Creeping fat and gut microbiota in Crohn’s disease

Abstract

In this article, we explored the role of adipose tissue, especially mesenteric adipose tissue and creeping fat, and its association with the gut microbiota in the pathophysiology and progression of Crohn’s disease (CD). CD is a form of inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract, influenced by genetic predisposition, gut microbiota dysbiosis, and environmental factors. Gut microbiota plays a crucial role in modulating immune response and intestinal inflammation and is associated with the onset and progression of CD. Further, visceral adipose tissue, particularly creeping fat, a mesenteric adipose tissue characterized by hypertrophy and fibrosis, has been implicated in CD pathogenesis, inflammation, and fibrosis. The bacteria from the gut microbiota may translocate into mesenteric adipose tissue, contributing to the formation of creeping fat and influencing CD progression. Although creeping fat may be a protective barrier against bacterial invasion, its expansion can damage adjacent tissues, leading to complications. Modulating gut microbiota through interventions such as fecal microbiota transplantation, probiotics, and prebiotics has shown potential in managing CD. However, more research is needed to clarify the mechanisms linking gut dysbiosis, creeping fat, and CD progression and develop targeted therapies for microbiota modulation and fat-related complications in patients with CD.

Key Words: Creeping fat; Mesenteric adipose tissue; Gut microbiota; Crohn’s disease; Inflammatory bowel disease

Core Tip: Crohn’s disease is associated with creeping fat accumulation, influenced by factors such as gut microbiota. Dysbiosis, characterized by an increase in proteobacteria and species such as Clostridium innocuum, contributes to mesenteric fat accumulation and exacerbates inflammation. Modulating the microbiota through individualized interventions, such as environmental exposure modifications, fecal microbiota transplantation, and probiotics and prebiotics use, may be a potential strategy to reduce intestinal inflammation and mesenteric fat proliferation, improving therapeutic outcomes. However, further research is needed to elucidate the molecular mechanisms involved and develop biomarkers to identify patients who would benefit most from these approaches, considering their individual characteristics.

INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract resulting from a combination of genetic predisposition, alterations of the gut microbiota, and environmental factors[1]. It comprises two distinct disorders: Crohn’s disease (CD) and ulcerative colitis (UC). The symptoms of both diseases include diarrhea, rectal bleeding, and abdominal pain; however, they present some differences. The inflammation in CD is transmural and can affect any part of the gastrointestinal tract, while UC affects the mucosa and submucosa and is limited to the colon and rectum[2].

The incidence of IBD is increasing probably due to a combination of factors such as changes in diet and lifestyle, leading to changes in microbiota, and other environmental factors related to improvements in the socioeconomic status of newly industrialized countries[3,4]. Although the etiology of IBD is complex and involves several factors, it reflects the dysregulated immunity that develops in genetically susceptible individuals after exposure to noxious environmental stimuli, including gut microbes[5].

The gut microbiota comprises a dynamic community of microorganisms that plays a fundamental role in intestinal homeostasis and other physiological processes, including digestion, metabolism, and immune function[6]. The gut microbiota modulates the immune system and inflammatory response through several mechanisms, including intestinal barrier function and the production of short-chain fatty acids (SCFAs)[7]. An imbalance of the gut microbiota, known as gut dysbiosis, is associated with an increased risk of chronic diseases such as obesity, diabetes, cardiovascular disease, and IBD[8].

A recent study by the Crohn’s and Colitis Canada - Genetic, Environmental, Microbial project, identified five essential gut microbial taxa: Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus from Oscillospiraceae family, and Roseburia, associated with an increased risk of CD development[9]. The study demonstrated that microbial alterations could precede the onset of CD by several years[9]. The individuals with increased susceptibility to CD can be identified by analyzing the gut microbiota composition and calculating a microbiome risk score[9]. Early interventions, particularly those targeting the exposome, such as dietary modifications, could be beneficial in modulating the gut microbiota and increasing alpha diversity. These strategies could potentially mitigate the risk of developing dysregulated inflammatory processes associated with the onset of CD.

Visceral adipose tissue, an organ active in metabolism, immunity, and endocrinology, plays a complex role in the pathogenesis of IBD. Its strategic location and ability to secrete inflammatory mediators make it a vital regulator of the intestinal immune response[10-12]. Mesenteric adipose tissue, which is in close contact with the intestine and is often referred to as “creeping fat”, acts as a physical barrier and modulator of inflammation. However, its function can be altered in chronic inflammatory conditions, contributing to disease progression[11-13].

The interaction between the gut microbiota and visceral adipose tissue in patients with CD was explored in a recently published article[14]. The authors evaluated the complex relationship between gut microbiota and mesenteric adipose tissue, more specifically creeping fat, in 12 patients with CD and in an experimental study with 2,4,6-trinitro-benzenesulfonic acid (TNBS)-induced intestinal inflammation in mice[14]. The histological examination of the mesenteric adipose tissue showed more significant structural disorganization, neutrophilic infiltration, presence of inflammatory cytokines such as interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, leptin, and adiponectin, and areas of fibrosis in regions affected by the disease compared to unaffected areas, showing the involvement of adipose tissue in the pathophysiology of CD[14]. The authors suggest that the gut microbiota and mesenteric adipose tissue hypertrophy and fibrosis may complement each other in the pathogenesis of CD and may be related to CD progression. In the experimental study, the mice with TNBS-induced intestinal inflammation that received fecal microbiota transplantation (FMT) from healthy donors showed improvements in clinical parameters, intestinal barrier function, and inflammatory cytokines. However, the mice with TNBS-induced intestinal inflammation that received FMT from patients with CD showed worsening of intestinal permeability, barrier function, and levels of cytokines and adipokine, indicating that the gut microbiota might mediate the effects of mesenteric adipose tissue on disease progression[14].

Despite the role of the gut microbiota as a triggering factor for IBD and the recent evidence of the association between obesity, creeping fat, and the presence of complications in CD, more evidence is required to validate these factors. Therefore, in this article, we aimed to explore the role of adipose tissue, especially mesenteric adipose tissue and creeping fat, and its association with the gut microbiota in the pathophysiology and progression of CD.

ADIPOSE TISSUE AND CREEPING FAT

The adipose tissue is classified as an energy store with some endocrine function. However, in addition to its role in energy storage, the adipose tissue is a metabolic organ involved in immunological, metabolic, and regulatory functions[15,16]. Adipose tissue is distributed in two main compartments, subcutaneous and visceral adipose tissues, with distinct metabolic and immunological profiles[12,15,16], proven by the presence of cells such as adipocytes, preadipocytes, macrophages, adipose-derived stroma cells, endothelial cells, fibroblasts, and leukocytes in the visceral adipose tissue[12].

The visceral adipose tissue plays a role in the pathogenesis of several gastrointestinal diseases, including fatty liver disease, colon cancer, and IBD[12,15-17]. The disposition accumulation of visceral adipose tissue and impaired release of adipokines (adipocyte-derived biologically active substances, such as adiponectin), disturbance in the gut microbiota, increased levels of lipopolysaccharides (an endotoxin that activates Toll-like receptors 2 and 4), and chronic inflammation are considered possible interconnecting links[12,18].

The visceral adipose tissue may play a crucial role in the outset and chronic intensification of the inflammatory process in CD since their increase may be associated with pro-inflammatory adipokines, mainly TNF-α, IL-6, and IL-1β, corroborating that the inappropriate activation of the innate immune system is a significant cause of inflammation in CD[19]. Some studies show the negative impact of obesity on patients with IBD[16]. However, the visceral adipose tissue is more related to the progression of CD than the obesity diagnosed based on body mass index[12,18]. The ratio of the area of visceral adipose tissue to that of subcutaneous fat has been correlated with the postoperative recurrence of CD[20], and the visceral adiposity, measured by imaging methods such as computed tomography, has been associated with an increased risk of invasive disease and surgery in CD[21].

The mesenteric adipose tissue, a subtype of visceral adipose tissue, consists of tissues that maintain the position of all abdominal digestive organs and presents a tight anatomical relationship with the intestine, being a unique and contiguous organ emerging from the superior mesenteric root region and extending from the duodenum to the rectum[17]. Mesenteric adipose tissue has an affluent network of blood and lymph vessels, which transport cells and molecules[17]. Mustain et al[15] demonstrated an increased cytokine expression from mesenteric adipose tissue adjacent to the affected bowel in CD, suggesting a potential causal role of mesenteric adipose tissue in the pathophysiology of this disease. Thus, mesenteric adipose tissue could contribute to the pathogenesis of CD from the initiation of inflammation[10].

In CD, hyperplasia and hypertrophy of the white adipose tissue of the mesentery may occur, close to the intestinal serosa, surrounding the inflamed bowel, turning into “creeping fat” or “fat wrapping”[12,17]. Creeping fat is limited to the inflamed and fibrotic areas in patients with CD[16] and is observed in patches, extending as finger-like projections gripping the inflamed segment of the intestine, adjacent to the regular mesenteric adipose tissue[22].

Creeping fat is a dynamic component that determines the natural history of CD through its immunomodulatory properties and is not merely an extraintestinal manifestation[19], since creeping fat is often found in patients with CD with fibrotic and stricturing complications. It presents as hyperplastic mesenteric adipose tissue, which expands and surrounds the sites of intestinal inflammation, primarily in the small bowel and commonly the ileum[22,23]. Several authors have demonstrated the coexistence of CD and creeping fat without determining whether this altered type of fat is the cause or result of intestinal inflammation.

Tsounis et al[19] refer to another role of creeping fat, contrary from the previous observations, associating creeping fat as a reactive tissue that acts as a protective immunoregulatory “bandage” that prevents the systematic leakage of inflammatory products. Mesenteric adipose tissue in CD is highly infiltrated by macrophages, with the M2-like phenotype predominating and promoting an IL-10 milieu, corresponding to an anti-inflammatory rather than a pro-inflammatory function[19]. Remodeled mesenteric adipose tissue in creeping fat leads to a greasy barrier that prevents systemic dissemination of bacteria, thereby protecting the body and retaining the inflammation as localized[23]. This hypothesis could influence therapeutic decisions, such as the extent of mesenteric resections during intestinal surgery. Consistent studies on the role of creeping fat in CD are lacking; another factor that could be related to the inflammatory or anti-inflammatory profile of creeping fat is its colonization by bacteria from the intestinal microbiota, as discussed below.

GUT MICROBIOTA, CREEPING FAT, AND CD

The involvement of the microbiota in the pathogenesis of IBD is well-recognized. Dysbiosis, characterized by an altered composition and function of the gut microbiota, is a hallmark of IBD. The etiology of dysbiosis in IBD is multifactorial, encompassing inflammation, infection, antibiotic exposure, genetic predisposition, early-life dietary exposures, lifelong dietary patterns, physical inactivity, and other lifestyle factors. It is typically characterized by a significant reduction in microbial diversity, with a loss of beneficial species and an overgrowth of potentially pathogenic bacteria[4,24]. Dysbiosis may play a role in the pathogenesis of CD and can contribute to unfavorable patient prognosis[14]. Additionally, it can impair the mucus layer by reducing mucin production or degrading existing mucin, facilitating the penetration of luminal contents and microbial invasion into the submucosa[2]. However, the temporal relationship between intestinal barrier disruption and gut microbiota dysbiosis remains unclear[14]. Dysbiosis is a contributing factor in the multifactorial pathogenesis of CD. Intestinal inflammation can promote dysbiosis, and inflammatory control may lead to improvements in the microbiome. However, the microbiome of patients with CD, even after achieving inflammatory control, often remains distinct from that of healthy individuals[25].

One of the most studied bacteria related to CD pathogenesis is the adherent-invasive Escherichia coli (AIEC)[26]. AIEC invades intestinal cells and adheres to the intestinal epithelial cells through adhesins, colonizing the intestinal mucosa and surviving in intestinal macrophages, resulting in the production of pro-inflammatory cytokines through the activation of TNF-α and in the promotion of granuloma formation[24,27]. The enrichment of AIEC is associated with the loss of obligate anaerobes, including Faecalibacterium prausnitzii, in the colon. Faecalibacterium prausnitzii is known to improve intestinal inflammation and barrier function via multiple mechanisms and targets. Thus, decreasing this species reduces the intestinal barrier function[5], such as lowering the Roseburia genera, associated with increased regulatory T cell and reduced IL-17 production[28].

Studies on the microbiota and IBD emerged in the early 2000s, leading to a deeper understanding of the diverse microbial communities inhabiting various human tissues, including the mesenteric adipose tissue[29]. Although bacterial translocation from the gut to mesenteric adipose tissue occurs in healthy individuals, it typically does not result in significant inflammation or immune cell infiltration[22]. However, in chronic inflammation in CD, in which the microbiota is constantly altered, opportunistic pathogens may exploit compromised host and microbial defenses. This can lead to increased bacterial translocation, with a distinct set of bacteria migrating from the gut to the mesenteric adipose tissue[22]. In this condition, the altered gut microbiota and mesenteric adipose tissue may engage in a reciprocal interaction, potentially contributing to the progression of CD[16]. Evidence suggests that some bacteria persisted in the creeping fat samples within surgically excised specimens, confirming that the peritoneal creeping fat surrounding the intestines prevents the spread of bacteria from the affected site into the bloodstream, thereby slowing CD progression. Bacteria entering the mesentery after barrier damage may be the main cause of creeping fat formation[19,23].

Creeping fat and mesenteric adipose tissue are characterized by bacteria predominantly belonging to the proteobacteria phylum[19]. Moreover, Achromobacter pulmonis (Phylum Pseudomonadota) levels are elevated in both the mesenteric fat and mucous layers of patients with CD, and this abnormal colonization is associated with excessive translocation rates. Evaluations in murine models demonstrate that these granulomas can exacerbate colitis, indicating their potential role in the pathogenesis[30].

The transmural inflammation in CD is considered to facilitate bacterial translocation from the gut to mesenteric adipose tissue and is present in approximately 30% of patients with CD[17]. Mycobacterium avium species, paratuberculosis, and Clostridium innocuum (C. innocuum) are the most prevalent bacteria in the mesenteric adipose tissue surrounding the injured intestine[4,17]. Ha et al[22] proposed a microbial mechanism driven by C. innocuum that transforms mesenteric adipose tissue into creeping fat in patients with CD. C. innocuum includes type-IV pili and twitching motility that can distinguish mucosa from adipose tissue, besides presenting several genes for lipid metabolism, with a preference for lipid-derived metabolic substrates such as β-hydroxybutyrate, a by-product of fatty acid oxidation[22].

Gilliland et al[4] found that the C. innocuum strain isolated from creeping fat is functionally and genetically different from luminal strains and seems to be adapted to lipid metabolization and can promote extracellular matrix production and fat expansion, both of which are hallmarks of creeping fat[23]. C. innocuum, known to cause extraintestinal infections and antibiotics-associated diarrhea, is vancomycin-resistant[4]. It colonizes the ileum and colon but only appears to translocate in the small bowel[22]. The fat hypertrophy induced by C. innocuum associated with mesenteric lymphatic vessels with weakened tight junctions may transform healthy mesenteric fat into creeping fat[31]. According to Suau et al[17], adipocytes and pre-adipocytes sense the tissue-translocated bacteria and antigens through pattern-recognition receptors and initiate the hypertrophy phenomenon and innate immune response. Figure 1 illustrates the mechanism by which increased intestinal permeability allows the translocation of bacteria from the intestinal lumen to the mucosa and submucosa, leading to inflammation, fibrosis formation, and intestinal stenosis.

Figure 1 Increased intestinal permeability during Crohn’s disease allows bacterial translocation from the intestinal lumen into the mucosa and sub-mucosa. These bacteria, in particular Clostridium innocuum, can migrate to the adjacent adipose tissue and remain “trapped” in the fat. The immune cell migration and differentiation of macrophages increase, leading to fibrosis and stenosis, and ultimately the formation of creeping fat.

The immune system activation drives the mesenteric adipose tissue to expand and cover the gut, preventing other bacteria from translocating[4,32], thereby delaying the disease progression[14]. On the other hand, with the increase in creeping fat, these bacteria are trapped in fat tissue, continuing to migrate and proliferate towards the lesion site[14]. In these patients, creeping fat often coincides with intestinal stricture, with patients having higher levels of fibrosis, along with significantly higher expression of the fibrosis marker α-smooth muscle actin[33], suggesting that the gut microbiota, mesenteric adipose tissue hypertrophy, and intestinal fibrosis may mutually promote each other in the pathogenesis of CD[14]. Table 1 summarizes the mechanisms involved in the formation of creeping fat in CD.

Table 1 Mechanisms involved in the formation and maintenance of creeping fat in Crohn’s disease.

Mechanism	Description	Ref.
Bacterial translocation	Migration of bacteria from the intestinal lumen to the mesenteric adipose tissue, stimulating local inflammation	Ha et al[22]
Chronic inflammation	Continuous production of inflammatory cytokines (such as tumor necrosis factor-α, interleukin-6, and interleukin-1β) that affect the mesentery	Wu et al[14]; Foppa et al[24]
Local adipokine production	Release of leptin and adiponectin from adipose tissue, which modulates the immune and inflammatory responses	Tsounis et al[19]
Hypoxia and local fibrosis	The expansion of mesenteric fat can generate hypoxia, favoring fibrosis and aggravating the inflammatory condition	Wu et al[14]; Li et al[33]
Alteration of gut microbiota	Changes in the composition of the intestinal microbiota that affect the metabolism and function of the adipose tissue	Gilliland et al[4]; Ha et al[22]
Activation of macrophages and T cells	Infiltration of macrophages and T cells into adipose tissue, perpetuating inflammation and tissue remodeling	Karaskova et al[12]; Tsounis et al[19]

TARGETING GUT MICROBIOTA IN CD

Despite creeping fat representing a protective response by the body against systemic inflammation to retain the localization of inflammation, mesenteric adipose tissue hypertrophy damages the adjacent tissue, including creeping fat encroachment into the bowel wall[22]. Therefore, modulation of microbiota and creeping fat could be a new target in high-risk patients developing fibrotic complications[14,22].

The use of antibiotics to eliminate pathogenic microorganisms was one of the earliest attempts to modulate the gut microbiota in IBD. Although the role of the microbiota in IBD pathogenesis is well-established, the effectiveness of antibiotic therapy remains uncertain[4]. More recent strategies have focused on directly intervening the gut microbiota to restore intestinal barrier function. FMT and the use of probiotics are prominent examples of such interventions. FMT is hypothesized to indirectly target harmful bacteria by introducing a diverse gut microbiota to the patients with IBD[4]. Various clinical trials have explored FMT for IBD, but the evidence base remains limited due to the small number of completed studies and methodological heterogeneity[34]. A meta-analysis by Paramsothy et al[35] reported remission in 50% of patients with CD treated with FMT, but the short follow-up period and methodological differences limit the strengths of these findings. The conflicting data on FMT efficacy can be attributed to factors such as study design, pre-procedure antibiotic use, route of administration, donor origin, infusion frequency, and therapeutic outcomes[35]. Future studies should prioritize personalized FMT approaches tailored to individual patient characteristics, including disease phenotype, inflammatory activity, immunosuppression status, and recipient microbiota composition. Safety is of paramount concern, considering the potential for unidentified microorganisms in transplanted material and the lack of long-term safety data. The long-term persistence of transplanted microbiota in the host further underscores the need for careful consideration of safety and efficacy in FMT protocols.

Probiotics are live microorganisms that confer health benefits to the host when consumed in adequate amounts[36,37]. By increasing the abundance of beneficial bacteria, probiotics may compete with harmful bacteria for nutrients, potentially limiting their growth and activity[37]. In CD, several studies have investigated the potential benefits of probiotic supplementation, with Enterococcus faecium, Bifidobacterium, Bacillus, Lactobacillus, and Saccharomyces boulardii being among the most used strains[37]. The primary mechanisms proposed for probiotic efficacy in CD include the production of SCFAs, particularly butyrate, reduced secretion of pro-inflammatory cytokines, and increased expression of mucin-2 and autophagy[37]. Despite these potential preclinical and mechanistic findings, a systematic review identified only two studies that evaluated probiotics for the treatment of active CD, and neither demonstrated significant benefits[38].

Prebiotics, on the other hand, are non-digestible carbohydrates that selectively stimulate the growth of beneficial bacteria[39]. Fibers such as oligofructose and inulin, two well-known prebiotics, promote the growth of Bifidobacterium and Lactobacillus in the colon, contributing to intestinal barrier function[36]. Prebiotics can stimulate the proliferation of native gut bacteria, leading to increased SCFA production, which is associated with enhanced host immunity and colonic integrity. According to Guandalini and Sansotta[40], the benefits of prebiotics are achieved indirectly by improving the mucosal barrier through the stimulation of beneficial bacteria that can positively regulate epithelial defense mechanisms. Despite these potential benefits, a recent systematic review and meta-analysis found no evidence supporting the use of prebiotics for inducing or maintaining remission in CD[41].

While targeting gut microbiota presents a promising avenue for managing CD, the efficacy of current interventions remains inconclusive. Strategies like antibiotics, FMT, probiotics, and prebiotics offer potential benefits by modulating the gut environment; however, significant variability in the study design, patient response, and methodological limitations hinder definitive conclusions. Therefore, personalized treatment approaches tailored to individual microbiota profiles and disease characteristics are essential to maximize therapeutic outcomes. Furthermore, the safety and long-term implications of these treatments require further research, and the elucidation of the real role of dysbiosis in the maintenance of creeping fat requires more evidence, before indicating the modulation of the intestinal microbiota and integrating this approach into clinical practice.

CONCLUSION

Creeping fat, a distinctive feature of CD, exhibits a complex interplay between protective and detrimental roles in disease pathophysiology. The intimate relationship between the gut microbiota and mesenteric adipose tissue underscores the intricate link between intestinal inflammation and creeping fat development. Bacterial translocation, particularly involving strains such as C. innocuum, can drive creeping fat expansion and contribute to disease progression, potentially contributing to complications such as stenosing CD. Although modulating the gut microbiota appears to be a potential therapeutic approach for addressing complications related to creeping fat expansion, further research is necessary to elucidate these mechanisms and develop individualized treatment strategies. Traditional interventions such as FMT and probiotics, with limited potential, require additional investigation and refinement. A deeper understanding of the complex interactions between the gut microbiota, mesenteric adipose tissue, and creeping fat is crucial for developing effective therapeutic approaches tailored to individual patients with CD.