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

The interplay between creeping fat (CrF) and gut microbiota offers a novel perspective on the use of fecal microbiota transplantation (FMT) in Crohn's disease (CD). Creeping fat, a hallmark feature of CD, is a specific type of mesenteric adipose tissue (MAT) that surrounds inflamed intestinal segments. It is closely associated with disease activity, severity, and postoperative recurrence. Historically considered a passive bystander, creeping fat is now understood as an active immunometabolic organ that significantly contributes to the progression of CD through its interaction with the gut microbiota.

### Key Insights into the Interplay:

1. **Creeping Fat's Role in CD Pathogenesis:**

• Creeping fat is not merely a structural feature but actively participates in the inflammatory processes of CD.
• In CD, intestinal barrier dysfunction allows translocation of gut-derived bacteria into MAT. These bacteria interact with immune cells, polarizing macrophages and promoting adipogenesis (the accumulation of fat cells), which leads to the expansion of creeping fat.
• Creeping fat produces proinflammatory cytokines and adipokines, further amplifying inflammation. It also disrupts immune balance and contributes to fibrosis through interactions with T helper cell pathways and macrophage subtypes.
• This creates a vicious cycle where intestinal inflammation, microbial dysbiosis (an imbalance in gut microbiota), and mesenteric fat expansion continuously reinforce each other.

2. **Gut Microbiota's Influence on Creeping Fat:**

• The gut microbiota plays a critical role in shaping the behavior of creeping fat. Microbial dysbiosis in CD has been shown to exacerbate intestinal inflammation and alter MAT's function.
• Specific bacterial communities may drive the persistence of creeping fat by modulating immune responses and promoting inflammatory signaling.

3. **Fecal Microbiota Transplantation (FMT) as a Therapeutic Tool:**

• FMT involves transferring fecal material, including beneficial microbiota, from healthy donors to patients with dysbiosis. It has been explored as a potential treatment for CD, particularly due to its ability to restore microbial balance.
• Recent experimental studies highlight the impact of FMT on the gut–fat axis:
• In animal models, FMT from healthy donors improved intestinal inflammation, enhanced barrier integrity, and reduced inflammatory signaling. This, in turn, mitigated the expansion and inflammatory activity of creeping fat.
• Conversely, FMT from CD donors worsened intestinal inflammation, barrier dysfunction, and creeping fat activity.
• These findings suggest that the composition of the microbiota is a critical determinant of MAT behavior and disease outcomes.

4. **Therapeutic Implications:**

• Targeting the interaction between gut microbiota and creeping fat represents a novel and promising therapeutic avenue for CD.
• FMT or related microbiota-modulating strategies could potentially disrupt the self-reinforcing loop between intestinal inflammation, microbial dysbiosis, and creeping fat expansion.
• By restoring a healthy microbial balance, FMT may not only improve intestinal health but also mitigate the pathological role of creeping fat in CD.

### A New Perspective:

This emerging perspective emphasizes the importance of the gut–fat axis in CD pathogenesis and introduces the possibility of using FMT as a targeted therapy to modulate this interaction. By addressing both microbial dysbiosis and the immunometabolic activity of creeping fat, FMT could offer a dual benefit in managing CD. Future research should focus on identifying the specific microbial species or metabolites that influence MAT behavior, optimizing FMT protocols, and exploring other microbiota-based therapies to refine this innovative approach.

In summary, the interplay between creeping fat and the gut microbiota provides a groundbreaking framework for understanding CD and highlights fecal microbiota transplantation as a novel strategy to disrupt the pathogenic cycle underlying the disease.