Creeping fat in Crohn’s disease is likely caused by microbial translocation from the gut to neighboring mesenteric adipose tissue (MAT), based on a recent study.
Dr. Suzanne Devkota
This finding may lead to early risk stratification for creeping fat, and nonsurgical interventions, according to principal author Suzanne Devkota, PhD, assistant professor at Cedars-Sinai Medical Center in Los Angeles.
Creeping fat, which is unique to Crohn’s disease, is characterized by hyperplastic MAT that grips areas of intestinal inflammation with invasive “fingerlike projections,” the investigators wrote in Cell. This phenomenon was first described by the eponymous Dr. Crohn in 1932; since then, despite associations with fibrotic strictures that may require surgical resection, underlying mechanisms have remained mysterious and largely unexplored.
That changed during a session of grand rounds at Cedars-Sinai in September 2016; Dr. Devkota was discussing adipose tissue when her surgeon colleague, Phillip Fleshner, MD, asked: “What about creeping fat?”
“Yeah, that’s cool,” Dr. Devkota replied, “but I don’t have access to creeping fat.”
“I see it all the time,” Dr. Fleshner said. “I can get you some.”
And so a partnership was born, allowing Dr. Devkota and colleagues to pursue the translocation hypothesis.
The present report involved tissue samples from 11 patients with Crohn’s disease and 13 patients with ulcerative colitis. Healthy tissue controls were taken from four subjects without inflammatory bowel disease who underwent ileostomy.
Microbial cultivation of Crohn’s disease and healthy patient samples revealed bacteria in the mesenteric tissue of both groups, suggesting that microbial translocation from the gut to MAT “may not be unusual;” however, Crohn’s disease samples were associated with an exclusive consortium of five species: Clostridium innocuum, Erysipeloclostridium ramosum, Parabacteroides distasonis, Clostridium symbiosum, and Bifidobacterium pseudolongum.
C. innocuum was isolated most frequently; and its unique characteristics increased suspicions that it was the creeping fat culprit.
“Core genomic features of C. innocuum include type IV pili and twitching motility, a preference for lipid-derived metabolic substrates, and multiple genes for lipid catabolism, as well as a functional substrate preference for b-hydroxybutyrate, a byproduct of fatty acid oxidation,” the investigators wrote. “This suggests that C. innocuum is well suited for, and perhaps prefers, a lipid-rich environment and seeks these out when the opportunity arises.”
To observe this opportunism firsthand, the investigators gavaged gnotobiotic mice with C. innocuum. Indeed, these mice demonstrated “dramatic mesenteric adiposity,” compared with controls.
Cotreatment with dextran sulfate sodium (DSS) was unnecessary to induce translocation of C. innocuum, which “suggests that overt inflammation is not a prerequisite for its translocation,” the investigators noted.
The profibrotic potential of C. innocuum was supported by in vitro experiments, in which adipose-derived stem cells and primary fibroblasts from Crohn’s disease MAT were exposed to either C. innocuum lysate or macrophage-conditioned media from C. innocuum–exposed macrophages. While the lysate alone did not alter genes involved in fibrosis and remodeling, the macrophage-conditioned media did, indicating that C. innocuum alters MAT indirectly via macrophage activity.
Although multiple signs suggest that C. innocuum causes creeping fat, Dr. Devkota noted that systematic testing is needed to confirm this likelihood.
“But I do think we’ve honed in on the consortium that is at play,” she said, referring to the five identified species.
According to Dr. Devkota, awareness of these microbes could lead to diagnostic and interventional benefits for patients with Crohn’s disease. For example, gut microbiota profiling could be used to measure levels of C. innocuum in newly diagnosed patients, thereby stratifying risk of creeping fat. And phage therapy, with its high specificity for bacterial species, could be an ideal intervention.
“I’m very eager to hear from the surgeons, and hear what their opinion is, and whether this will affect their treatment or how they approach [creeping fat],” Dr. Devkota said.
Beyond Crohn’s disease, the study findings could inform obesity research, as bacterial DNA has been found in obese adipose tissue, which is characteristically fibrotic.
“There are a lot of gene-expression patterns [in the present study], that are also seen in obesity literature,” Dr. Devkota said.
“Obviously there’s a lifestyle caloric aspect to [obesity],” she added. “I definitely don’t claim that microbes are the end-all and be-all of obesity – I want to make that clear. But it could be possible, and particularly related to abdominal fat. Expanded abdominal fat could be a sign that there’s underlying intestinal inflammation ... that there’s something deeper going on that may be unrelated to a metabolic defect.”
The study was funded by Leona M. and Harry B. Helmsley Charitable Trust and the National Institutes of Health. Dr. Devkota and Dr. Ha are inventors on U.S. patent application #62/679,624.
SOURCE: Ha CWY et al. Cell. 2020 Oct 29. doi: 10.1016/j.cell.2020.09.009.