The Fibrosis in Inflammatory Bowel Disease: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Helena Tavares de Sousa.

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation mediated by dysregulated immune responses to such factors as diet and microbiota. Fibrosis, which is a healing mechanism, becomes progressive and damaging in the scope of long-lasting IBD, in which persistent tissue damage and healing result in scar tissue formation.

  • inflammatory bowel disease
  • fibrosis
  • inflammation
  • imaging
  • histopathology

1. The Importance of Fibrosis in IBD

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation mediated by dysregulated immune responses to such factors as diet and microbiota [1,2,3,4][1][2][3][4].
In both CD and UC, chronic inflammation causes disruption of the epithelial barrier and tissue destruction. Fibrosis, which is a healing mechanism, becomes progressive and damaging in the scope of long-lasting IBD, in which persistent tissue damage and healing result in scar tissue formation [5,6][5][6]. At tissue and cellular levels, fibrosis is an amplified response characterized by the accumulation of collagen-rich extracellular matrix (ECM) produced by an increased number of mesenchymal cells, including fibroblasts, myofibroblasts, and smooth muscle cells (SMCs) [7]. The proliferation of fibroblastic cells, along with the accumulation of ECM, are the hallmarks of intestinal strictures in IBD [8]. Fibrosis is a frequent outcome in the natural history of IBD and is the background for most of the IBD complications, such as strictures, bowel penetration, and obstruction, often demanding surgery [5,6,9][5][6][9]. It has been estimated that about 30% to 50% of CD patients and 1% to 12% of UC patients would suffer from fibrosis complications during the disease course [6,10,11][6][10][11]. Until recently, intestinal fibrosis was considered an unavoidable complication of IBD in patients that did not respond to anti-inflammatory therapy, often requiring surgical intervention [6]. The emergence of the possibility of an anti-fibrotic approach changed this paradigm, creating challenges in terms of diagnosis and treatment of bowel fibrosis [6,12][6][12]. As such, understanding the molecular and cellular mechanisms underpinning fibrosis and improving techniques for the assessment of fibrosis in IBD patients are still relevant research topics.

1.1. Fibrosis in CD

In CD, both inflammation and fibromuscular changes are transmural, leading to progressive thickening of the bowel wall and stricture development, even in the absence of inflammation. Pathologically, intestinal fibrosis in CD is characterized by ECM accumulation and mesenchymal cell expansion affecting all layers of the bowel wall along the intestinal tract [13]. In addition, recent pathologic consensus defined small bowel strictures in CD as a combination of decreased luminal diameter and increased thickness of all layers of the intestinal wall, including expansion of the muscularis mucosae (MM) and inner muscularis propria (MP), muscularization of the submucosa, and fibrosis of the submucosa and intestinal wall [14]. Notwithstanding, the universality of this concept was recently challenged by the description of a non-hypertrophic, constrictive type of stricture in CD [15]. Regardless of the type of stricture, these remain common complications of CD with serious clinical relevance and impact on the patients’ quality of life [12,15,16][12][15][16].
Aside from fibrosis in strictures, it has been proposed that a certain degree of fibrosis would exist in nearly all CD phenotypes, even from early onset. In addition, it has been demonstrated that the degree of fibrosis may be similar in both stricturing and penetrating CD, with differences regarding the degree of transmural inflammation [17].
Though still used in clinical practice, the classification of CD in three-category phenotypes, as inflammatory or non-stricturing, non-penetrating (B1), stricturing (B2), and penetrating (B3) disease, is now considered too rigid [18,19][18][19]. As an alternative, CD shall be viewed through the lens of a progressive accumulation of intestinal fibrosis and damage over the course of the disease, leading to stricturing and/or penetrating complications, as supported by epidemiological natural history studies [16,20,21,22,23,24,25,26][16][20][21][22][23][24][25][26]. This progressive and cumulative structural bowel damage would occur irrespective of symptoms and, considering current fibrogenesis knowledge, of the degree of intestinal inflammation [6,27,28][6][27][28]. Hence, clinical symptoms, disease activity [29[29][30],30], and progression of bowel damage [4,31][4][31] are not totally correlated.
Considering that population-based studies have shown a 10-year cumulative risk of surgery between 40% and 71% [32,33,34][32][33][34] and that fibrosis is a marker of advanced disease, its importance is central in the setting of CD, as it underlies the need for surgical resection in stricturing disease and, maybe, also in penetrating complications, as strictures coexist in over 85% of penetrating CD [4,30,31,32,33,34,35][4][30][31][32][33][34][35].
In this context, to further understand pathology changes in CD, deep research on the basic cellular and molecular mechanisms of fibrogenesis is warranted.

1.2. Fibrosis in UC

In UC patients, fibrosis is characterized by a thickening of MM and excessive ECM deposition in the submucosa, affecting deeper layers only after profound ulceration of the submucosa [36,37,38][36][37][38]. Strictures are uncommon in UC, and the majority are benign and reversible [39]. However, in UC, fibrosis originates the increased wall stiffness, which may result in motility abnormalities, anorectal dysfunction, rectal urgency, and incontinence [10,38][10][38].
The evidence regarding fibrosis in UC is limited and controversial, but a comprehensive assessment performed by Gordon et al. in 2018 demonstrated that UC is characterized by progressive fibrosis and MM thickening in correlation with the severity and chronicity of inflammation. Hence, deep remission, including histological remission, should be a priority and a therapeutic target [40]. Recent research in mice with dextran sulfate sodium (DSS)-induced colitis has shown that, in UC, changes in motility may also be related to neuronal modification. The study highlighted that UC does not promote neuron death but induces changes in the chemical code of myenteric neurons [41]. A better comprehension of these data and the translation of these results depend on studies on human tissue.

2. The Future Holding for Fibrosis

2.1. Radiomics

In a 2020 commentary, Lin and colleagues discussed the concept of computer-assisted image analysis in the context of IBD and suggested radiomics as a tool to transform qualitative fibrosis evaluations on quantitative data [114][42]. The path to this discussion was opened by a study on the applicability of semi-automated analysis to the measurement of bowel structural damage, with evidence of high consistency with measurements performed by experienced radiologists [117][43]. In line with data from other diseases, at this point, a few studies support that radiomics of MRE and CTE, consisting of the extraction of high-dimensional data from CSI images, are viewed as a potential source of valuable data for the assessment of IBD fibrosis [115,116,117][43][44][45]. In 2021, Li and colleagues developed a novel CTE-radiomic model for the characterization of intestinal fibrosis in CD, which distinguished the histological non-mild from moderate–severe fibrosis with an AUC of 0.888 on the training cohort and AUCs between 0.724 and 0.816 (95% CI) in the three test cohorts. Moreover, the model performed better than visual interpretations by two experienced radiologists (p < 0.001) [116][45]. The potential of radiomics in this setting was also evidenced in a recent study that reported the integration of CTE on a deep-learning model based on a 3D deep convolutional neural network with 10-fold cross-validation. This model also presented higher accuracy for the assessment of fibrosis severity than CTE evaluation by two radiologists, with the advantage of having a shorter processing time [115][44]. Despite the robustness of these data, in a letter to the Editor of Gastroenterology, Zhang considered that the validation of these results depends on the development of reliable radiomic biomarkers and criteria to evaluate the design and report of radiomic studies in prospective cohorts [175][46]. Very recently, the STAR consortium presented the results of a machine-reader evaluation of severe inflammation and fibrosis in CD strictures through quantitative radiomic features and expert radiologist scoring on CTE [176][47]. Based on the evidenced association of two distinct sets of radiomic features for severe inflammation and fibrosis (p < 0.01), the authors considered that the combination of quantitative radiomics with radiological visual assessment might favor more personalized treatments by providing more accurate phenotyping of CD strictures. In the validation study, however, while confirming the value of radiomics in the identification of fibrosis but not inflammation in stricturing CD, the same group did not find advantages in combining radiomic features with the radiologist’s visual assessment [177][48]. Hence, it seems very likely that radiomics and AI will set the path for the future in the scope of fibrosis assessment by the CSI techniques in CD. However, it is still not clear whether AI alone (without concomitant human intervention) will be able to accomplish this purpose.

2.2. Others

Even though imaging techniques have been the focus of most of the developed research regarding fibrosis assessment, studies have diverted to other approaches, such as biochemical and genetic markers, including proteomics, genomics, metabolomics, and transcriptomics. The efforts are supported by the assumption that fibrosis biomarkers would provide useful data for risk stratification and treatment optimization of IBD patients. However, the available evidence includes conflicting data and is focused on markers with low diagnostic and prognostic value. Still, considering that past and ongoing research has provided promising data, an update of the most relevant candidate biomarkers seems appropriate in the context of this revision. In 2014, the fourth scientific workshop of the European Crohn’s and Colitis Organization (ECCO) focused on understanding basic mechanisms and markers of intestinal fibrosis and considered that, as none of the available biomarkers were able to accurately assess fibrosis, research for novel targets should proceed, as it is pivotal for the development of novel therapeutic options for intestinal fibrosis [119][49]. In 2012, based on previous findings in the scope of renal disease, Chen and coworkers explored the role of miR-200a and miR-200b in intestinal fibrosis in a colorectal adenocarcinoma epithelial cell line [178][50]. The results showed that miR-200b was overexpressed in the serum of the fibrosis group and could have diagnostic and therapeutic applications for CD patients with fibrosis. This study leveraged further research on this topic, including a revision on the emerging role of micro-RNAs (miRNAs) in IBD [179][51], exploring their involvement in the pathways of inflammation and fibrosis in IBD. At that point, the authors considered that miR-200 [178,180][50][52] and miR-29b [181][53] seemed to deserve further research due to evidence of their potential as IBD biomarkers. The importance of these two miRNA families was addressed in two 2015 and 2023 reviews [182,183][54][55]. In both, it is stated that the research performed so far still warrants confirmation in more robust studies due to small sample sizes, lack of control of patients’ heterogeneity, and absence of a standard protocol to assess miRNAs. Other studied candidate biomarkers include serum and plasma proteins, such as collagen [184][56], ECM [185][57], pentraxin-2 [186][58], serum glycoproteins [187][59], enzymes, such as metalloproteinases [188][60], antimicrobial antibodies [189,190][61][62], and serum growth factors, such as YKL-40 [191,192][63][64] and gene variants [193][65]. Similar to miRNAs, data on these topics are conflicting and do not support their utility in the scope of fibrosis measurement. In conclusion, considering the vast evidence on this topic, it seems that the efforts on the discovery of novel biomarkers to assess fibrosis would be more consequent through the development of more robust clinical trials based on solid and validated endpoints.

2.3. Anti-Fibrotic Therapy

The discussion of fibrosis in the context of IBD can only be completed by addressing the current therapeutic challenges and perspectives toward fibrosis. In the scope of CD, ECCO recommends endoscopic balloon dilatation (EBD) or surgery for patients with short strictures (<5 cm), and strictureplasty for the resection of long segments of the bowel; strictureplasty of the colon is not recommended [194][66]. Regarding EBD, the PRODILAT study—an RCT with CD patients with the obstructive disease and predominantly fibrotic strictures of less than 10 cm—showed that 80% of the patients approached with this technique were free of a new therapeutic intervention at 1 year; compared with fully covered self-expandable metal stents, EBD proved to be more effective for CD strictures [195][67]. So far, past and ongoing research did not generate evidence to support the approval of any anti-fibrotic agent. Considering that the fibrosis process is similar in IBD and in systemic and pulmonary fibrosis, several drugs are under investigation as anti-fibrotic agents, in a pre-clinical setting resorting mainly to UC animal models, with promising results in the TGF-β [196[68][69][70][71][72][73][74][75][76],197,198,199,200,201,202,203,204], TNF [205][77], IL-36 [206][78], rho-kinase [207][79], peroxisome-proliferator activated receptor (PPAR) [208][80], HMG-CoA reductase [209][81] pathways, among others (Table 2) [5,210][5][82]. Table 21 includes the most promising targets and molecules and is not an exhaustive description of all the ongoing research in this field. Regarding phase 2 studies, spesolimab proved to be well tolerated with an adverse event rate similar to placebo (without meeting efficacy criteria) [206][78], and PF-06480605 demonstrated an acceptable safety profile with concomitant endoscopic improvement (week 14) in patients with moderate to severe UC [205][77].
Table 21.
Potential anti-fibrotic agents under research.
Agent Pathway Model Research Status Reference
Pirfenidone TGFβ Human cells Pre-clinical [196,197,198,199,200,201][68][69][70][71][72][73]
Murine models
Mice
Tranilast TGFβ Rats Pre-clinical [202,203][74][75]
Rat models
Patients with CD
EW-7197 TGFβ Murine model Pre-clinical [204][76]
PF-06480605 TNF Patients with UC Phase 2 [205][77]
Spesolimab IL-36 Patients with UC Phase 2 [206][78]
AMA0825 Rho-kinase inhibitor Mice models Pre-clinical [207][79]
Cells
CD biopsies
GED-0507-34 PPARγa agonist Mice Pre-clinical [208][80]
Statins HMG-CoA reductase inhibitors Human intestinal fibroblasts Pre-clinical [209][81]
CD: Crohn’s disease; IL-36: interleukin 36; HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA; PPARγa: peroxisome proliferator-activated receptor-γ; TGFβ: transforming growth factor β; TNF: tumor necrosis factor; UC: ulcerative colitis.
Several molecules are now awaiting clinical trials in humans, and in the near future, new therapeutic agents may be approved. Further improvements in this field have been hindered by the reduced research in CD models and by the lack of research standards. The intensive work of the STAR consortium regarding the standardization of the conditions to measure response to anti-fibrotic agents will be determinant for the success of these processes.

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