麻豆传媒

Investigators at the Cleveland Clinic are exploring the possibility that blocking "creeping fat" may in the future help to reduce stricture formation in Crohn's disease, as described at the annual Digestive Disease Week conference.

In this exclusive 麻豆传媒 video, lead investigator , vice-chair of the Department of Gastroenterology, Hepatology, and Nutrition at the Cleveland Clinic in Ohio, explains the and the next steps toward preventing stricturing disease.

Following is a transcript of his remarks:

Crohn's disease is a progressive disease. Patients that start with inflammation develop complications over time, such as stricturing disease and fistulizing disease that then lead to surgical intervention. And we really have very limited tools at the moment to influence this natural history towards surgery and complications. So there's a dire need to study why patients develop these structural changes of the intestinal wall.

One observation that has been made close to a hundred years ago already was this phenomenon of creeping fat, where the mesenteric fat that connects the gut to the human body where the mesenteric fat wraps around the intestine. And this is a phenomenon that is selectively found in Crohn's disease. You cannot find it in other relapsing remitting disorders such as ulcerative colitis or diabetic colitis.

We got interested in it because our surgical colleagues, when they perform resections for stricturing disease and they open the abdominal cavity, the first thing they look at is where is creeping fat located. Because in this area, when they start palpating, it's highly associated with the strictures. And about 85% of the cases when you have creeping fat, you find an underlying stricture.

We then started very simply by first looking at the histology of the connection of the creeping fat with the intestine. And in fact, it turns out that the creeping fat creeps underneath the submucosa directly on top of the muscularis propria, the outer layer of the intestine. And we feel it's relevant because the muscularis propria thickens dramatically in stricturing disease, which is a major contributor to the luminal narrowing. And the luminal narrowing is a major contributor to the symptoms of obstruction that our patients experience.

And so this is how this whole project started and seeing the strong association. And so we're wondering how do the fat and the muscle relate to each other?

So what we did in our study then to explore this is we first performed measurements of the muscle thickness underneath the creeping fat compared to underneath not creeping fat. And it turns out the muscle is really thicker if it's exposed to the creeping fat.

And you can stain them for proliferation markers, and the thickness of the muscle is linked to increased proliferation of the muscle cells. And to see if one compartment affects the other, we then generated a mouse where we can delete all fat in the mouse over the timeframe of about 2 weeks, and then you induce experimented intestine inflammation.

And it turns out if the fat is present, the mouse muscle thickens in the gut, just like in humans. But if you take the fat away, the muscle doesn't thicken as it would if the fat would still be there, which suggests that the fat is really important for the muscle thickening.

And then we performed in vitro experiments. So we took human tissues from the fat human tissues, from the muscle, co-cultured them together and identified if in fact the human fat is exposed to the muscle, the muscle proliferates. We then perform screening experiments to find out what does the muscle actually see, what does the fat secrete that makes the muscle proliferate, and identified certain free fatty acids that may be the cause for this proliferation.

And then we zoomed in really deep into the muscle cell to find out what happens in the muscle cell when they see the fatty acids that drive proliferation. And we believe that the uptake of these fatty acids through a transporter on the cell membrane called CD36, and then transport it into the mitochondria of the cell drives the proliferation in the mitochondrial transporter, called carnitine palmitoyltransferase 1, or CPT-1. And when you inhibit CPT-1 in a mouse model, it can prevent the muscle thickening from occurring.

So in totality, we went 360 degrees from the human situation. We reverse-translated into animals, confirmed it in the human situation again, and then confirmed it in an animal model. So we believe this could be a relevant mechanism why patients get restricting disease as a complication.

So the very first grant we wrote on this topic was in fact a collaboration with David Van Wagoner, [PhD], from our cardiology department. Because the only other organ that has a comparable finding is the cardiac atrium in atrial fibrillation. It's a different type of muscle, but also when you have the atrium contract in an uncontrolled manner, the fat around the heart wraps around the atrium.

So there also is an interface between the two. And in fact, cardiology also has a large program to look at the interactions of the fat and the muscle and how this could affect muscle function in atrial fibrillation. And this is a very unexpected finding for us that these two organs are related in such a way.

So the next steps are to publish our initial findings. We generated additional transgenic knockout animals to confirm what we found in a variety of animal models as well as chronic animal models. At the moment, we restricted this to the acute setting, which is a very clean system to establish the observation first.

And then after that, we hope there will be an opportunity to test it in humans and see if this really can treat or prevent stricturing disease.

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