Creeping Fat in the Pathogenesis of Crohn’s Disease: An Orchestrator or a Silent Bystander?

Abstract

Although the phenomenon of hypertrophied adipose tissue surrounding inflamed bowel segments in Crohn’s disease has been described since 1932, the mechanisms mediating the creeping fat formation and its role in the pathogenesis of the disease have not been fully unraveled. Recent advances demonstrating the multiple actions of adipose tissue beyond energy storage have brought creeping fat to the forefront of scientific research. In Crohn’s disease, dysbiosis and transmural injury compromise the integrity of the intestinal barrier, resulting in an excessive influx of intraluminal microbiota and xenobiotics. The gut and peri-intestinal fat are in close anatomic relationship, implying a direct reciprocal immunologic relationship, whereas adipocytes are equipped with an arsenal of innate immunity sensors that respond to invading stimuli. As a result, adipocytes and their progenitor cells undergo profound immunophenotypic changes, leading to adipose tissue remodeling and eventual formation of creeping fat. Indeed, creeping fat is an immunologically active organ that synthesizes various pro- and anti-inflammatory cytokines, profibrotic mediators, and adipokines that serve as paracrine/autocrine signals and regulate immune responses. Therefore, creeping fat appears to be involved in inflammatory signaling, which explains why it has been associated with a higher severity or complicated phenotype of Crohn’s disease. Interestingly, there is growing evidence for an alternative immunomodulatory function of creeping fat as a second barrier that prevents an abnormal systemic inflammatory response at the expense of an increasingly proliferating profibrotic environment. Further studies are needed to clarify how this modified adipose tissue exerts its antithetic effect during the course of Crohn’s disease.

Anastomosis after Bowel Resection for Crohn's Disease: State of the Art Review

“…30 Recent evidence also suggests that creeping fat may contain systemic leakage of inflammatory products. 31…”

Creeping Fat in Crohn’s Disease—Surgical, Histological, and Radiological Approaches

“…Additionally, in an experimental colitis model, gastrointestinal neurotensin (NT) synthesis (a neuropeptide closely involved in intestinal inflammation) and its corresponding receptor NTR1 were significantly upregulated in mesenteric fat, leading to IL-6 secretion by preadipocytes [54]. These findings suggest that creeping fat, rather than expressing genes involved in lipid metabolism, displays immunological characteristics that contribute to reciprocal signaling with the mucosal immune system [55]. The excessive expression of chemoattractant molecules plays a crucial role in coordinating the recruitment of immune cells, ultimately leading to the development of tertiary lymphoid organs (TLOs) within adipose tissue, which actively sustain intestinal inflammation [55].…”

“…The excessive expression of chemoattractant molecules plays a crucial role in coordinating the recruitment of immune cells, ultimately leading to the development of tertiary lymphoid organs (TLOs) within adipose tissue, which actively sustain intestinal inflammation [55]. As a result, creeping fat has the potential to worsen intestinal inflammation by exacerbating transmural injury and precipitating fibromuscular proliferation, which are closely related to Crohn's disease complications [55].…”

Dermal injury drives a skin to gut axis that disrupts the intestinal microbiome and intestinal immune homeostasis in mice

“…A similar, but more severe phenotype was also observed in a genetic mouse model that promoted the digestion of hyaluronan (HA) in the skin by targeted transgenic overexpression of human hyaluronidase-1 ( HYAL1 ) in the epidermis 15 . Intestinal tissue exposed in this manner to increased circulating fragments of hyaluronan were asymptomatic under control conditions but demonstrated increased inflammation, disruption of the epithelial barrier and development of increased adipose tissue in the colon reflective of “creeping fat” commonly seen in patients with IBD 16 , 17 . Although these observations provided a potential mechanism for communication from skin to gut, it remained unknown why the release of HA from the skin after injury or inflammation would impart an increased risk of colitis.…”