Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), leading to a high incidence of surgical interventions and significant disability. Despite its clinical relevance, no targeted pharmacological therapies are currently available. This review aims to explore the underlying mechanisms driving intestinal fibrosis and address unresolved scientific questions, offering insights into potential future therapeutic strategies. We conducted a literature review using data from PubMed up to October 2024, focusing on studies related to IBD and fibrosis. Intestinal fibrosis results from a complex network involving stromal cells, immune cells, epithelial cells, and the gut microbiota. Chronic inflammation, driven by factors such as dysbiosis, epithelial injury, and immune activation, leads to the production of cytokines like interleukin (IL)-1β, IL-17, and transforming growth factor (TGF)-β. These mediators activate various stromal cell populations, including fibroblasts, pericytes, and smooth muscle cells. The activated stromal cells secrete excessive extracellular matrix components, thereby promoting fibrosis. Additionally, stromal cells influence the immune microenvironment through cytokine production. Future research would focus on elucidating the temporal and spatial relationships between immune cell-driven inflammation and stromal cell-mediated fibrosis. Additionally, investigations are needed to clarify the differentiation origins of excessive extracellular matrix-producing cells, particularly fibroblast activation protein (FAP) + fibroblasts, in the context of intestinal fibrosis. In conclusion, aberrant stromal cell activation, triggered by upstream immune signals, is a key mechanism underlying intestinal fibrosis. Further investigations into immune-stromal cell interactions and stromal cell activation are essential for the development of therapeutic strategies to prevent, alleviate, and potentially reverse fibrosis.
Humans ; Fibrosis/metabolism* ; Inflammatory Bowel Diseases/pathology* ; Animals ; Transforming Growth Factor beta/metabolism* ; Intestines/pathology*

The pathogenesis of inflammatory bowel disease (IBD) is not fully elucidated. However, it has been considered that inflammatory macrophages may be involved in the imbalance of the intestinal mucosal immunity to regulate several signaling pathways, leading to IBD progression. The ratio of M1 to M2 subtypes of activated macrophages tends to increase in the inflamed intestinal section. There are challenges in the diagnosis and treatment of IBD, such as unsatisfactory specificity of imaging findings, low drug accumulation in the intestinal lesions, unstable therapeutic efficacy, and drug-related systemic toxicity. Recently developed nanoparticles may provide a new approach for the diagnosis and treatment of IBD. Nanoparticles targeted to macrophages can be used as contrast agents to improve the imaging quality or used as a drug delivery vector to increase the therapeutic efficiency of IBD. This article reviews the research progress on macrophage-targeting nanoparticles for the diagnosis and treatment of IBD to provide a reference for further research and clinical application.
Humans ; Inflammatory Bowel Diseases/therapy* ; Intestines ; Macrophages/metabolism* ; Intestinal Mucosa/pathology* ; Nanoparticles

No abstract available.
Adult ; Aged ; Biopsy ; Colon/*microbiology/pathology ; Fusobacterium/genetics/*isolation & purification ; Humans ; Inflammatory Bowel Diseases/microbiology/*pathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; RNA, Ribosomal, 16S/chemistry/genetics/metabolism ; Republic of Korea ; Sequence Analysis, DNA ; Young Adult

Galectin-4, a tandem repeat member of the β-galactoside-binding proteins, possesses two carbohydrate-recognition domains (CRD) in a single peptide chain. This lectin is mostly expressed in epithelial cells of the intestinal tract and secreted to the extracellular. The two domains have 40% similarity in amino acid sequence, but distinctly binding to various ligands. Just because the two domains bind to different ligands simultaneously, galectin-4 can be a crosslinker and crucial regulator in a large number of biological processes. Recent evidence shows that galectin-4 plays an important role in lipid raft stabilization, protein apical trafficking, cell adhesion, wound healing, intestinal inflammation, tumor progression, etc. This article reviews the physiological and pathological features of galectin-4 and its important role in such processes.
Animals ; Axons ; metabolism ; Endocytosis ; Galectin 4 ; blood ; genetics ; metabolism ; Humans ; Inflammatory Bowel Diseases ; metabolism ; pathology ; Membrane Microdomains ; metabolism ; Neoplasms ; metabolism ; pathology ; Neurons ; metabolism ; Wound Healing

Inflammatory bowel disease (IBD) is a chronic progressive idiopathic inflammatory disorder that involves the digestive tract from the mouth to the anus. Over the past decades, many therapeutic strategies have been developed to manage IBD, but therapeutic strategies based only on relief of clinical symptoms have not changed the natural history of this disease entity. This underlines the importance of understanding the natural history of IBD itself. When we look at the natural history of Crohn's disease (CD), it first begins with inflammation of the intestinal mucosa and this inflammatory reaction proceeds to stenosing or penetrating reaction if not adequately controlled. However, it takes a considerable amount of time before mucosal inflammation proceeds to stenosis of the intestinal lumen or penetration into the adjacent bowel. Therefore, it can be expected that if proper care is given during that period, progression of CD to such a complicated disease could be prevented. Even though the concept of mucosal healing was introduced in the early 1990s, no correlation could be observed between healing of mucosal lesions and relief of clinical symptoms. However, the introduction of biologic agents targeting tumor necrosis factor has changed the way to treat IBD that is refractory to standard medications and has allowed us to aim for a new therapeutic goal, 'deep remission'. Further advances in biologic agents have provided highly effective treatments for IBD, making deep remission a realistic goal. Whether IBD patients may benefit by experiencing a 'deep' remission beyond the control of clinical symptoms need to be evaluated in further investigation. Nevertheless, it can be anticipated that attaining deep remission might ultimately have an impact on important outcomes such as the need for surgery and the quality of life.
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Colitis, Ulcerative/drug therapy/metabolism/pathology ; Crohn Disease/drug therapy/metabolism/pathology ; Humans ; Inflammatory Bowel Diseases/drug therapy/metabolism/*pathology ; Intestinal Mucosa/metabolism/pathology ; Mesalamine/therapeutic use ; Tumor Necrosis Factor-alpha/immunology/metabolism

OBJECTIVETo develop an experimental rat model of inflammatory bowel disease (IBD) by administration of dextran sulfate sodium (DSS), and to observe changes in the tight junction protein expression and permeability of colon mucosa.

METHODSMale Sprague-Dawley (SD) rats were randomly divided into control (n=27) and IBD model groups (n=27). In the IBD model group, IBD was induced by 6-day administration of 3% DSS in water followed by 14-day administration of water only. The control group was fed with water only. Pathological changes in colon mucosae were observed on days 7, 14 and 21 after DSS administration. Colon tissue specimens were collected on day 21 for measuring myeloperoxidase (MPO) activity. The transepithelial electric resistance (TEER), transepithelial potential difference (TEPD) and short circuit current (Isc) of the specimens were measured by Ussing chamber. Real-time PCR and Western blot were used to measure the mRNA and protein expression of tight junction proteins in colon epithelia.

RESULTSIn the IBD model group, diarrhea, hemafecia and weight loss were seen. Inflammation occurred mainly in the distal colon and was characterized by crypt abscess and inflammatory cell infiltration. The IBD model group showed significantly increased MPO activity (P<0.01), significantly decreased TEER (P<0.01) and TEPD (P<0.01), and significantly increased Isc (P<0.01) compared with the control group. No claudin 2 expression of mRNA and protein was detected in the control group, and they were expressed in the IBD model group. The expression levels of claudin 3, occludin and ZO-1 in the IBD model group were significantly decreased compared with in the control group (P<0.01).

CONCLUSIONSIBD rats show colonic barrier dysfunction and changes in the expression of tight junction proteins. The changes in the expression of tight junction proteins may contribute to colonic barrier dysfunction in cases of IBD in the chronic recovery stage.

Animals ; Claudin-3 ; analysis ; Colon ; metabolism ; pathology ; Dextran Sulfate ; Disease Models, Animal ; Inflammatory Bowel Diseases ; chemically induced ; metabolism ; Intestinal Mucosa ; metabolism ; Male ; Occludin ; analysis ; Permeability ; Rats ; Rats, Sprague-Dawley ; Tight Junction Proteins ; analysis ; Zonula Occludens-1 Protein ; analysis

OBJECTIVETo explore the role of annexin A2 (ANXA2) expression in the intestinal mucosa in the pathogenesis of inflammatory bowel disease (IBD).

METHODSIntestinal or colonic mucosal biopsy samples were obtained from 54 patients with ulcerative colitis (UC), 37 with Crohn's disease (CD), and 15 healthy control subjects. Immunohistochemistry was employed to examine the expression of ANXA2 in the intestinal mucosa, and mRNA expression of ANXA2 was detected using real-time PCR.

RESULTSImmunohistochemistry showed a ANXA2 positivity rate of 83.3% (45/54) in patients with UC, 27.0% (10/37) in patients with CD, and 53.3% (8/15) in the control subjects. ANXA2 expression in the intestinal or colonic mucosa was significantly up-regulated in patients with UC compared with the patients with CD and healthy control subjects, but was significantly lower in patients with CD than in the healthy controls (P<0.05). The expression levels of ANXA2 were strongly associated with the severity of clinical manifestations and the histopathological grades of UC (P<0.05). Compared with the healthy controls and patients with CD, patients with UC showed a significantly increased ANXA2 mRNA expression level in the inflamed mucosa of UC (P<0.05).

CONCLUSIONANXA2 can serve as a marker for differential diagnosis of IBD, and its up-regulated expression is closely related to the pathogenesis of UC.

Annexin A2 ; metabolism ; Case-Control Studies ; Colitis, Ulcerative ; metabolism ; pathology ; Crohn Disease ; metabolism ; pathology ; Female ; Humans ; Inflammatory Bowel Diseases ; metabolism ; pathology ; Intestinal Mucosa ; metabolism ; pathology ; Male

Inflammatory bowel disease (IBD), the most important entities being ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory conditions that result from chronic dysregulation of the mucosal immune system in the intestinal tract. Although the precise pathogenesis of IBD is still incompletely understood, increased levels of proinflammatory cytokines, including interleukin (IL)-1beta, IL-18 and tumor necrosis factor-alpha, are detected in active IBD and correlate with the severity of inflammation, indicating that these cytokines may play a key role in the development of IBD. Recently, the intracellular nucleotide-binding oligomerization domain-like receptor (NLR) family members, including NLRP1, NLRP3, NLRC4 and NLRP6, are emerging as important regulators of intestinal homeostasis. Together, one of those aforementioned molecules or the DNA sensor absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein containing 'a caspase recruitment domain (CARD)' (ASC) and caspase-1 form a large (>700 kDa) multi-protein complex called the inflammasome. Stimulation with specific microbial and endogenous molecules triggers inflammasome assembly and caspase-1 activation. Activated caspase-1 leads to the secretion of proinflammatory cytokines, including IL-1beta and IL-18, and the promotion of pyroptosis, a form of phagocyte cell death induced by bacterial pathogens, in an inflamed tissue. Therefore, inflammasomes are assumed to mediate host defense against microbial pathogens and gut homeostasis, so that their dysregulation might contribute to IBD pathogenesis. This review focuses on recent advances of the role of NLRP3 inflammasome signaling in IBD pathogenesis. Improving knowledge of the inflammasome could provide insights into potential therapeutic targets for patients with IBD.
CARD Signaling Adaptor Proteins/metabolism ; Carrier Proteins/metabolism/physiology ; Caspase 1/metabolism ; Humans ; Inflammasomes/*metabolism ; Inflammatory Bowel Diseases/metabolism/*pathology ; Interleukin-18/metabolism ; Interleukin-1beta/metabolism ; Signal Transduction

OBJECTIVEIt is demonstrated that excessive activation of NF-κB is central to the pathogenesis of inflammatory bowel disease (IBD). Zinc finger protein A20 (A20) is a key player in the negative feedback regulation of NF-κB signaling in response to multiple stimuli and has been described as central gatekeeper in inflammation and immunity. Mice genetically deficient in A20 develop severe intestinal inflammation and have increased susceptibility to dextran sodium sulfate (DSS)-induced colitis. Few studies have been done to explore the role of A20 in the pathogenesis of IBD. To clarify the relationship between intestinal inflammation and the expression level of A20 in IBD patients, the expression level of A20 and a series of inflammatory cytokines, such as NF-κB, IL-6, and IL-8, in children with IBD and controls were examined.

METHODTerminal ileal mucosal samples were obtained via endoscopy. Fifty-seven mucosal samples were divided into 4 groups: normal control group (n = 16), IBD remission group (n = 12), IBD active group (n = 13) and non-IBD enteritis group (n = 16). According to disease activity index scores, the IBD patients were divided into IBD remission group and IBD active group. Normal control group was consisted of patients with functional bowel disorders or intestinal polyps. Non-IBD enteritis was defined as changes in which endoscopy and histological examination showed inflammatory changes but could not be diagnosed as IBD. Real-time PCR was adopted for detecting the mRNA levels of A20, IL-6 and IL-8. Meanwhile immunohistochemistry was performed to measure the expression of A20 and NF-κB.

RESULT(1) The expression of A20 and NF-κB were very low in normal control group, but significantly up-regulated in IBD active group and non-IBD enteritis group (P < 0.01 for both); (2) Compared with normal control group, expression of NF-κB [(9.35 ± 4.84)% vs. (0.57 ± 0.44)%, P < 0.01], IL-6 (t' = 1.34, P > 0.05), IL-8 (t = 1.38, P > 0.05) increased in IBD remission group, while the expression of A20 in both mRNA (t = 1.03, P > 0.05) and protein levels [(0.36 ± 0.18)% vs. (0.87 ± 0.29)%, P < 0.01] decreased; (3) Compared with non-IBD enteritis group, although the expression of NF-κB [(24.17 ± 11.27)% vs. (55.29 ± 21.84)%, P < 0.01], IL-6 (t = 2.22, P < 0.05), IL-8 (t = 2.97, P < 0.01) were highly increased in IBD active group, the expression of A20 in both mRNA(t = 2.26, P < 0.05) and protein levels [(29.23 ± 11.70)% vs. (16.81 ± 5.90)%, P < 0.01]significantly decreased; (4) The expression of IL-6, IL-8 were similar in IBD remission group and non-IBD enteritis group (both P > 0.05), but the expression of A20 was much lower in both mRNA (t = 4.42, P < 0.01) and protein levels [(29.23 ± 11.70)% vs. (0.47 ± 0.25)%, P < 0.01] in IBD remission group.

CONCLUSIONThe results demonstrate that there is an excessive inflammatory response but insufficient up-regulation of A20 expression in IBD patients. Low levels expression of A20 may play an important role in the pathogenesis of IBD.

Case-Control Studies ; Child ; Endopeptidases ; metabolism ; Female ; Humans ; Inflammatory Bowel Diseases ; metabolism ; pathology ; Interleukin-6 ; metabolism ; Interleukin-8 ; metabolism ; Intestinal Mucosa ; metabolism ; pathology ; Male ; NF-kappa B ; metabolism

TNF-alpha is a major cytokine involved in inflammatory bowel disease (IBD). In this study, water extract of Grifola frondosa (GFW) was evaluated for its protective effects against colon inflammation through the modulation of TNF-alpha action. In coculture of HT-29 human colon cancer cells with U937 human monocytic cells, TNF-alpha-induced monocyte adhesion to HT-29 cells was significantly suppressed by GFW (10, 50, 100 microg/ml). The reduced adhesion by GFW correlated with the suppressed expression of MCP-1 and IL-8, the major IBD-associated chemokines. In addition, treatment with GFW significantly suppressed TNF-alpha-induced reactive oxygen species production and NF-kappaB transcriptional activity in HT-29 cells. In differentiated U937 monocytic cells, LPS-induced TNF-alpha production, which is known to be mediated through NF-kappaB activation, was significantly suppressed by GFW. In an in vivo rat model of IBD, oral administration of GFW for 5 days (1 g/kg per day) significantly inhibited the trinitrobenzene sulfonic acid (TNBS)-induced weight loss, colon ulceration, myeloperoxidase activity, and TNF-alpha expression in the colon tissue. Moreover, the effect of GFW was similar to that of intra-peritoneal injection of 5-aminosalicylic acid (5-ASA), an active metabolite of sulfasalazine, commonly used drug for the treatment of IBD. The results suggest that GFW ameliorates colon inflammation by suppressing production of TNF-alpha as well as its signaling through NF-kappaB leading to the expression of inflammatory chemokines, MCP-1 and IL-8. Taken together, the results strongly suggest GFW is a valuable medicinal food for IBD treatment, and thus may be used as an alternative medicine for IBD.
Animals ; Cell Adhesion/drug effects/immunology ; Cell Extracts/administration & dosage/*pharmacology ; Chemokine CCL2/biosynthesis/genetics ; Coculture Techniques ; Colon/drug effects/*metabolism/pathology ; Grifola ; HT29 Cells ; Humans ; Inflammatory Bowel Diseases/chemically induced/*drug therapy/pathology/physiopathology ; Interleukin-8/biosynthesis/genetics ; Intestinal Mucosa/*drug effects/metabolism/pathology ; Monocytes/*drug effects/metabolism/pathology ; NF-kappa B/genetics/metabolism ; Peroxidase/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Stomach Ulcer ; Transcription, Genetic/drug effects ; Trinitrobenzenesulfonic Acid/administration & dosage ; Tumor Necrosis Factor-alpha/*biosynthesis/genetics ; U937 Cells ; Weight Loss