Fibrosis is a pathological feature of a variety of chronic inflammatory diseases that can affect almost all organs, which can cause severe consequences and even lead to death. Fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) due to disruption of the balance between ECM production and degradation. Although overabundance of ECM proteins has long been the focus of studies on fibrosis, another facet of the problem—impaired degradation of the ECM—is gaining increasing attention. Matrix metalloproteinase (MMP) and the tissue inhibitor of metalloproteinase (TIMP) system is the main molecular system contributing to ECM degradation, and macrophages are the major regulators of ECM. However, the relationship among macrophages, the MMP/TIMP system and the ECM is not fully understood in the context of fibrosis. Here, we discuss in detail the role played by the ECM in the development of fibrosis and highlight the macrophage-MMP-ECM interaction that is involved in fibrogenesis and may be a potential therapeutic target for fibrosis.

Intestinal fibrosis, a severe complication of Crohn’s disease (CD), is characterized by excessive extracellular matrix (ECM) deposition and induces intestinal strictures, but there are no effective antifibrosis drugs available for clinical application. We performed single-cell RNA sequencing (scRNA-Seq) of fibrotic and nonfibrotic ileal tissues from patients with CD with intestinal obstruction. Analysis revealed mesenchymal stromal cells (MSCs) as the major producers of ECM and the increased infiltration of its subset FAP ⁺ fibroblasts in fibrotic sites, which was confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomic profiling of chronic dextran sulfate sodium salt murine colitis model revealed that CD81 ⁺ Pi16 ^– fibroblasts exhibited transcriptomic and functional similarities to human FAP ⁺ fibroblasts. Consistently, FAP ⁺ fibroblasts were identified as the key subtype with the highest level of ECM production in fibrotic intestines. Furthermore, specific knockout or pharmacological inhibition of TWIST1, which was highly expressed by FAP ⁺ fibroblasts, could significantly ameliorate fibrosis in mice. In addition, TWIST1 expression was induced by CXCL9 ⁺ macrophages enriched in fibrotic tissues via IL-1β and TGF-β signal. These findings suggest the inhibition of TWIST1 as a promising strategy for CD fibrosis treatment.

Crohn's disease (CD) is a chronic inflammatory disease that leads to intestinal stricture in nearly 35% of cases within 10 years of initial diagnosis. The unknown pathogenesis, lack of universally accepted criteria, and absence of an effective management approach remain unconquered challenges in structuring CD. The pathogenesis of stricturing CD involves intricate interactions between factors such as immune cell dysbiosis, fibroblast activation, and microecology imbalance. New techniques such as single‐cell sequencing provide a fresh perspective. Non‐invasive diagnostic tools such as serum biomarkers and novel cross‐sectional imaging techniques offer a precise understanding of intestinal fibrostenosis. Here, we provide a timely and comprehensive review of the worthy advancements in intestinal strictures in 2023, aiming to dispense cutting‐edge information regarding fibrosis and to build a cornerstone for researchers and clinicians to make greater progress in the field of intestinal strictures.

Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

Background and Objectives: A majority of pancreatic malignancies are unresectable at the time of presentation and require EUS–guided fine-needle aspiration or fine-needle biopsy (EUS-FNA/FNB) for diagnosis. With the advent of precision therapy, there is an increasing need to use EUS-FNA/FNB sample for genetic analysis. Next-generation sequencing (NGS) is a preferred technology to detect genetic mutations with high sensitivity in small specimens. We performed a meta-analysis to evaluate the adequacy of EUS-FNA/FNB for NGS in pancreatic malignancies. Methods: PubMed, Embase, Cochrane Library, and Web of Science were searched from database inception to November 11, 2023. The primary outcome was the proportion of sufficient sample acquired by EUS-FNA/FNB in pancreatic malignancies for NGS. Secondary outcomes were the proportion of sufficient sample for NGS in pancreatic ductal adenocarcinoma (PDAC) and the detection rates of mutations in KRAS, TP53, CDKN2A, and SMAD4 and actionable mutations in PDAC. The pooled proportions were calculated using a random-effects model. Potential sources of heterogeneity were investigated with subgroup analyses and meta-regression. Results: Twenty studies with 881 samples were included. The pooled adequacy of EUS-FNA/FNB sample for NGS was 89.9% (95% CI, 80.8%–96.7%) in pancreatic malignancies and 92.0% (95% CI, 81.3%–98.8%) in PDAC. Screening sample suitability before NGS testing was associated with lower adequacy in subgroup analysis (79.7% vs. 98.4%, P = 0.001). The pooled prevalences of mutations in KRAS, TP53, CDKN2A, and SMAD4 in PDAC were 87.4% (95% CI, 83.2%–91.2%), 62.6% (95% CI, 53.2%–71.7%), 20.6% (95% CI, 11.9%–30.8%), and 19.4% (95% CI, 11.2%–29.1%), respectively. The pooled prevalence of potentially actionable mutations in PDAC was 14.5% (95% CI, 8.2%–22.0%). Conclusions: In the majority of cases, EUS-FNA/FNB can acquire adequate sample for NGS and identify tumor-specific mutations in patients with pancreatic malignancies. Strict pre-analysis screening criteria may negatively impact the sample adequacy and the success rate for NGS.

Solid pancreatic lesions (SPLs) encompass a variety of benign and malignant diseases and accurate diagnosis is crucial for guiding appropriate treatment decisions. Endoscopic ultrasonography-guided fine-needle aspiration/biopsy (EUS-FNA/B) serves as a front-line diagnostic tool for pancreatic mass lesions and is widely used in clinical practice. Artificial intelligence (AI) is a mathematical technique that automates the learning and recognition of data patterns. Its strong self-learning ability and unbiased nature have led to its gradual adoption in the medical field. In this paper, we describe the fundamentals of AI and provide a summary of reports on AI in EUS-FNA/B to help endoscopists understand and realize its potential in improving pathological diagnosis and guiding targeted EUS-FNA/B. However, AI models have limitations and shortages that need to be addressed before clinical use. Furthermore, as most AI studies are retrospective, large-scale prospective clinical trials are necessary to evaluate their clinical usefulness accurately. Although AI in EUS-FNA/B is still in its infancy, the constant input of clinical data and the advancements in computer technology are expected to make computer-aided diagnosis and treatment more feasible.