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.