Gut microbiota and mesenteric adipose tissue interactions in shaping phenotypes and treatment strategies for Crohn’s disease

Abstract

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.

Key Words: Crohn’s disease; Intestinal microbiota; Dysbiosis; Intestinal barrier; Mesenteric adipose tissue; Creeping fat; Fecal microbiota transplantation

Core Tip: The interplay between gut microbiota, mesenteric adipose tissue, and creeping fat is crucial in Crohn’s disease management. Dysbiosis is characterized by decreased beneficial bacteria and increased pathogenic bacteria and exacerbates inflammation and disease progression. Targeting microbial imbalances and the inflammatory roles of mesenteric adipose tissue and creeping fat may lead to novel therapeutic approaches, including fecal microbiota transplantation, which shows promise in restoring microbial balance and achieving sustained remission in patients with Crohn’s disease. Ongoing research should focus on identifying specific microbial communities and their roles in different phenotypes to optimize personalized treatment strategies and improve clinical outcomes.

TO THE EDITOR

Crohn’s disease (CD), which is a form of inflammatory bowel disease, is characterized by chronic inflammation of the gastrointestinal tract. CD was first identified as a distinct condition in 1932. Its incidence has surged dramatically, and it now affects approximately 7000 individuals each year in Europe[1]. This rapid increase highlights CD as a significant global public health challenge. The exact causes of CD remain unidentified; however, genetic predisposition, environmental influences, and gut microbiota are believed to have a complex interplay in its pathogenesis[2]. Dysbiosis in gut microbiota has been consistently observed in patients with CD, yet its precise impact on disease progression remains unclear[3]. Consequently, research aimed at elucidating the role of the gut microbiota in CD as well as studies targeting this pathogenetic mechanism could offer critical insights into the underlying processes of the disease[4]. Such investigations may pave the way for novel therapeutic approaches that enhance both short-term and long-term clinical outcomes[4].

Mesenteric adipose tissue (MAT) and creeping fat (CF) play a crucial role in the pathogenesis of CD through their inflammatory contributions and interactions with disease progression[5]. In patients with CD, these fat tissues exhibit a distinctive profile characterized by the production of elevated levels of inflammatory cytokines and adipokines, which promote the inflammatory response within the digestive tract[6]. Simultaneously, they inhibit the production of beneficial adipokines, making the disease more difficult to control[6]. MAT and CF are not merely passive tissues; they are actively involved in the disease process[7]. The selective enlargement of MAT and the histopathological changes leading to the accumulation of CF around affected bowel regions suggest a direct association between these tissues and the progression of CD[7]. Moreover, CF may also contribute to bacterial translocation in CD, further complicating the progression of the disease[8].

During CD, ongoing changes in the gut microbiota lead to dysbiosis, which ultimately results in damage and disruption of the intestinal barrier[9]. This stage in the progression of CD is considered a critical turning point, as the altered microbiota becomes capable of migrating into the mesentery and potentially entering the bloodstream, spreading the disease throughout the digestive tract[9].

In the early phases of CD, the interaction between CF and the altered microbiota may be beneficial, as CF helps contain the bacteria, preventing them from spreading to other areas[10]. However, as the disease advances and the amount of CF increases, this adipose tissue becomes saturated with altered bacteria that continue to proliferate and migrate towards lesion sites, worsening the condition over time[10]. Some researchers suggest that the bacteria that infiltrate the mesentery following intestinal barrier disruption may be the initial trigger for the formation of CF[11]. Although the intricate interactions among MAT, CF, and the intestinal microbiota are not yet fully understood, a study, published in the recent issue of the World Journal of Gastroenterology, has suggested that the complex influence of intestinal microbiota on MAT and CF in shaping CD phenotypes could pave the way for novel therapeutic approaches[12].

INTERACTIONS BETWEEN MAT, CF, AND INTESTINAL MICROBIOTA AND THEIR ROLE IN GENERATING CD PHENOTYPES

Dysbiosis and obesity in CD

A central element in chronic inflammation during CD is dysbiosis, which is characterized by an imbalance in the composition of gut microbial communities[13]. A consistent finding in CD patients is the notable decrease in anti-inflammatory bacteria. For instance, Faecalibacterium prausnitzii (F. prausnitzii) levels are significantly lower compared to healthy individuals[14]. This bacterium, which is known for its anti-inflammatory properties, is particularly important as its reduction correlates with an elevated risk of relapse in patients with ileal CD[15]. Additionally, other beneficial bacteria such as Blautia faecis, Roseburia inulinivorans, Ruminococcus torques, and Clostridium lavalense also show reduced abundance in CD patients[16]. The loss of these microbes, which play crucial roles in maintaining intestinal homeostasis and reducing inflammation, may exacerbate the disease course[17].

Conversely, there is a notable increase in pathogenic bacteria in the gut microbiota of CD patients. Particularly, an expansion in Proteobacteria, including adhesion-invasive Escherichia coli (E. coli), is observed[18]. According to a clinical study published in 2004, adhesion-invasive E. coli was present in approximately 38% of CD patients compared to just 6% in healthy controls, highlighting its significant association with the disease[19]. Additionally, sulfate-reducing bacteria such as Desulfovibrio are more prevalent in patients with CD, leading to the production of hydrogen sulfide, which is a compound known to cause damage to intestinal epithelial cells and contribute to mucosal injury and inflammation[20]. These pathogenic bacteria can adhere to the intestinal mucosa, disrupting gut barrier integrity and promoting inflammatory responses through a cascade of immune responses[21].

Moreover, this inflammatory process is not limited to the intestinal mucosa; it actually extends to the surrounding MAT and CF[22]. Both MAT and CF are sites of active immune responses in CD, contributing to the chronic inflammation that defines the disease[22]. MAT and CF take on an active role in CD by responding to the inflammatory cues generated by the gut microbiota. Inflammatory signals from the microbiota induce MAT and CF to produce additional proinflammatory cytokines, including interleukin-6 (IL-6), IL-1 beta, and tumor necrosis factor-alpha[10]. These cytokines are crucial in sustaining the inflammatory state that characterizes the intestinal environment in CD[10]. The interplay between dysbiotic microbiota and these adipose tissues exacerbates the inflammatory state, leading to persistent and often severe inflammation that can affect the entire gastrointestinal tract[23] (Figure 1).

Figure 1 Interactions between mesenteric adipose tissue and the microbiota in Crohn’s disease. Pathogenic bacteria adhere to the intestinal mucosa, thereby disrupting gut barrier integrity and causing bacterial translocation. Inflammatory signals from the microbiota induce the mesenteric adipose tissue to produce additional proinflammatory cytokines, thus sustaining the inflammatory state that characterizes the intestinal environment in Crohn’s disease.

Obesity contributes to worsening inflammation in CD by increasing visceral adiposity, which is associated with elevated levels of circulating inflammatory markers such as IL-6 and C-reactive protein[24]. This amplifies systemic inflammation, while obesity-related alterations in the gut microbiota further disrupt intestinal barrier function. This allows bacterial translocation into mesenteric fat, leading to adipocyte hyperplasia and activating local immune responses[25,26]. Moreover, research has revealed that the gene expression profile of CF in CD is similar to that of visceral fat in obesity, suggesting that obesity could intensify inflammatory and fibrotic activities in the mesenteric fat seen in CD[27]. Thus, obesity may boost the immune activity of CF, potentially leading to more severe disease outcomes and posing challenges in the management of CD.

Fibrostenotic phenotype in CD

In addition to its role in driving inflammation, the gut microbiota also contributes to the development of fibrosis, which is a common and serious complication in CD[12]. Fibrosis in CD is characterized by the excessive deposition of extracellular matrix components, such as collagen, which leads to the thickening and stiffening of the intestinal wall[12]. This fibrotic phenotype is closely linked to the activities of certain bacterial species within a dysbiotic microbiota[28]. When translocating into MAT, pathogenic bacteria from the gut microbiota can activate immune cells, particularly macrophages[29]. This activation triggers the release of fibrotic markers, including alpha-smooth muscle actin and vimentin[29]. These markers are critical in the transformation of fibroblasts into myofibroblasts, which are the cells responsible for producing the extracellular matrix that contributes to fibrosis[28].

As the disease advances, the continuous interaction between the dysbiotic microbiota, MAT, and CF perpetuates the cycle of inflammation leading to fibrosis[30]. This process transforms the intestinal environment into one that is prone to strictures and obstructions, both of which are complications associated with the fibrotic phenotype in CD[30]. Moreover, the fibrosis driven by these interactions is not just a local phenomenon, it has systemic implications as well[31]. The altered microbiota in patients with CD has been shown to influence not only the local intestinal environment but also the overall immune response, further complicating the disease and making it more resistant to conventional treatments[32]. Therefore, understanding the role of gut microbiota in the fibrotic phenotype of CD is crucial for developing targeted therapies that can effectively manage or even reverse this debilitating aspect of the disease.

Ileal vs colonic CD

Through a study published in 2016, the microbiota in ileal and colonic CD were found to be distinct, with specific bacterial species showing different abundances in each phenotype[33]. In ileal CD, severe dysbiosis is consistently observed, characterized by a notable reduction in beneficial bacteria such as F. prausnitzii and an increase in pathogenic taxa like Fusobacterium, which is often associated with heightened disease activity[33]. In contrast, colonic CD tends to display a microbiota profile closer to that of healthy individuals, with less pronounced dysbiosis[33]. These differences suggest that while both forms of CD share inflammatory processes, the microbial ecosystems in the ileum and colon behave differently[34]. The differences in microbial composition between ileal and colonic CD highlight the potential role of genetic factors in driving these distinct phenotypes[35].

Among the most studied ones are genes involved in autophagy, a crucial process for maintaining cellular homeostasis and immune defense[35]. Extensive research has identified more than 30 genomic loci associated with genetic susceptibility to CD, implicating eight key autophagy-related genes such as ATG16 L1, NOD2, IRGM, and LRRK2[36]. These genes play a crucial role in regulating the immune response and microbial homeostasis, particularly in the ileum. Variations in these genes are believed to contribute to the differential inflammatory patterns observed in CD by altering the host’s ability to manage gut bacteria, thus providing insights into disease mechanisms and potential therapeutic targets[36].

In addition to genetic influences, mucosal immune receptors are pivotal in shaping the intestinal environment and influencing inflammatory responses[37]. These mucosal receptors interact with the gut microbiota and contribute to the differential immune profiles seen in ileal vs colonic CD[37]. Understanding the variations in receptor expression and function between these phenotypes can provide deeper insights into the pathophysiology of CD.

ASSESSING CF AND TREATMENT STRATEGIES

CF quantification in CD

CF is a hallmark of CD and plays a central role in its pathogenesis, extending beyond its interaction with gut microbiota and the secretion of proinflammatory cytokines and adipokines[22]. Accurately quantifying CF is crucial for evaluating the severity and extent of CD[23]. Furthermore, its active involvement in disease progression serves as a potential biomarker for monitoring disease activity, providing valuable insights for optimizing patient management and therapeutic strategies[23]. While direct measurement from surgical specimens remains the gold standard, non-invasive imaging techniques such as magnetic resonance enterography (MRE) and computed tomography enterography offer promising alternatives for accurate assessment[38]. These imaging techniques are valuable for monitoring disease progression and predicting complications in CD patients.

MRE has shown utility in visualizing CF, with studies indicating that it persists even during endoscopic remission, suggesting ongoing tissue injury rather than active inflammation[39]. Importantly, the presence of CF on MRE has been linked to more severe disease phenotypes and poorer therapeutic responses, highlighting its potential as a prognostic marker[40]. Computed tomography enterography has also advanced in assessing CF, particularly through the development of the Mesenteric CF Index, which correlates strongly with histopathological findings of fat wrapping and fibrosis[38]. The Mesenteric CF Index has demonstrated superior accuracy in assessing the extent of fibrostenosis, making it a valuable tool in non-invasive evaluation.

Role of fecal microbiota transplantation

Fecal microbiota transplantation (FMT) involves transferring intestinal microbiota from a healthy donor with the objective of re-establishing a balanced microbial community in the recipient’s gut[41]. In recent years, this approach has gained attention driven by the concept that a disrupted microbiota can be restored by introducing the colonic microbiota from a healthy individual[41].

In 2012, FMT was introduced through randomized controlled trials as a preventive measure against pouchitis, ulcerative colitis, and E. coli infections in patients with hemorrhagic rectocolitis[42]. It was not until 2016 that FMT was recognized as a second-line treatment for preventing recurrent infections of Clostridium difficile, demonstrating an efficacy of up to 80%[43]. Since then, numerous case series and studies with low to moderate levels of evidence have been published regarding the role of FMT in CD. The first randomized controlled trial investigating the use of FMT for this condition was published in 2020 by Sokol et al[44]. This single-blinded pilot study revealed that, although none of the patients reached the primary endpoint of successful donor microbiota engraftment, FMT still showed considerable promise in maintaining remission. The FMT group had a higher steroid-free clinical remission rate (87.5% at 10 weeks) compared to the sham group (44.4%), though the difference was not statistically significant (P = 0.23). Additionally, FMT led to a significant reduction in disease severity (P = 0.03) and prevented an increase in inflammatory markers.

A more recent double-blind, randomized, placebo-controlled pilot study published in 2024 by Zhang et al[45] introduced several novel insights into the use of FMT for treating CD. It was observed that greater residual microbial diversity following antibiotic treatment was significantly correlated with successful donor engraftment (P < 0.05). Furthermore, increased levels of donor engraftment were strongly associated with improved clinical response over time (P < 0.05). Notably, a transient rise in the relative abundance of Lactobacillus was positively correlated with successful engraftment (P < 0.05).

All these findings highlight the critical role of microbial diversity and specific bacterial taxa in predicting the success of FMT, potentially guiding future strategies to optimize therapeutic outcomes in CD patients.

Surgical options

Despite considerable progress in medical management, including the use of biologic agents and immunosuppressants, a significant proportion of patients with CD still require surgery[46]. It is estimated that 75% of patients with CD will undergo at least one surgical procedure in their lifetime[47]. However, surgery is not curative, and postoperative recurrence remains a significant challenge[46]. Endoscopic recurrence occurs in approximately 60% of patients within the first 6 months after surgery, with nearly 50% of these patients exhibiting clinical recurrence in the first 5 years in the postoperative course[47]. In the ongoing quest to optimize surgical outcomes in CD, two surgical approaches have gained attention: The extended mesenterectomy and the Kono-S anastomosis. Both approaches aim to minimize postoperative recurrence, but they address different aspects of CD pathology[48].

The extended mesenterectomy involves a comprehensive removal of mesenteric tissue, targeting inflammatory mechanisms directly and potentially reducing recurrence by addressing the role of the mesentery in disease progression[49]. However, The SPICY Trial, which is an international multicenter randomized controlled study, found no significant difference in endoscopic recurrence of CD between extended mesenteric resection and conventional resection[50].

The Kono-S anastomosis has gained attention as a promising technique for reducing recurrence in CD, though existing studies show mixed results[51]. A systematic review and meta-analysis, published in 2024[51], compared the outcomes of Kono-S anastomosis with conventional methods in patients undergoing bowel resection for CD. The analysis significantly revealed lower recurrence rates in the Kono-S group, with an endoscopic recurrence rate of 41% compared to 48% in the conventional group and a surgical recurrence rate of 2.7% vs 21%[51].

Clinical implications

Monitoring microbial changes: Regular assessment of gut microbiota composition, especially beneficial strains such as F. prausnitzii, can inform us about disease activity and relapse risk, thereby aiding clinical management decisions.

Therapeutic targeting of adipose tissue: The inflammatory roles of MAT and CF indicate potential therapeutic strategies that focus on these tissues to reduce inflammation and improve outcomes in CD patients.

Efficacy of FMT in clinical practice: The promising results of FMT suggest its potential as a second-line treatment for CD, particularly for individuals exhibiting dysbiosis in their gut microbiota.

Microbial diversity as a prognostic indicator: The correlation between enhanced microbial diversity and successful donor microbiota engraftment following FMT highlights the importance of evaluating microbial diversity to guide treatment approaches and improve patient outcomes.

Long-term benefits of microbiota restoration: Achieving successful microbiota restoration through FMT may result in sustained remission and decreased inflammatory markers, underscoring the need for further investigation into optimizing FMT protocols for CD management.

Personalized therapeutic approaches: The identification of unique microbial profiles in different CD phenotypes suggests the potential for personalized treatment strategies tailored to individual microbiota characteristics, enhancing therapeutic effectiveness and patient care.

CONCLUSION

CD represents a complex interplay of genetic, environmental, and microbial factors that contribute to its pathogenesis and progression[2]. The dysbiosis observed in patients with CD highlights the crucial role of gut microbiota in maintaining intestinal homeostasis and mitigating inflammation[14]. Additionally, the involvement of MAT and CF in the inflammatory processes associated with CD offers a new perspective on potential treatment avenues[10]. These adipose tissues not only contribute to the inflammatory milieu but also interact dynamically with the altered gut microbiota[22]. Consequently, therapeutic strategies that focus on modulating the activity of MAT and CF may provide significant benefits in managing inflammation and preventing disease complications[29].

Furthermore, FMT has emerged as a promising therapeutic modality for CD, demonstrating potential in re-establishing a balanced gut microbiota and achieving sustained remission in some patients[42]. The correlation between microbial diversity and successful treatment outcomes further emphasizes the importance of tailoring FMT protocols to enhance efficacy[45]. Future research should focus on elucidating the specific microbial communities involved in CD and their functional roles in the disease process[33]. This knowledge will not only enhance our understanding of CD but also inform the development of personalized treatment strategies that address the unique microbial profiles associated with different CD phenotypes[33].

ACKNOWLEDGEMENTS

The authors wish to express their sincere appreciation to Dorra Maalej, Assistant Professor of English, for her invaluable contribution in the linguistic revision of this manuscript.