal microecology affects the occurrence of UC from many aspects.

5. mucosal barrier

Intestinal mucosal barrier is mainly composed of microbiota, mucus layer, antimicrobial peptide, secretory immunoglobulin A (sIgA),epithelial cell layer and mucosal immune system. Intestinal mucosal barrier function (MBF)[54] refers to the ability of intestinal cavity to absorb nutrients and accommodate microorganisms and molecules in intestinal cavity[55]. The core component of MBF is the epithelial cell layer. The epithelial cells maintain the stability of the internal environment of the intestinal cavity through the tight connection between cells and the orderly filling of the intercellular stroma,ensuring the orderly transportation of various substances. The mucus layer formed by mucin, SIgA and antimicrobial peptide is further strengthened on the outer side of the epithelium, and various immune cells are monitored on the inner side, which ensures the integrity of MBF[54,56,57]. The main changes of MBF are increased permeability and bacterial translocation, which are closely related to the occurrence of UC[54,55]. Studies have found that the increase of intestinal permeability occurs before the development of colon disease[58], and the shift and abundance of intestinal flora destroy the intestinal barrier by affecting the immune system[59]. It can be seen that MBF affects the occurrence of UC through multiple dimensions.

6. immune response

The immune response and inflammatory pathway of UC showed that antigen presenting cells, auxiliary T cells, regulatory T cells and natural killer T cells, up regulation of Pro inflammatory cytokines and down regulation of anti-inflammatory cytokines play an important role in UC mucosal injury[60]. The relative balance between the T-cells and the regulatory T cells is dominant in intestinal immunity and inflammation[61]. Natural killer cells (NKT)are a special kind of lymphocytes, and the T-2 helper cells (Th2 cells) factors that are produced by them mediate the occurrence of UC[62,63]. Neutrophil, as an effect cell of innate immunity,is an active cell to prevent pathogen invasion. The unregulated mechanism of neutrophil inflammation will accelerate tissue damage and further damage the balance of the intestinal environment.Abnormal neutrophil function can be used as early screening for chronic inflammation in the intestine, and also reflect adaptive immune function, Neutrophil infiltration in intestinal mucosa is a characteristic of UC pathophysiology. The migration degree and time of neutrophils are related to the severity of disease. Activated neutrophils migrate to the inflammatory site through epithelial cell gap, and accumulate in the crypt cavity to cause crypt abscess. Crypt abscess is a characteristic histopathological change of UC[64]. The new research creatively proposes the “microbial group nourishing immunity” from the perspective of microorganism and immunity.The immune mechanism of “colonization resistance” is endowed with the microbiological nourishing immunity. The colonization resistance is the immune function displayed by the microbial groups implanted in the intestinal cavity, and the destruction of the trophoblastic immunity of the microbial group can cause the aggravation of intestinal inflammation[65]. Some scholars analyzed the components of 24 immune cells by immunocytochemistry. The results showed that 18 immune cells had significant changes in UC patients. The cytotoxic T cells, exhausted T cells, type 1 regulatory T cells, induced regulatory T cells, T-1 auxiliary cells, central memory T cells, dendritic cells, B cells, and so on The abundance of monocytes and macrophages was higher than that of the control group; In contrast, the abundance of naive CD8+T cells, Th2 cells,effective memory T cells, NKT cells, mucosa related invariant T cells, natural killer cells, neutrophils and CD8+T cells in UC patients were lower than that of the control group. It can be seen that immune mechanism affects UC through multi-dimensional.

7. Mitochondrial disease

Mitochondrial disease is dominated by homeostasis imbalance,showing energy production defects, increased oxidative stress and release of related pro-inflammatory injury molecules[12]. The mitochondrial gene and function of patients with active UC are decreased, and MCJ is a mitochondrial inner membrane protein. In patients with UC, the level of MCJ is decreased, and the expression of TIMP-3 factor is increased[67]. Mitochondrial genome encodes 13 genes regulating ATP production, which are significantly reduced in UC[68]. UC is a risk factor for colorectal cancer (CRC)[69]. The risk of CRC in UC patients begins to increase after 10 years[70]. The risk of CRC in UC patients is 2.4 times higher than that in ordinary people[71]. Mitochondrial DNA (mtDNA) mutation is very common in precancerous lesions of ulcerative colitis. MtDNA mutation increases the risk of CRC in UC patients[72]. MtDNA mutation is related to complex autoimmune diseases and inflammatory diseases,MtDNA polymorphisms and haplotypes may act independently or synergistically on nuclear genetic factors, and the interaction between mitochondrial genes may provide a reasonable explanation for the partial genetic deletion of UC[73]. The multidrug resistance-1(MDR1) gene encodes an alpha-TP-dependent efflux transporter that is highly expressed in the colon and has a protective effect on mitochondria. If MDR1 is deficient, it can lead to mitochondrial dysfunction, increase reactive oxygen species, and eventually lead to UC[74]. The increased concentration of extracellular free state DNA (cfDNA) was positively correlated with the clinical severity of UC patients[75]. In a variety of inflammatory diseases and acute injuries, the increased level of mitochondrial derived cfdna was observed[76,79]. Therefore, the changes of mitochondrial structure and function play an important role in the pathogenesis of UC.

Although the pathogenesis of UC has not been completely clear, the majority of scholars respectively from the genetic, environmental,intestinal microecology, intestinal mucosal barrier, immune response and mitochondrial disease and other aspects of research, in order to explore the pathogenesis of UC, the author through reading the relevant literature, the majority of scholars on the pathogenesis of UC review as above, I hope that colleagues consider the profit and loss, some gain.