Cellular and molecular mechanisms of intestinal fibrosis

Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelialand endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic proc-ess, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

Network pharmacology and molecular docking reveal zedoary turmeric-trisomes in Inflammatory bowel disease with intestinal fibrosis

BACKGROUND Inflammatory bowel disease(IBD) is a complex chronic IBD that is closely associated with risk factors such as environment, diet, medications and lifestyle that may influence the host microbiome or immune response to antigens. At present, with the increasing incidence of IBD worldwide, it is of great significance to further study the pathogenesis of IBD and seek new therapeutic targets. Traditional Chinese medicine(TCM) treatment of diseases is characterized by multiple approaches and multiple targets and has a long history of clinical application in China. The mechanism underlying the effect of zedoary turmerictrisomes on inducing mucosal healing in IBD is not clear.AIM To explore the effective components and potential mechanism of zedoary turmeric-trisomes in the treatment of IBD with intestinal fibrosis using network pharmacology and molecular docking techniques.METHODS The chemical constituents and targets of Rhizoma zedoary and Rhizoma sanarum were screened using the TCMSP database. The GeneCards database was searched to identify targets associated with intestinal fibrosis in IBD. The intersection of chemical component targets and disease targets was obtained using the Venny 2.1 online analysis platform, and the common targets were imported into the STRING 11.0 database to construct a protein interaction regulatory network. A “zedoary turmeric-trisomes-chemical composition-target-disease” network diagram was subsequently constructed using Cytoscape 3.7.2 software, and the topological properties of the network were analyzed using the “Network Analysis” plug-in. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses of the common targets were performed using the DAVID 6.8 database to elucidate the mechanism of zedoary turmeric-trisomes in the treatment of IBD. Subsequently, molecular docking of the compounds and targets with the highest intermediate values in the “zedoary turmeric-trisomes-chemical composition-target-disease” network was performed using Sybyl-x 2.1.1 software.RESULTS A total of 5 chemical components with 60 targets were identified, as well as 3153 targets related to IBD and 44 common targets. The protein-protein interaction network showed that the core therapeutic targets included JUN, MAPK14, CASP3, AR, and PTGS2. The GO enrichment analysis identified 759 items, and the KEGG enrichment analysis yielded 52 items, including the cancer pathway, neuroactive ligand-receptor interaction, hepatitis B, and the calcium signaling pathway, reflecting the complex biological processes of the multicomponent, multitarget and multipathway treatment of diseases with zedoary turmeric-trisomes. Molecular docking showed that the compound bonded with the target through hydrogen bond interactions and exhibited good docking activity.CONCLUSION This study identified the potential mechanism of action of zedoary turmeric-trisomes in the treatment of inflammatory bowel fibrosis using network pharmacology and molecular docking technology, providing a scientific basis for further expansion of their clinical use.

Role of gut microbiota in Crohn’s disease pathogenesis:Insights from fecal microbiota transplantation in mouse model

BACKGROUND Inflammatory bowel disease,particularly Crohn’s disease(CD),has been associated with alterations in mesenteric adipose tissue(MAT)and the phenomenon termed“creeping fat”.Histopathological evaluations showed that MAT and intestinal tissues were significantly altered in patients with CD,with these tissues characterized by inflammation and fibrosis.AIM To evaluate the complex interplay among MAT,creeping fat,inflammation,and gut microbiota in CD.METHODS Intestinal tissue and MAT were collected from 12 patients with CD.Histological manifestations and protein expression levels were analyzed to determine lesion characteristics.Fecal samples were collected from five recently treated CD patients and five control subjects and transplanted into mice.The intestinal and mesenteric lesions in these mice,as well as their systemic inflammatory status,were assessed and compared in mice transplanted with fecal samples from CD patients and control subjects.RESULTS Pathological examination of MAT showed significant differences between CDaffected and unaffected colons,including significant differences in gut microbiota structure.Fetal microbiota transplantation(FMT)from clinically healthy donors into mice with 2,4,6-trinitrobenzene sulfonic acid(TNBS)-induced CD ameliorated CD symptoms,whereas FMT from CD patients into these mice exacerbated CD symptoms.Notably,FMT influenced intestinal permeability,barrier function,and levels of proinflammatory factors and adipokines.Furthermore,FMT from CD patients intensified fibrotic changes in the colon tissues of mice with TNBS-induced CD.CONCLUSION Gut microbiota play a critical role in the histopathology of CD.Targeting MAT and creeping fat may therefore have potential in the treatment of patients with CD.

Contribution of gut microbiota to the development of Crohn's disease:Insights gained from fecal microbiota transplantation studies in mice

We would like to present some new thoughts on the publication in the journalpublished in August 2024 in World Journal of Gastroenterology.We specificallyfocused on the alterations in the intestinal tract,mesenteric adipose tissue(MAT),and systemic inflammatory changes in mice following fecal flora transplantationinto a mouse model of Crohn's disease(CD).Accumulating evidence suggests thatthe occurrence of CD is influenced by environmental factors,host immune status,genetic susceptibility,and flora imbalance.One microbiota-based intervention,fecal microbiota transplantation,has emerged as a potential treatment option forCD.The MAT is considered a"second barrier"around the inflamed intestine.Theinteraction between gut microbes and inflammatory changes in MAT has attractedconsiderable interest.In the study under discussion,the authors transplantedfetal fecal microorganisms from patients with CD and clinically healthy donors,respectively,into 2,4,6-trinitrobenzene sulfonic acid-induced CD mice.Theresearch explored the complex interplay between MAT,creeping fat,inflammation,and intestinal flora in CD by evaluating intestinal and mesenteric lesions,along with the systemic inflammatory state in the mice.This article providesseveral important insights.First,the transplantation of intestinal flora holdssignificant potential as a therapeutic strategy for CD,offering hope for patientswith CD.Second,it presents a novel approach to the diagnosis and treatment ofCD:The inflammatory response in CD could potentially be assessed throughpathological or imaging changes in the MAT,and CD could be treated bytargeting the inflammation of the MAT.

Resveratrol inhibits collagen Ⅰ synthesis by suppressing IGF-1R activation in intestinal fibroblasts

AIM: To investigate whether resveratrol (3,4,5-trihydroxy-trans-stilbene) inhibits collagen I synthesis induced by insulin growth factor-1 (IGF-1) in intestinal fibroblasts, and to explore the possible molecular mechanisms.

Visceral adipose volume is correlated with surgical tissue fibrosis in Crohn’s disease of the small bowel

Background This study explored the diagnostic performance of visceral adiposity to predict the degree of intestinal inflammation and fibrosis.Methods The patients with Crohn’s disease(CD)who underwent surgical small bowel resection at the First Affiliated Hospital of Sun Yat-sen University(Guangzhou,China)between January 2007 and December 2017 were enrolled.We evaluated the intestinal imaging features of computed tomography enterography(CTE),including mesenteric inflammatory fat stranding,the target sign,mesenteric hypervascularity,bowel wall thickening,lymphadenopathy,stricture diameter,and maximal upstream diameter.We used A.K.software(Artificial Intelligence Kit,version 1.1)to calculate the visceral fat(VF)and subcutaneous fat(SF)volumes at the third lumbar vertebra level.Pathological tissue information was recorded.Diagnostic models were established based on the multivariate regression analysis results,and their effectiveness was evaluated by area under the curve(AUC)and decision curve analyses.Results Overall,48 patients with CD were included in this study.The abdominal VF/SF volume ratio(odds ratio,1.20;95%confidence interval,1.05–1.38;P=0.009)and the stenosis diameter/upstream intestinal dilatation diameter(ND)ratio(odds ratio,0.90;95%confidence interval,0.82–0.99;P=0.034)were independent risk factors for the severe fibrosis of the small intestine.The AUC values of the VF/SF ratio,the ND ratio,and their combination were 0.760,0.673,and 0.804,respectively.The combination of the VS/SF volume ratio and ND ratio achieved the highest net benefit on the decision curve.Conclusion The VF volume on CTE can reflect intestinal fibrosis.The combination of the VF/SF volume ratio and ND ratio of CD patients assessed using CTE can help predict severe fibrosis stenosis of the small intestine.