Creeping fat: A promising radiological predictor in small bowel Crohn’s disease

Abstract

In this manuscript, we comment on the article by Hasnaoui et al. Specifically, we delve into the characteristic manifestation of Crohn’s disease (CD) known as creeping fat (CF). Our primary focus is to investigate the potential of imaging features of CF in predicting the response of small bowel CD to biologic therapies and fecal microbiota transplantation. We believe that further research should be dedicated to developing methods for quantifying CF in order to provide more accurate predictive tools for the treatment of small bowel CD.

Key Words: Crohn’s disease; Creeping fat; Biologic agents; Fecal microbiota transplantation; Prediction

Core Tip: Creeping fat is a characteristic manifestation of Crohn’s disease (CD). We explored the relationship between creeping fat and gut microbiota and proposed potential significance of its radiological features in predicting the therapeutic response of small bowel CD to biological therapy and fecal microbiota transplantation. Although further validation is required, these findings can help establish precise predictive tools for CD treatment, thereby guiding personalized therapeutic strategies.

TO THE EDITOR

Crohn’s disease (CD) is a chronic gastrointestinal inflammatory disease leading to progressive intestinal damage and disability[1]. Creeping fat (CF) is a characteristic manifestation of CD that primarily occurs in the small intestine, most commonly in the ileum[2]. It is associated with transmural inflammation, ulceration, and stricture formation, and forms proliferative mesenteric adipose tissue that expands and envelops the sites of intestinal inflammation[3]. Selecting Therapeutic Targets in Inflammatory Bowel Disease-II has set long-term treatment goals for CD, which include endoscopic healing (simple endoscopic score in CD < 3), normal quality of life, no disability, and growth recovery in children[4]. Transmural healing in CD has been recognized as an important adjunctive assessment; however, it has not yet been formally approved as a new therapeutic target owing to limitations in assessment methods and the limited effectiveness of currently available treatments to achieve transmural healing.

Endoscopic examinations require bowel preparation and sedation or anesthesia; moreover, a small risk of complications, including bowel perforation, can be involved. Unlike colonic CD, ileal CD is often inaccurately assessed for disease activity and response to treatment owing to the presence of impassable strictures, lack of well-validated and widely accepted radiological endpoints, and differences in the accuracy of reported noninvasive biomarkers[5]. Therefore, further radiological studies may provide alternatives to endoscopy or diagnostic information associated with endoscopic examinations. According to Kredel et al[6], CF in small-bowel CD (SBCD) is characterized by adipocyte proliferation, intense infiltration of immune cells, and fibrosis, whereas mesenteric fat near the colon exhibits neither CF nor proliferation, and immune cell infiltration is less prominent. Although it remains to be proven whether CF is unique to the small intestine or reflects a different disease state, we can speculate that CF is associated with specific characteristics of SBCD. Recent studies have indicated that the radiological features of CF on imaging can serve as important indicators for predicting the response of patients with SBCD to biological therapy[7,8]. Rimola et al[9] suggested that CF revealed by pre-treatment magnetic resonance enterography is a negative predictor for the response of patients with CD to tumor necrosis factor-α inhibitors. Simultaneously, the presence of CF is associated with long-term poor healing of severe inflammatory lesions, especially those in the ileum. Additionally, Song et al[10] indicated that the presence of CF on computed tomography enterography is an independent predictor of poor response to infliximab treatment. Ma et al[11] reported that intestinal ultrasound parameters help predict the response of stenotic CD to biological therapy. Specifically, a CF wrapping angle of > 180° is an independent predictor of surgery, and a that of < 180° is the only predictor of steroid-free clinical remission and mucosal healing[11]. These studies suggest that CF imaging can be used to predict the efficacy of biological therapy for SBCD. However, there is no consensus on which biological therapies can be predicted based on radiological features. Moreover, none of these studies have included the quantification of CF. Li et al[12] developed a novel computed tomography-based mesenteric CF index in CD, which grades mesenteric fat extension around the circumference of the intestine using blood vessels in the fat as markers, thereby accurately quantifying the severity of CF. The introduction of mesenteric CF index indicates that quantifying CF is a promising method. In the future, CF quantification can be used to enhance accuracy in the assessment of treatment effects in SBCD and disease prognosis prediction, which can provide an important basis for clinical decision-making.

Gut microbiota are crucial for regulating host health. The partially aerobic Firmicutes and Proteobacteria are the most abundant phyla in the small intestine microbiome, whereas the microbiome of the colon primarily comprises anaerobic bacteria[13]. Dysfunction of the gut microbiota is closely associated with CD pathogenesis; hence, fecal microbiota transplantation (FMT) has been extensively studied as an emerging treatment for CD. Notably, although the term “dysbiosis” is commonly used to describe abnormal taxonomic composition of the microbiota, recent perspectives suggest that “dysfunction” more accurately reflects functional changes in microbial communities[14]. Additionally, a recent study reported that specific gut bacteria such as Achromobacter pulmonis can induce the upregulation of indoleamine 2,3-dioxygenase 1 in macrophages, leading to increased biosynthesis of L-kynurenine. L-kynurenine activates the aryl hydrocarbon receptor in adipocytes, mediating CF formation in CD[15]. This finding indicates that the formation of CF is associated with the metabolic activities of functional microbial communities. As demonstrated by Hasnaoui et al[16], the interaction between the gut microbiota and CF promotes inflammatory responses in CD, and FMT may modulate CF-associated inflammatory pathways to improve the treatment outcomes of CD. However, FMT efficacy is influenced by factors such as donor selection, delivery mode (upper gut, mid-gut, or lower gut), disease severity, and the status of the recipient[17,18]. For CD with ileal involvement, Giordano et al[19] reported higher rates of biologic use, surgical intervention, and poorer treatment persistence. This may suggest that ileal CD has a more severe disease course and requires more aggressive therapeutic strategies, such as combination therapy with dual-target treatments and FMT. CF, as a characteristic manifestation of SBCD, is a potential predictive marker for the quantitative assessment of FMT efficacy. Despite this potential, the correlation between CF and the therapeutic response remains unclear. Further research can clarify the association between CF and the effectiveness of FMT as well as the specific value of CF as a predictive indicator.

CONCLUSION

In conclusion, predictive factors for SBCD-related prognosis are constantly being explored. CF, a characteristic manifestation of CD, plays an important role in the pathogenesis of the disease and is a potential predictor for the response of SBCD to biological therapy and FMT. With the advances in imaging technology and microbiome research, treatments with improved preciseness can be established to manage CD.