CD is a severe chronic inflammatory disease of the gastrointestinal tract (GIT) with relapsing–remitting behavior. It is also called regional ileitis due to its frequent involvement of the ileum, which can occur anywhere in the GIT, being typically transmural. Its etiology is still unknown, but studies defend a multifactorial environmental, immunological, and genetic interaction that contributes to uncontrolled mucosal inflammation. The pathogenesis of CD involves changes in the intestinal microbiota, dysfunctions in the epithelium, and immune hyperreactivity, generating an uncontrolled inflammatory state due to dysregulation of the intestinal epithelial immune response, with the stimulation of pro-inflammatory and inhibition of regulatory pathways. Genetic factors play an essential role, as the concordance rate for monozygotic twins reaches 50%, contributing to the disease’s phenotypic expression. There are more than 160 genes associated with IBDs; many are shared between CD and UC. Several genes associated with IBD overlap with genes involved in the response against mycobacteria, supporting the idea that host interactions with such microorganisms are essential in the pathophysiology of CD. Environmental factors such as pathogenic microorganisms, microbiota, diet, smoking, and psychosocial factors also play an important role in its pathogenesis. Thus, improving life habits could change the microbiome to eubiosis, contributing to the stabilization of the disease ^{[1][2][3][4][5][6][7][8][9]}.

The genes involved in CD may be involved in three stages of inflammation, namely (1) the recognition of pathogens, (2) the elimination of pathogens via innate and cellular immunity, and (3) the prevention of the invasion of pathogens through the intestinal barrier. Therefore, in comparisons of single nucleotide polymorphisms (SNPs) in patients with and without IBDs, there are abnormalities mainly in the functions of modulators of immune function, autophagy, and epithelial function that participate in the interaction between the host and microorganism ^[5][9].

The gene most associated with CD is nucleotide oligomerization binding domain 2 (NOD2). It encodes an innate immune intracellular protein involved in recognizing bacteria, binding to bacterial peptidoglycans, and subsequent stimulation of the immune system, activating signaling cascades, including the NF-κB pathway, expressed mainly by immune cells and antigen-presenting cells (APCs). As a result, pro-inflammatory and antimicrobial molecules such as interleukin (IL)1-β, IL6, IL8, tumor factor necrosis alfa (TNF-α), and α-defensins are released, which recruit innate immune cells with subsequent activation of adaptive immunity. Furthermore, NOD2 is an essential regulator of cell proliferation, differentiation, and apoptosis mediated by the mitogen-activated protein kinase (MAPK) pathway. Mutations in this gene impair the recognition of invading pathogens by Paneth cells, causing inflammatory intestinal lesions and the lower release of antimicrobial proteins, such as α-defensin. These mutations are probably related to a weakened immune response due to lower activation of the NF-κB transcription factor. However, even with the increased risk associated with NOD2 polymorphisms, only 10% of people with such variants will develop the disease. Finally, NOD2 is central to bacterial autophagy, which initiates by recruiting the molecular autophagy ATG16L1 (type-16 related to autophagy) to the bacterial uptake site. The mutation in ATG16L1 increases the risk of developing IBDs by impairing the ability of autophagy in Paneth cells in cases of intracellular pathogen degradation, indirectly affecting their ability to secrete antimicrobial products, which favors bacterial proliferation and invasion. The ER stress of specialized intestinal epithelial cells (IECs) can be induced by various external factors, initiate a pathological unfolded protein response (UPR), and thus trigger intestinal inflammation. ATG16L1 polymorphisms in IECs determine the tolerable level of ER stress. It defines the activation of the UPR sensor inositol-requiring enzyme 1α (IRE1α), and the hyperactivation of this enzyme spontaneously generates ileitis in mice. Furthermore, signal transducer and activator of transcription 3 (STAT3) and NF-κβ signaling in IECs are also relevant since defects in these two pathways favor the formation of colitis. The NF-κβ kinase-α inhibitor (IKKα) phosphorylates ATG16L1 and thus prevents its degradation. Without this inhibitor, IRE1α accumulates and relays a pathological UPR. The IRGM gene (immunity-related GTPase M), which encodes guanosine triphosphate M, in addition to LRRK2, which encodes leucine-rich repeat protein kinase 2, when mutated, increases the risk of CD. Patients with CD with LRRK2 mutation have increased activation of intestinal dendritic cells, with the exaggerated release of pro-inflammatory molecules. The non-receptor tyrosine phosphatase type 2 (PTPN2) is an autophagy-related gene expressed by lymphoid and Paneth cells and causes the defective formation of autophagosomes. Its loss-of-function mutation in T cells increases the differentiation of T helper (TH) TH0 cells into TH1 and TH17 and reduces regulatory T cells. Therefore, the genes above manifest their polymorphisms as abnormalities in the activity of Paneth cells, which are IECs at the base of Lieberkühn’s crypts in the small intestine. The Cadherin 1 (CDH1) gene is susceptible to IBDs, thus increasing risks for CD. Its function encodes the epithelial protein E-cadherin, which is necessary for tight intestinal junctions. Mutations in this gene generate a more permeable intestinal wall, facilitating the invasion of pathogenic microbes. The HNF4-α gene encodes the hepatocyte nuclear factor 4-alpha, which modulates the expression of genes related to epithelial proliferation and tight junction formation, in addition to regulating adhesion and junction proteins, and, in its absence, malformation of the intestinal wall occurs. Human leukocyte antigen (HLA) genes play a role in the presentation of antigens to effector T cells and may be related to the acquisition of immunological tolerance. Specific mutations in its structure can generate greater risk, while others can act as protectors for CD ^{[1][2][6][7][9]}.

Several factors reinforce the role of mucosal immune responses in the pathogenesis of CD. Innate and adaptive immunities are the primary controllers of CD pathogenesis. The inflammatory process seems to be caused mainly by the failure of innate recognition of several bacteria, by the impaired intestinal barrier integrity, and by the spread of luminal pathogens through the intestinal wall, as previously mentioned, overloading innate immune cells to recognize and eliminate invaders ^[1][4][9].

Cells such as neutrophils, macrophages, innate lymphoid cells (ILCs), monocytes, dendritic cells, and Paneth cells make up the intestinal innate immune response. Neutrophils, in a balanced environment, phagocytose pathogenic microorganisms. Still, when there is accumulation in the intestinal epithelium, it ends up compromising the intestinal epithelial barrier, stimulating the production of substances that result in inflammation. By phagocytosing microorganisms, they mainly fight extracellular bacteria and fungi, in addition to forming extracellular neutrophil traps (NETs), which immobilize large pathogens and allow localized lysis. Due to the digestive action of neutrophils, the damage may even be greater than the initial insult for which it had been recruited. In addition, the antimicrobial defense of neutrophils is defective in patients with CD, with impaired nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity of these cells and reduced inflammatory response against dead Escherichia coli compared to patients with UC. Macrophages in a healthy intestinal mucosa control tissue remodeling by clearing apoptotic or senescent cells, and the alteration in their phagocytic function may contribute to the pathogenesis of CD. Studies have shown that such cells were significantly affected in CD patients, with reduced secretion of protective substances, such as IL-10, and increased synthesis of inflammatory molecules, generating a late elimination of microbial agents with an exacerbated inflammatory response. On the other hand, ILCs produce cytokines responsible for communication between the innate and adaptive immune systems. In patients with CD, in the inflamed ileum and colon, there is an increase in ILC1 and ILC3. Furthermore, areas with inflammation have high levels of interferon (IFN)-γ-producing ILC1s at the expense of ILC3, which synthesizes the anti-inflammatory cytokines IL-17 and IL-22, which suggests the increased transformation of ILC3 to ILC1, mediated by the inflammatory cytokine IL-12, may contribute to the disease ^[7][9].

Monocytes perform phagocytosis, respond to damage-associated molecular patterns (DAMPs) through toll-like receptor (TLR) signals, are tumor factor necrosis (TNF) producers, and stimulate mucosal inflammation, increasing tissue damage. In acute inflammation, monocytes differentiate into mature macrophages. In homeostasis, IECs produce transforming growth factor beta (TGF-β), thus increasing the synthesis of the anti-inflammatory cytokine IL-10 by dendritic cells. In inflammatory states, these cells express toll-like receptor 2 (TLR2) and TLR4, which stimulate the production of pro-inflammatory cytokines in scenarios of frequent interaction with the intestinal microbiota. They also promote cell activation and differentiation of TH0 cells into TH1, TH2, and TH17 and induce other essential inflammatory cells, such as natural killer cells. TH cells are activated and exert a TH1-like response. Most lymphocytes are activated in the intestinal lymphoid tissue and then go to the site of inflammation. Integrins, present on the leukocyte surface, are essential for leukocyte extravasation, as they make them bind to cell adhesion molecules present on the endothelial wall. In patients with CD, it is relevant that mucosal effector T cells may be resistant or less responsive to suppression mediated by Treg cells, which contributes to the maintenance of intestinal inflammation ^{[1][7][9][10]}.

Furthermore, humoral immunity is also relevant, given that altered levels of mucosal and secretory antibodies were detected in patients with CD with considerably elevated IgG levels against bacterial cytoplasmic proteins and reduced secretory IgA. In addition, CD patients often have anti-Saccharomyces disruption antibodies (ASCAs). However, the contribution of plasma cells and B cells in the pathogenesis of IBDs has not yet been elucidated ^[2][9][10].

Thus, in a few words, CD originates due to the exacerbated responses of TH1 and TH17 cells to inflammatory cytokines synthesized by APCs and the release of pro-inflammatory cytokines IL-17, TNF, and IFN-γ, which maintain inflammation by stimulating the synthesis of more inflammatory cytokines, such as IL-1, IL-6, IL-8, IL-12, IL-18, and TNF by other cell types such as endothelial, monocytes, and macrophages. IL-12 and IL-23, produced by innate immune cells such as dendritic cells and macrophages and act as modulators of intestinal inflammation. Given the importance of inflammation in CD, current therapies block the synthesis of inflammatory mediators, stopping the accelerated inflammation ^[7][9].