Intestinal stricture remains one of the most challenging complications in Crohn's disease, and its underlying mechanisms are poorly understood. Accumulating evidence suggests that gut microbiota is significantly altered in stenotic intestines and may play a key role in the development of fibrogenesis in Crohn's disease. Additionally, the presence of hypertrophic mesenteric adipose tissue, also known as creeping fat, is closely correlated with intestinal stricture and fibrosis. Recent findings have revealed that bacterial translocation to creeping fat might exacerbate colitis and promote intestinal fibrosis. However, there is still a gap in determining whether gut microbiota links the formation of creeping fat to intestinal fibrosis. Hence, this review aims to summarize the known microbial influences on intestinal fibrosis, describes the microbial characteristics of creeping fat in Crohn's disease, and discusses the crosstalk between creeping fat-associated dysbiosis and the development of intestinal fibrosis.

Ulcerative colitis (UC) is a chronic relapsing disease with significant associated risks such as colectomy, hospitalization, or colorectal cancer. A treat-to-target approach that mitigates disease activity and progression from an early stage is needed. The latest STRIDE II guidelines advocate for clinical and endoscopic remission as the main therapeutic targets in the management of UC; however, histological remission is increasingly being recognized as an important outcome. The concept of disease clearance, a composite outcome comprising clinical, endoscopic, and histological remission, has been proposed as a potential target for patients with UC and has been precisely defined by the International Organization for the Study of Inflammatory Bowel Disease, with the aim of standardizing its use in clinical practice and research. Despite challenges, including variable standardized definitions and uncertainties regarding the timing of reaching different definitions of remission, disease clearance corresponds to comprehensive disease control, and its use as an outcome could help clinicians to better evaluate the actual status of the disease. Furthermore, achieving disease clearance may be related to an improved disease course, positive long-term outcomes, and an improvement in health-related quality of life. Real-world evidence supports the feasibility of achieving disease clearance with various treatment modalities, including vedolizumab, the only gut-selective antilymphocyte trafficking drug. The aim of this narrative review is to explore the concept of disease clearance in patients with disease clearance, mainly focusing on trials evaluating vedolizumab but also other biologics.

Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.

Chronic liver damage, such as metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis B or C, cholestatic hepatitis (PBC, PSC), toxic damage (alcohol) or genetic alterations (hemochromatosis, Wilson's disease, etc.) usually cause a chronic inflammatory response in liver cells or bile duct epithelial cells. In the long term this chronic inflammatory response can lead to scarring of the liver, a condition known as fibrosis. The development of liver fibrosis is largely independent of the causative agent, although the pattern of initial fibrosis (periportal, pericentral or sinusoidal) can vary. Untreated and progressive fibrosis can sometimes lead to complete architectural deconstruction and deposition of connective tissue in the liver, intestines and other parenchymal organs, with a gradual loss of function. In the end stage of liver cirrhosis, portal hypertension, encephalopathy, bleeding or carcinomas, e.g., hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (iCCCa), can occur. Intestinal fibrosis is one of the most devastating complications of Crohn's disease. With novel and consistent therapeutic interventions, fibrotic processes can be stopped and reversed. New research technologies have substantially improved our knowledge of liver fibrogenesis and intestinal fibrosis. The focus of this review article is on MASLD and Crohn's disease, chronic inflammatory diseases of the liver and intestines with increasing prevalence and a major impact on the general population. The current principles and potential possibilities of preventive and therapeutic antifibrotic interventions are illustrated.

Intestinal fibrous stenosis due to Crohn's disease (CD) is highly prevalent. Although several clinical risk factors for fibrous stenosis have been identified, such as perianal fistulizing disease, small bowel disease location, and deep mucosal ulceration, predicting fibrous stenosis remains challenging. The intestinal microbiota plays a crucial role in the development and progression of CD. However, its role in intestinal fibrous stenosis is poorly understood. Leveraging a single-center cross-sectional study, we aimed to investigate the role of fecal microbiota in CD-associated fibrous stenosis.

Using metagenomic analysis, we examined the differences in fecal microbiota between CD patients with intestinal fibrous stenosis and those without stenosis. We identified specific microbiota and assessed their predictive accuracy for intestinal fibrous stenosis. Additionally, we explored functional differences in intestinal microbiota between the two groups.

: Our investigation of fecal samples revealed no significant differences in the gut microbiota structure between patients with fibrous stenosis and those without stenosis in CD. However, taxonomically, we found 70 taxa with significantly different abundance (p < 0.05) between the two groups. Furthermore, LEfSe analysis indicated that g_Bacteroides and g_Enterocloster could predict intestinal fibrous stenosis while p_Actinobacteria, c_Actinomycetia, c_Bacilli, o_Lactobacillales, f_Streptococcaceae and g_Streptococcus could predict CD without stenosis. Functional analysis revealed differential enrichment in five metabolic pathways at the KEGG pathway level in CD patients with fibrous stenosis, including sphingolipid metabolism, lipoic acid metabolism, and biosynthesis of neomycin, kanamycin and gentamicin. In the eggNOG database, we observed differences in four functional categories between the two groups, encompassing cellular process, signaling, and metabolism.

Fecal microbiota significantly impacted intestinal fibrous stenosis in CD. Although there were no significant differences in alpha and beta diversities, fibrous stenosis was associated with changes in microbiota composition and function, suggesting the potential of fecal microbiota in predicting CD-associated fibrous stenosis.

Inflammatory Bowel Disease (IBD) is a lifelong chronic disease affecting any part of the gastrointestinal tract with a predilection for the terminal ileum. IBD patients require repeat imaging throughout the course of their disease, necessitating a safe, noninvasive, available, and repeatable method. Imaging is required at diagnosis, routine surveillance, and acute exacerbation of disease. Ultrasound imaging meets these demands with a high degree of accuracy and wide patient acceptance. Ultrasound provides high-resolution imaging and is excellent for detailed evaluation of the bowel wall and surrounding soft tissues. Regular greyscale bowel evaluation and color Doppler imaging now have accepted standards for evaluating disease activity based on wall thickness, perienteric inflammatory fat, and blood flow, which is invaluable in staging and grading disease. High-resolution dynamic real-time imaging on ultrasound has the ability to show functional as well as morphologic detail, including dysfunctional peristalsis associated with bowel stricture and incomplete mechanical bowel obstruction. Fibrostenotic and penetrating complications of IBD may be associated with an acute or chronic presentation that is easily assessed using ultrasound. Newer software technologies for ultrasound, including Contrast-Enhanced ultrasound and Shear wave elastography, have transformed ultrasound from a basic preliminary imaging technique into a highly sophisticated modality that is now competitive with CT and MR enterography for managing IBD patients. Our long experience with ultrasound of the bowel suggests that the new best practice would include ultrasound as the first test for evaluation of the bowel at any stage of the disease.

In this letter, we commented on the article by Wu et al. We examined the interactions between mesenteric adipose tissue, creeping fat, and gut microbiota in Crohn's disease (CD), a condition marked by chronic gastrointestinal inflammation with a rising global incidence. The pathogenesis of CD involves complex genetic, environmental, and microbial factors. Dysbiosis, which is an imbalance in gut microbial communities, is frequently observed in CD patients, highlighting the pivotal role of the gut microbiota in disease progression and the inflammatory response. Recent studies have shown that mesenteric adipose tissue and creeping fat actively contribute to inflammation by producing proinflammatory cytokines. The relationship between creeping fat and altered microbiota can shift from a potentially protective role to one that encourages bacterial translocation, further complicating disease management. Recent research has suggested that fecal microbiota transplantation could help restore microbial balance, offering a promising therapeutic strategy to improve clinical disease response.

Management of inflammatory bowel disease (IBD) poses significant challenges, and there is a need for innovative therapeutic approaches. This study investigates the anti-inflammatory properties of the dietary sesquiterpene lactone (SL) 11β,13-dihydrolactucin, which can be found in chicory, in three distinct complementary models of intestinal inflammation (two cell models and a zebrafish model), offering comprehensive insights into its potential application for IBD treatment alternatives. In a triple cell co-culture composed of Caco-2, HT29-MTX-E12, and Raji B, 11β,13-dihydrolactucin demonstrated remarkable anti-inflammatory activity at several levels of the cellular inflammatory response. Notably, 11β,13-dihydrolactucin prevented the activation of critical signalling pathways associated with inflammation, namely NF-κB and MAPK p38. This SL also decreased the release of the neutrophil-recruiting chemokine IL-8. Additionally, the compound reduced the gene expression of IL-6 and TNF-α, as well as the gene and protein expression of the inflammatory inducible enzymes iNOS and COX-2. In a myofibroblast-like human cell model, 11β,13-dihydrolactucin decreased the release of the cytokine TNF-α and the COX-2-derived inflammation mediator PGE2. Finally, in a zebrafish model of gut inflammation, 11β,13-dihydrolactucin effectively reduced neutrophil infiltration, further supporting its anti-inflammatory efficacy in a physiological context. Collectively, our findings highlight the promising anti-inflammatory potential of 11β,13-dihydrolactucin across various facets of intestinal inflammation, providing a foundation for the consideration of chicory as a promising candidate for incorporation in food or nutraceutical products for the potential prevention of IBD.

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.

To evaluate the complex interplay among MAT, creeping fat, inflammation, and gut microbiota in CD.

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.

Pathological examination of MAT showed significant differences between CD-affected 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.

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.

Intestinal fibrosis is a common complication of Inflammatory Bowel Disease (IBD), namely Crohn's disease (CD) and ulcerative colitis (UC), but the precise mechanism by which it occurs is incompletely understood hampering the development of effective therapeutic strategies. Here, we aimed at inducing and characterizing an inflammation-mediated fibrosis in patient-derived organoids (PDOs) issued from crypts isolated from colonic mucosal biopsies of IBD pediatric patients and age matched-control subjects (CTRLs).

Inflammatory-driven fibrosis was induced by exposing CTRL-, CD- and UC-PDOs to the pro-inflammatory cytokine TNF-α for one day, followed by a co-treatment with TNF-α and TGF-β1 for three days. Fibrotic response was proven by analyzing inflammatory and fibrotic markers by RT-qPCR and immunofluorescence. Transcriptomic changes were assessed by RNA-sequencing.

Co-treatment with TNF-α and TGF-β1 caused in CTRL- and IBD-PDOs morphological changes towards a mesenchymal-like phenotype and up-regulation of inflammatory, mesenchymal, and fibrotic markers. Transcriptomic profiling highlighted that in all intestinal PDOs, regardless of the disease, the co-exposure to TNF-α and TGF-β1 regulated EMT genes and specifically increased genes involved in positive regulation of cell migration. Finally, we demonstrated that CD-PDOs display a specific response to fibrosis compared to both CTRL- and UC-PDOs, mainly characterized by upregulation of nuclear factors controlling transcription.

This study demonstrates that intestinal PDOs may develop an inflammatory-derived fibrosis thus representing a promising tool to study fibrogenesis in IBD. Fibrotic PDOs show increased expression of EMT genes. In particular, fibrotic CD-PDOs display a specific gene expression signature compared to UC and CTRL-PDOs.

Crohn's disease (CD) progresses with periods of remission and exacerbations. During exacerbations, chronic inflammation leads to tissue destruction. As a result, intestinal fibrosis may develop in response to the ongoing inflammatory process. Fibrosis in CD should be considered the result of the response of the intestinal wall (over) to the presence of inflammation in the deep structures of the intestinal wall. In the absence of ideal noninvasive methods, endoscopic evaluation in combination with biopsy, histopathological analysis, stool analysis, and blood analysis remains the gold standard for assessing both inflammation and fibrosis in CD. On the contrary, the ability to identify markers of intestinal fibrosis would help to develop new diagnostic and therapeutic methods to detect early stages of fibrosis. It is speculated that miRNAs may, in the future, become biomarkers for early noninvasive diagnosis in the treatment of intestinal fibrosis. The purpose of this review is to summarise existing diagnostic methods for Crohn's disease and present recent scientific reports on molecular testing.

Intestinal fibrosis is a common complication of chronic intestinal diseases with the characteristics of fibroblast proliferation and extracellular matrix deposition after chronic inflammation, leading to lumen narrowing, structural and functional damage to the intestines, and life inconvenience for the patients. However, anti-inflammatory drugs are currently generally not effective in overcoming intestinal fibrosis making surgery the main treatment method. The development of intestinal fibrosis is a slow process and its onset may be the result of the combined action of inflammatory cells, local cytokines, and intestinal stromal cells. The aim of this study is to elucidate the pathogenesis [e.g., extracellular matrix (ECM), cytokines and chemokines, epithelial-mesenchymal transition (EMT), differentiation of fibroblast to myofibroblast and intestinal microbiota] underlying the development of intestinal fibrosis and to explore therapeutic advances (such as regulating ECM, cytokines, chemokines, EMT, differentiation of fibroblast to myofibroblast and targeting TGF-β) based on the pathogenesis in order to gain new insights into the prevention and treatment of intestinal fibrosis.

Inflammatory Bowel Disease (IBD) is a complex and challenging health problem that exerts a significant impact on the quality of life of millions of individuals worldwide [...].

Advancements in murine modeling systems for ulcerative colitis have diversified our understanding of the pathophysiological factors involved in disease onset and progression. This has fueled the identification of molecular targets, resulting in a rapidly expanding therapeutic armamentarium. Subsequently, management strategies have evolved from symptomatic resolution to well-defined objective endpoints, including clinical remission, endoscopic remission and mucosal healing. While the incorporation of these assessment modalities has permitted targeted intervention in the context of a natural disease history and the prevention of complications, studies have consistently depicted discrepancies associated with ascertaining disease status through clinical and endoscopic measures. Current recommendations lack consideration of histological healing. The simultaneous achievement of clinical, endoscopic, and histologic remission has not been fully investigated. This has laid the groundwork for a novel therapeutic outcome termed disease clearance (DC). This article summarizes the concept of DC and its current evidence.

Intestinal fibrosis is a long-term complication of inflammatory bowel diseases (IBD). Changes in microbial populations have been linked with the onset of fibrosis and some food additives are known to promote intestinal inflammation facilitating fibrosis induction. In this study, we investigated how polysorbate 80, sucralose, titanium dioxide, sodium nitrite and maltodextrin affect the gut microbiota and the metabolic activity in healthy and IBD donors (patients in remission and with a flare of IBD). The Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) with a static (batch) configuration was used to evaluate the effects of food additives on the human intestinal microbiota. Polysorbate 80 and sucralose decreased butyrate-producing bacteria such as Roseburia and Faecalibacterium prausnitzii. Both compounds, also increased bacterial species positively correlated with intestinal inflammation and fibrosis (i.e.: Enterococcus, Veillonella and Mucispirillum schaedleri), especially in donors in remission of IBD. Additionally, polysorbate 80 induced a lower activity of the aryl hydrocarbon receptor (AhR) in the three groups of donors, which can affect the intestinal homeostasis. Maltodextrin, despite increasing short-chain fatty acids production, promoted the growth of Ruminococcus genus, correlated with higher risk of fibrosis, and decreased Oscillospira which is negatively associated with fibrosis. Our findings unveil crucial insights into the potential deleterious effects of polysorbate 80, sucralose and maltodextrin on human gut microbiota in healthy and, to a greater extent, in IBD patients.

Fibrosis represents a process characterized by excessive deposition of extracellular matrix (ECM) proteins. It often represents the evolution of pathological conditions, causes organ failure, and can, in extreme cases, compromise the functionality of organs to the point of causing death. In recent years, considerable efforts have been made to understand the molecular mechanisms underlying fibrotic evolution and to identify possible therapeutic strategies. Great interest has been aroused by the discovery of a molecular association between epithelial to mesenchymal plasticity (EMP), in particular epithelial to mesenchymal transition (EMT), and fibrogenesis, which has led to the identification of complex molecular mechanisms closely interconnected with each other, which could explain EMT-dependent fibrosis. However, the result remains unsatisfactory from a therapeutic point of view. In recent years, advances in epigenetics, based on chromatin remodeling through various histone modifications or through the intervention of non-coding RNAs (ncRNAs), have provided more information on the fibrotic process, and this could represent a promising path forward for the identification of innovative therapeutic strategies for organ fibrosis. In this review, we summarize current research on epigenetic mechanisms involved in organ fibrosis, with a focus on epigenetic regulation of EMP/EMT-dependent fibrosis.

The stiffening of the extracellular matrix, and changes in its cellular and molecular composition, have been reported in the pathogenesis of fibrosis. We analyze the mechanisms that perpetuate ileal fibrosis in surgical resections of complicated Crohn's disease patients.

Ileal resections were obtained from affected and non-affected tissue of stenotic or penetrating Crohn's disease behavior. Ilea from non-IBD patients were used as control tissue. All samples underwent RNA sequencing. Human small intestinal fibroblasts were treated for 48 h with IL-1β, TFGβ1, PDGFB or TNF-α. Resistance to apoptosis was analysed by RT-PCR, western blot and immunohistochemistry in ileal tissue and by RT-PCR and FACS in cultured cells.

Growth factor-driven signaling pathways and increased RAS GTPase activity were up-regulated in affected ilea in which we found expression of both the antiapoptotic molecule MCL1 and the transcription factor ETS1 in submucosal fibroblasts, and a senescence-associated secretory phenotype. In cultured intestinal fibroblasts, PDGFB induced an ETS1-mediated resistance to apoptosis that was associated with the induction of both of TGFB1 and IL1B, a cytokine that replicated the expression of SASP detected in ileal tissue. ETS1 drove fibroblast polarization between inflammatory and fibrogenic phenotypes in IL1β-treated cells.

Our data show resistance to apoptosis in complicated ileal CD, and demonstrate that PDGFB induce an ETS1-mediated resistance to apoptosis associated with an inflammatory and fibrogenic pattern of expression in intestinal fibroblasts. Results point to PDGFRB, IL1R1 or MCL1 as potential targets against ileal fibrosis.

In inflammatory bowel disease (IBD), chronic inflammation in the gastrointestinal tract can lead to tissue damage and remodelling, which can ultimately result in fibrosis. Prolonged injury and inflammation can trigger the activation of fibroblasts and extracellular matrix (ECM) components. As fibrosis progresses, the tissue becomes increasingly stiff and less functional, which can lead to complications such as intestinal strictures, obstructive symptoms, and eventually, organ dysfunction. Epithelial cells play a key role in fibrosis, as they secrete cytokines and growth factors that promote fibroblast activation and ECM deposition. Additionally, epithelial cells can undergo a process called epithelial-mesenchymal transition, in which they acquire a more mesenchymal-like phenotype and contribute directly to fibroblast activation and ECM deposition. Overall, the interactions between epithelial cells, immune cells, and fibroblasts play a critical role in the development and progression of fibrosis in IBD. Understanding these complex interactions may provide new targets for therapeutic interventions to prevent or treat fibrosis in IBD. In this review, we have collected and discussed the recent literature highlighting the contribution of epithelial cells to the pathogenesis of the fibrotic complications of IBD, including evidence of EMT, the epigenetic control of the EMT, the potential influence of the intestinal microbiome in EMT, and the possible therapeutic strategies to target EMT. Finally we discuss the pro-fibrotic interactions epithelial-immune cells and epithelial-fibroblasts cells.

Chronic idiopathic intestinal inflammation is an increasing worldwide problem that affects companion animals, especially dogs, and human patients. Although these disease entities have been intensely investigated recently, many questions remain, and alternative therapeutic options are needed. Diarrhea caused by dysregulation of intestinal electrolyte transport and subsequent fluid and electrolyte losses often leads to secondary consequences for the patient. Currently, it is not exactly clear which mechanisms are involved in the dysregulation of intestinal fluid absorption, but differences in intestinal electrolyte shifts between human and canine patients suggest species-specific regulatory or counterregulatory mechanisms. Several intestinal electrolyte transporters are differentially expressed in human patients with inflammatory bowel disease (IBD), whereas there are virtually no studies on electrolyte transporters and their endocrine regulation in canine chronic inflammatory enteropathy. An important mechanism involved in regulating fluid and electrolyte homeostasis is the renin-angiotensin-aldosterone-system (RAAS), which may affect intestinal Na⁺ transport. While RAAS has previously been considered a systemic regulator of blood pressure, additional complex roles of RAAS in inflammatory processes have been unraveled. These alternative RAAS pathways may pose attractive therapeutic targets to address diarrhea and, thus, electrolyte shifts in human IBD and canine chronic inflammatory enteropathy. This article comparatively summarizes the current knowledge about electrolyte transport in human IBD and canine chronic inflammatory enteropathy and the role of RAAS and offers perspectives for novel therapeutic avenues.