Interplay between creeping fat and gut microbiota: A brand-new perspective on fecal microbiota transplantation in Crohn's disease

Abstract

Inflammatory bowel disease, particularly Crohn's disease (CD), has been linked to modifications in mesenteric adipose tissue (MAT) and the phenomenon known as "creeping fat" (CrF). The presence of CrF is believed to serve as a predictor for early clinical recurrence following surgical intervention in patients with CD. Notably, the incorporation of the mesentery during ileocolic resection for CD has been correlated with a decrease in surgical recurrence, indicating the significant role of MAT in the pathogenesis of CD. While numerous studies have indicated that dysbiosis of the gut microbiota is a critical factor in the development of CD, the functional implications of translocated microbiota within the MAT of CD patients remain ambiguous. This manuscript commentary discusses a recent basic research conducted by Wu et al. In their study, intestinal bacteria from individuals were transplanted into CD model mice, revealing that fecal microbiota transplantation (FMT) from healthy donors alleviated CD symptoms, whereas FMT from CD patients exacerbated these symptoms. Importantly, FMT was found to affect intestinal permeability, barrier function, and the levels of proinflammatory factors and adipokines. Collectively, these findings suggest that targeting MAT and CrF may hold therapeutic potential for patients with CD. However, the study did not evaluate the composition of the intestinal microbiota of the donors or the subsequent alterations in the gut microbiota. Overall, the gut microbiota plays a crucial role in the histopathology of CD, and thus, targeting MAT and CrF may represent a promising avenue for treatment in this patient population.

Key Words: Crohn's disease; Mesenteric adipose tissue; Creeping fat; Fecal microbiota transplantation; Gut microbiota

Core Tip: Some studies have indicated that dysbiosis of the gut microbiota is a significant characteristic in the development of Crohn's disease (CD). However, the functional role of translocated microbiota in the mesenteric adipose tissue (MAT) of CD patients remains ambiguous. Evidence has shown that the translocation of viable microbiota into human MAT can polarize macrophages, leading to adipogenesis within the MAT and contributing to the formation of creeping fat (CrF) in individuals with CD. Nonetheless, it remains an important inquiry to elucidate the role of MAT-associated microbiota in the pathogenesis of CD. This manuscript aims to discuss the article by Wu et al, which explores the potential therapeutic value of fecal microbiota transplantation in the management of CD. Study by Wu et al suggested that the interactions among gut microbiota, MAT hypertrophy, and intestinal fibrosis may mutually reinforce one another in the pathogenesis of CD. Consequently, targeting MAT and CrF may hold promise as a therapeutic strategy for patients suffering from CD.

TO THE EDITOR

Mesenteric adipose tissue (MAT) hypertrophy, commonly referred to as fat wrapping or creeping fat (CrF), is a characteristic feature of Crohn's disease (CD) and has been identified as a distinctive aspect of this condition[1]. The mesenteric mesoderm, which is encased by the intestinal endoderm, plays a crucial role in the development of the intestine through its contributions of cellular and connective tissue[2]. This pathobiological interaction persists into adulthood and is now recognized as a factor contributing to the pathological changes observed in CD. In cases of inflammation and intestinal strictures, CrF frequently envelops the affected intestine, and its presence correlates with the clinical activity and severity of inflammation associated with CD[3]. It is noteworthy that CrF predominantly occurs in the small intestine, particularly in the ileum, and is not observed in ulcerative colitis (UC), another type of inflammatory bowel disease[4]. Furthermore, CrF has been established as an anatomical marker that aids surgeons in delineating resection margins during surgical procedures. Additionally, it has been demonstrated that mesentery-based surgical approaches for CD are linked to enhanced long-term postoperative outcomes[5].

Numerous studies have indicated that dysbiosis of the gut microbiota is a significant characteristic in the development of CD[6]. However, the functional role of translocated microbiota in the MAT of CD patients remains ambiguous[7]. Additionally, human studies have shown a correlation between intestinal permeability and visceral adiposity[8], as well as metabolic syndrome in obese individuals[9]. A recent investigation has further substantiated the presence of bacteria and bacterial DNA in various MATs linked to the metabolic consequences of obesity[7]. Moreover, a study with a limited sample size identified a microbiotic signature at the phylogenetic level within the MAT of CD patients[10]. Notably, the translocation of viable microbiota into human MAT has been shown to polarize macrophages, which subsequently promotes adipogenesis in MAT and contributes to the development of CrF in CD patients[11]. Nonetheless, the precise role of MAT-associated microbiota in the pathogenesis of CD remains an important area for further exploration.

This manuscript examines the research conducted by Wu et al[12], focusing on the potential therapeutic benefits of fecal microbiota transplantation (FMT) in the management of CD. The findings of Wu et al[12] indicate that significant histopathological changes occur in the CrF and intestinal tissues of patients with CD. Additionally, there is a notable increase in the expression levels of pro-inflammatory cytokines within the CrF. Wu et al[12] suggested that the interplay between gut microbiota, MAT hypertrophy, and intestinal fibrosis might collectively contribute to the pathogenesis of CD. One method of modulating the microbiota is through FMT, which involves the transplantation of fecal microbiota from a healthy donor into the distal gastrointestinal tract of a patient. Notably, FMT was also employed by Wu et al[12], which demonstrated positive effects on body weight, colon length, and histopathological changes in mice treated with trinitrobenzenesulfonic acid. Additionally, FMT resulted in partial improvements in intestinal permeability, barrier function, serum levels of cytokines and adipokines, whereas FMT from CD patients exacerbated these parameters. FMT has been recognized as an effective therapeutic approach for Clostridium difficile infection[13] and is presently under investigation as a possible intervention for CD. In summary, Wu et al[12] emphasized the considerable promise of FMT in the management of CD.

MAT AND CRF IN CD

MAT and CrF have been implicated in the pathogenesis of CD, with studies indicating that the ratio of intra-abdominal fat to total abdominal fat is elevated in individuals with CD compared to healthy controls. Additionally, a higher proportion of visceral fat has been linked to an increased incidence of postoperative disease recurrence[14,15]. CrF, characterized by its pathological alterations, is frequently observed in proximity to inflamed intestinal regions and is associated with heightened disease severity[16]. This type of fat exhibits distinct characteristics, such as increased size and enhanced immune cell infiltration, which differentiate it from normal mesenteric fat[17,18]. Moreover, MAT also functions as a reservoir for C-reactive protein and is susceptible to bacterial translocation, thereby providing further insight into the complex relationships between adipose tissue and inflammatory mechanisms in CD[19]. The recognition of this complex relationship has expanded the understanding of CD's pathogenesis, underscoring the significance of MAT and CrF in the context of inflammation, immune responses, and disease progression[20,21].

CRF AND INTESTINAL INFLAMMATION

The inflammatory profile associated with MAT in patients diagnosed with CD is characterized by elevated levels of various cytokines, including tumour necrosis factor-α, interleukin (IL)-1β, and IL-6[22,23]. These elevated concentrations contribute to the inflammatory processes within the intestinal tract, while the downregulation of the protective adipokine adiponectin is implicated in the pathogenesis of CD. CrF have been identified as significant sources of pro-inflammatory and pro-fibrotic cytokines[24]. In the context of CD, the integrity of the intestinal barrier is compromised, facilitating the translocation of bacterial antigens and subsequently eliciting Th17 and Th1 immune responses[25]. The Th1 response is particularly characteristic of CD, leading to the secretion of cytokines such as IL-22, IL-1, interferon-γ, and IL-2, among others[26]. Notably, Th1 cells are more prevalent in CrF compared to the mucosal environment, which exhibits a higher infiltration of Th17 cells in response to bacterial infections. Furthermore, the CrF contains a greater proportion of M2 macrophages relative to M1 macrophages, in contrast to the lamina propria, where M1 macrophages are more predominant[27,28]. This preferential polarization towards M2 macrophages may facilitate fibrosis in the affected intestinal tissue through the secretion of substantial amounts of pro-fibrotic cytokines[29]. The intricate immune microenvironment present in CrF, along with its interactions with the inflamed intestinal tissue, plays a critical role in the pathogenesis and progression of CD.

BACTERIA AND CRF FORMATION

The compromised integrity of the intestinal barrier facilitates the translocation of gut-derived bacteria (Figure 1). Research indicates that up to 27% of patients with CD experience bacterial translocation to mesenteric fat, in contrast to 13% of healthy controls. This phenomenon has also been observed in models of experimental colitis and ileitis[19]. CD is associated with a microbiome profile characterized by an increased presence of Proteobacteria and Clostridium innocuum, with the relative abundance of these bacteria being influenced by the clinical status of the disease[10,11]. Furthermore, lymphatic flow is crucial for the transport of bacterial antigens and immune cells[30]. One hypothesis regarding lymphatic vessels suggests that CrF may be exacerbated by the leakage of fatty chylomicrons into the mesentery, facilitated by highly permeable lymphatic vessels[31,32]. Improving the integrity and pumping function of lymphatic vessels could potentially mitigate inflammation in MAT, thereby supporting the notion that the leakage of antigens triggers inflammatory responses and adipogenesis in MAT[33]. Indeed, single-cell RNA sequencing has identified CrF as both pro-fibrotic and pro-adipogenic, characterized by a diverse array of activated immune cells responding to microbial stimuli[11].

Figure 1 Interactions between gut microbiota, creeping fat, and fecal microbiota transplantation outcomes in Crohn's disease. FMT: Fecal microbiota transplantation.

FMT AND CD

The existing literature on FMT for CD is relatively limited compared to that for UC. Case reports have yielded mixed outcomes, with some indicating both clinical and endoscopic remission, while others reported no significant effects[34]. Notably, a case involving a patient with severe, complicated CD documented a successful response to FMT[35]. In a cohort study involving 30 patients with refractory mid-gut CD, a single FMT administered via the nasoduodenal route resulted in a 77% rate of clinical remission one month post-treatment[36]. Furthermore, FMT may represent a viable treatment option for pediatric CD, as a recent case series reported remission in 5 out of 9 patients (56%) following FMT, with 7 out of 9 patients (78%) exhibiting engraftment of donor microbiota[37]. Previous investigations into FMT for active CD have produced inconsistent results. Among 20 subjects enrolled in an FMT study, 19 provided complete follow-up data. Although most participants experienced improvement post-FMT, the clinical outcomes varied significantly, with one individual who had severe disease prior to FMT ultimately requiring colectomy afterward[38]. Conversely, a recent meta-analysis indicated that FMT significantly decreased CD activity index scores within 4 weeks to 8 weeks following the procedure[39]. Collectively, these findings suggest that FMT may hold potential as a therapeutic approach for CD. However, further research is essential to evaluate both its clinical efficacy and the associated alterations in the gut microbiota of affected patients. In the study conducted by Wu et al[12], the transplantation of intestinal bacteria from individuals into CD model mice revealed that FMT from healthy donors alleviated CD symptoms, whereas FMT from CD patients exacerbated these symptoms. Importantly, FMT was found to influence intestinal permeability, barrier function, and levels of pro-inflammatory factors and adipokines. These results imply that targeting MAT and CrF may provide promising avenues for therapeutic interventions in CD patients. Consequently, the gut microbiota appears to play a pivotal role in the histopathology of CD, and strategies aimed at targeting MAT and CrF may be beneficial in the treatment of CD.

GUT MICROBIOTA COMPOSITION CHANGES POST-FMT

Recent investigations have documented specific alterations in the gut microbiota of recipients following FMT. A study indicated a significant increase in alpha diversity post-FMT, in contrast to sham group. However, this enhancement was transient, with alpha diversity reverting to baseline levels 14 weeks after FMT[34]. Similarly, research conducted by Vaughn et al[38] suggested that a single colonoscopic FMT could induce short-term modifications in the fecal bacterial composition of patients with active CD, thereby increasing the diversity of the intestinal microbiota. Another study revealed that there was an increase in the abundance of Collinsella and several genera within the Lachnospiraceae family in FMT-responders. Nonetheless, certain genera from the Ruminococcaceae and Lachnospiraceae families remained underrepresented in post-FMT responders, and some members of the Enterobacteriaceae family persisted in two of the responders. Post-FMT, specific members of Lachnospiraceae were found to be more prevalent in responders, while Ruminococcaceae(e.g.,Faecalibacterium) and Bacteroides were predominantly more abundant in nonresponders[40]. It is important to note that the abundance of Oscillibacter has been negatively correlated with CD, as indicated by previous studies[41,42].

CONCLUSION

Overall, the gut microbiota plays a crucial role in the histopathology of CD, and thus, targeting MAT and CrF may represent a promising avenue for treatment in this patient population.

ACKNOWLEDGEMENTS

We thanks to Wang Y (Division of Digestive Endoscopy, Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University) for his support in revising this letter.