Current, New and Future Therapeutic Targets in Inflammatory Bowel Disease: A Systematic Review

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing conditions resulting from immune system activity in a genetically predisposed individual. IBD is based on progressive damage to the inflamed gut tissue. As its pathogenesis remains unknown, recent accumulating data have demonstrated that IBD is a complex and multi-factorial disorder correlated with host luminal factors, which lead to an imbalance between pro- and anti-inflammatory signaling. The growing understanding of the molecular mechanisms responsible for IBD has suggested a wide range of potential therapeutic targets to treat this condition. Some patients do not have a satisfactory response to current therapeutic medications such as antitumor necrosis factor (TNF) agents, or their response decreases over time. As a result, IBD therapeutics have been changed recently, with several new agents being evaluated. The identification of various inflammatory cascades has led to forming the idea to have novel medications developed. Medications targeting Janus kinases (JAK), leukocyte trafficking Interleukin (IL) 12/23, and Sphingosine 1 phosphate (S1P) are among these newly developed medications and highlight the role of microbial-host interaction in inflammation as a safe promising strategy. This systematic review aims to summarize different molecular targeting therapeutics, the most potent candidates for IBD treatment in recent studies.

Download Full-text

P755 Congenital chloride diarrhoea and inflammatory bowel disease: an emerging association

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.883 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S603-S603

Author(s):

L Norsa ◽

R Berni Canani ◽

R Duclaux- Loras ◽

E Bequet ◽

J Koeglmeier ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Clinical Characteristics ◽

Molecular Mechanisms ◽

Premature Delivery ◽

Case Report Form ◽

Colonic Inflammation ◽

Wide Range ◽

Inflammatory Bowel

Abstract Background Congenital chloride diarrhea (CLD) is a rare autosomal recessive disease caused by the mutation in member 3 of the solute carrier 26 (SLC26A3). The phenotypic expression is a life-long severe watery Chloride rich diarrhea. Anecdotal association with inflammatory bowel disease (IBD) has been reported suggesting that underlying molecular mechanisms could represent part of an evolving association between IBD and channelopathies. We aimed to investigate this association in a cohort of CLD pediatric patients. Methods A European-based call for cases was made in CLD patients followed up in five different countries. A case report form for each patient was then completed. Results A total of 74 patients with CLD with a range of different CLD mutations were enrolled in the study. Twelve patients of 64 (16%) demonstrated colonic inflammation and were finally diagnosed with IBD: 8 patients with Crohn’s Disease, 2 with Ulcerative Colitis, and 2 IBD-like colitis (IBD-U). The diagnosis was made at a median of 12 years old (IQR: 6–30). Patients had different ethnicities (7 European, 2 Middle East, 1 North Africa, 1 Pakistan, 1 Central Africa). Among the 12 IBD, 2 had a 5-ASA-based treatment, 3 required immunosuppressant and 6 had biologics (Infliximab, Adalimumab and Vedolizumab). Three patients underwent surgery for ileostomy formation for CD that was non-responsive to multiple line of biologics (anti-TNF and anti-integrin): one had colectomy the remnant two colon preservation. Clinical characteristics, such as premature delivery, low weight at birth, fecal Cl- at diagnosis and amount of Cl- supplementation (mmol/kg) did not differ between patients with or without IBD. All patients underwent genotyping for CLD diagnosis and we did not find any specific genetic mutation linked to the development of IBD. Conclusion Sixteen percent of patients enrolled with CLD in our cohort developed IBD. Despite different presentations (CD, UC, IBD-U) all patients had colonic without ileal/small bowel involvement, in line with preliminary murine models of CLD demonstrating a role of colonic mucous layer in the development of colonic inflammation (Xiao et al Acta Physiol Oxf Engl 2014; 211:161–175). Patients’ IBD treatment included a wide range with variable success. Patients with IBD did not differ in their clinical characteristics or genetic mutations compared with non-IBD CLD patients. The role of genetic variants outside the CLD-gene and the microbiome in this association are under investigation.

Download Full-text

Emerging roles of the Hedgehog signalling pathway in inflammatory bowel disease

Cell Death Discovery ◽

10.1038/s41420-021-00679-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Zhuo Xie ◽

Mudan Zhang ◽

Gaoshi Zhou ◽

Lihui Lin ◽

Jing Han ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Molecular Mechanisms ◽

Treatment Options ◽

Critical Role ◽

Signalling Pathway ◽

Hedgehog Signalling Pathway ◽

Inflammatory Bowel ◽

Effective Drugs

AbstractThe Hedgehog (Hh) signalling pathway plays a critical role in the growth and patterning during embryonic development and maintenance of adult tissue homeostasis. Emerging data indicate that Hh signalling is implicated in the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic treatments for IBD require optimisation, and novel effective drugs are warranted. Targeting the Hh signalling pathway may pave the way for successful IBD treatment. In this review, we introduce the molecular mechanisms underlying the Hh signalling pathway and its role in maintaining intestinal homeostasis. Then, we present interactions between the Hh signalling and other pathways involved in IBD and colitis-associated colorectal cancer (CAC), such as the Wnt and nuclear factor-kappa B (NF-κB) pathways. Furthermore, we summarise the latest research on Hh signalling associated with the occurrence and progression of IBD and CAC. Finally, we discuss the future directions for research on the role of Hh signalling in IBD pathogenesis and provide viewpoints on novel treatment options for IBD by targeting Hh signalling. An in-depth understanding of the complex role of Hh signalling in IBD pathogenesis will contribute to the development of new effective therapies for IBD patients.

Download Full-text

Role of Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjy201 ◽

2018 ◽

Vol 13 (5) ◽

pp. 659-668 ◽

Cited By ~ 9

Author(s):

Sara Lovisa ◽

Giannicola Genovese ◽

Silvio Danese

Keyword(s):

Inflammatory Bowel Disease ◽

Wound Healing ◽

Bowel Disease ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Clinical Manifestations ◽

Mesenchymal Transition ◽

Intestinal Fibrosis ◽

Inflammatory Bowel

Abstract Intestinal fibrosis is an inevitable complication in patients with inflammatory bowel disease [IBD], occurring in its two major clinical manifestations: ulcerative colitis and Crohn’s disease. Fibrosis represents the final outcome of the host reaction to persistent inflammation, which triggers a prolonged wound healing response resulting in the excessive deposition of extracellular matrix, eventually leading to intestinal dysfunction. The process of epithelial-to-mesenchymal transition [EMT] represents an embryonic program relaunched during wound healing, fibrosis and cancer. Here we discuss the initial observations and the most recent findings highlighting the role of EMT in IBD-associated intestinal fibrosis and fistulae formation. In addition, we briefly review knowledge on the cognate process of endothelial-to-mesenchymal transition [EndMT]. Understanding EMT functionality and the molecular mechanisms underlying the activation of this mesenchymal programme will permit designing new therapeutic strategies to halt the fibrogenic response in the intestine.

Download Full-text