Research News

According to new study results, a team of researchers from multiple institutions and led by Cleveland Clinic’s Thaddeus Stappenbeck, MD, PhD, have found that a diet high in fat and sugar is associated with impaired intestinal immune cell function in mice. The findings, published in Cell Host & Microbe, provide novel insights into pathways linking obesity and disease-driving gut inflammation, and have implications for developing targets to treat inflammatory bowel diseases (IBD) in patients.

Primary focus on Paneth cells

Using data from more than 900 patients, the researchers found that elevated body mass index is associated with abnormal Paneth cells among patients with Crohn’s disease and non-IBD patients.

Paneth cells are a type of anti-inflammatory immune cell found in the intestines that helps to protect against microbial imbalances and infectious pathogens. Dysfunction of these cells is known to be driven by a combination of genetic mutations and environmental factors. Dr. Stappenbeck and others have previously linked Paneth cell dysfunction to gut changes indicative of IBD in preclinical models and a subset of Crohn’s disease patients from multiple cohorts around the world.

“With this understanding, we set out to investigate whether diet-induced obesity—specifically caused by a diet high in fat and sugar, or a ‘western diet’—is one of the environmental factors that can lead to impaired Paneth cell function,” said Dr. Stappenbeck, chair of Lerner Research Institute’s Department of Inflammation & Immunity.

The researchers compared the effects of a western diet versus a standard diet. The team’s western diet contained about 40 percent fat and an elevated level of simple carbohydrates, which better resembles the diet of an average U.S. adult than regimens prescribed in other preclinical studies.

Diet-related bile acids affect inflammation signaling pathways

After eight weeks, the group that ate the western diet had more abnormal Paneth cells than the group that ate a normal diet. In the western diet group, other changes become apparent two months after the Paneth cell defects, including increased gut permeability, where bacteria and toxins are able to enter the gut and which is well-linked with chronic inflammation. Notably, however, switching the western diet group to a standard diet completely reversed the Paneth cell dysfunction.

“When we started to look into large-scale datasets for the specific mechanisms that might connect the high-fat, high-sugar diet with the Paneth cell dysfunction, a secondary bile acid called deoxycholic acid caught our attention,” said Dr. Stappenbeck.

Deoxycholic acid is a metabolic byproduct of intestinal bacteria. Researchers found that consuming a western diet increased the bile acid in a region of the intestines called the ileum and, as a result, increased the expression of two downstream molecules, farnesoid X receptor (FXR) and type I interferon (IFN).

“For the first time, we showed how coordinated elevation of FXR and type I IFN signals in multiple cell types contribute to Paneth cell defects in response to a diet high in fat and sugar. In previous research, stimulating FXR has shown to help treat other diseases, including fatty liver disease, so we are hopeful that with additional research we can interrogate how the combination of elevated FXR and IFN signals can be targeted to help treat diet-induced gut infections and chronic inflammation.”

Dr. Stappenbeck also explained that while the team was interested to learn that changing the diet regimen reversed the pathological changes, more research would be needed to determine if these changes also occur in patients.

Ta-Chiang Liu, MD, PhD, a former colleague of Dr. Stappenbeck’s from Washington University School of Medicine in St. Louis, is a co-corresponding author on the study, which was funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases (both parts of the National Institutes of Health).