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]. 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]. 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]. 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]. 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]. 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]. 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]. 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]. 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.

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].

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]. 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], exploring their involvement in the pathways of inflammation and fibrosis in IBD. At that point, the authors considered that miR-200 [178,180] and miR-29b [181] 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]. 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], ECM [185], pentraxin-2 [186], serum glycoproteins [187], enzymes, such as metalloproteinases [188], antimicrobial antibodies [189,190], and serum growth factors, such as YKL-40 [191,192] and gene variants [193]. 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.

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]. 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].

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 [196,197,198,199,200,201,202,203,204], TNF [205], IL-36 [206], rho-kinase [207], peroxisome-proliferator activated receptor (PPAR) [208], HMG-CoA reductase [209] pathways, among others (Table 2) [5,210]. Table 2 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], and PF-06480605 demonstrated an acceptable safety profile with concomitant endoscopic improvement (week 14) in patients with moderate to severe UC [205].

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.