Effect of Small Bowel Crohn's Disease on Chylomicron Secretion After Ingestion of a Fatty Meal

Background:

B1 Prior Literature and Studies Crohn's disease (CD) is characterized by spontaneous, chronic relapsing and remitting inflammation of the gastrointestinal tract. The underlying etiology of the disease is unknown but it likely develops secondary to an environmental stimulus in a genetically predisposed person that results in a dysregulated immune response to the intestinal microbiome. Considerable effort has been paid to understanding the role of the intestinal microbiome, the genetic susceptibilities at play, and the immunology behind the condition to tailor treatments aimed at reducing inflammation.

Prior to the advent of current medical therapies a defining characteristic of CD noted by early pathologists evaluating tissue specimen's was a significant alteration of the gastrointestinal lymphatic system with lymphocytic thrombi, aggregates of lymphocytes and granuloma-obstructed lymphatics consistent with chronic lymphangitis (2). Furthermore, early researchers showed that obstructing segments of the regional lymphatics of the small intestine resulted in a segmental intestinal disease similar to CD (3). Immunohistochemical staining has confirmed the presence of lymphangiectasias, lymphocytic perilymphangitis, lymphocyte or granuloma obstructed lymphatics and inflammatory lymphoid follicles in patients with CD (4). Upstream of these obstructed lymphatics the vessels remain distended with lymphocytes (5). More recent studies have shown that lymphatic density is also significantly increased in the ileal and colonic tissue of patients with CD (6). Furthermore, the relationship between intestinal health and lymphatics has been highlighted in studies that found certain types of bacteria and viruses had resulted in a profoundly remodeled mesenteric lymphatic system. Findings included the development of chronic lymphadenopathy and increased permeability, similar to what is seen in CD (7). Given the prominent structural changes that occur to the mesenteric lymphatic system in CD (1), studies are needed to evaluate if lymphatic function is altered as well.

Chylomicrons are cholesterol and triacylglycerol rich lipoproteins synthesized by the small intestine and transported through the lymphatics. Thus, oral uptake of trioleate and cholesterol will lead to incorporation of the tracers into chylomicrons.

Using ELISA and mass spectrometric analysis these labelled chylomicrons can be quantitated in the serum, thus serving as a marker of absorption and transit through the lymphatics. Studies of healthy subjects have utilized this validated means to assess lymphatic uptake and transport. After ingestion, there is a delay of <60 minutes in the appearance of 13C labelled chylomicrons in the serum, with a peak occurring between 180 and 240 minutes. Our protocol is designed to take advantage of the knowledge that other oral tracer studies at Washington University have learned in optimizing such studies, including ongoing studies by Dr. Todd Cade that focuses on chylomicron secretion in pre-diabetic patients. Our study will evaluate patients with significant small bowel CD and compare them to healthy controls using a similar method.