Lipid dysregulation of immune mediated intestinal epithelial healing A single layer of epithelial cells protects us from harmful interactions with the intestinal microbiota and harmful agents we inhale and ingest daily. Unresolved damage to this epithelial layer can lead to the development of chronic inflammatory diseases, including inflammatory bowel disease (IBD). High fat diets (HFD) correspond to increased incidence and severity of many chronic inflammatory diseases. Diets high in fat have been demonstrated to directly induce pro-inflammatory functions in macrophages, promoting chronic inflammation. In the intestine, HFD has been shown to decrease barrier function and promote chronic inflammation. However, it?s impact on intestinal immune function and tissue repair processes is less understood. Our immune system supports the proper functioning of tissue barriers. In response to tissue damage, tissue macrophages induce pro-inflammatory immune functions aiding in protection from pathogens. In the resolution phase of this response, these cells produce anti-inflammatory cytokines to dampen inflammation and promote tissue repair. Perturbations to any aspect of this response can lead to ineffective repair of tissue injury and development of inflammation. A key signal involved in this molecular switch of macrophages from pro- to anti-inflammatory responses is clearance of apoptotic cells, specifically apoptotic neutrophils. Defects in this response have been linked to many auto-immune and chronic inflammatory diseases including lupus, type 1 diabetes, atherosclerosis, COPD and cardiovascular disease. Tissue macrophages are important in intestinal homeostasis and their dysfunction is thought to drive disease pathogenesis in IBD. Further, defective barrier repair is seen in intestinal disease, but it is unclear whether defective apoptotic cell clearance by intestinal macrophages is involved and what mechanisms could modulate this process. To determine the impact of HFD on intestinal tissue repair responses, we utilized short-term HFD feeding in the context of mouse models of intestinal injury. Our data demonstrates that HFD increases susceptibility to colitis with increased weightloss, aberrant epithelial cell proliferation, loss of goblet cells and tight junction proteins necessary to prevent microbial penetration into the body. Further, we identified dysregulated immune responses resulting in an inability of intestinal immune cells to properly support barrier function and repair. We also find that HFD alters macrophage responses to and clearance of apoptotic neutrophils. Together, we find that HFD feeding directly promotes altered functions of intestinal immune cells leading to barrier repair defects. These findings led us to hypothesize that dietary lipids directly interfere with apoptotic cell recognition and uptake receptors and activation of downstream pro-repair signaling pathways resulting in dysregulated intestinal barrier repair. This is the basis of my K01 application.

Public Health Relevance

Dietary lipids are known to amplify inflammatory responses in chronic inflammatory diseases, which are associated with defective tissue repair processes. Although it is known that diets high in fat exacerbate inflammatory conditions such as inflammatory bowel disease (IBD), it is unclear how dietary lipids impact the intestinal immune system and tissue repair. Understanding how environmental components, such as diet, can induce or amplify inflammatory immune cell functions that support loss of tissue resolution will open the door to novel treatments for IBD and other inflammatory conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK121934-01A1
Application #
9976797
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
2020-04-07
Project End
2025-02-28
Budget Start
2020-04-07
Budget End
2021-02-28
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030