High-fat, high-sugar diet reduces intestinal immune cell activity in mice

A team of researchers led by Cleveland Clinic’s Thaddeus Stappenbeck, MD, Ph.D., discovered that a high-fat, high-sugar diet relates to reduced intestinal immune cell activity in mice.

High Sugar Diet. Image Credit: Oleksandra Naumenko/Shutterstock.com

The results, published in Cell Host & Microbe, shine new light on the mechanisms that link obesity and disease-causing gut inflammation and have implications for discovering strategies to treat inflammatory bowel disease (IBD) in patients.

Using information from over 900 individuals, the researchers discovered that high BMI is related to abnormal Paneth cells in both Crohn’s disease and non-IBD individuals.

Paneth cells are anti-inflammatory immune cells present in the intestines that aid in the defense against microbial imbalances and pathogenic diseases. The dysfunction of these cells is caused by a mix of environmental factors and genetic mutations.

Dr. Stappenbeck and colleagues have previously linked Paneth cell dysfunction to IBD-like gut changes in preclinical models and a subgroup of Crohn’s disease patients from multiple cohorts throughout 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.”

Dr Stappenbeck, Chair, Department of Inflammation & Immunity, Lerner Research Institute

The effects of a Western diet vs a regular diet were compared by the researchers. The team’s western diet had around 40% fat and an increased quantity of simple carbs, which resembled the diet of an average adult in the United States than regimens provided in earlier preclinical trials.

After eight weeks, the western diet group had more abnormal Paneth cells than the standard diet group. Other alterations emerge two months following the Paneth cell abnormalities in the Western diet group, including increased gut permeability, which allows toxins and bacteria to enter the gut and is associated with chronic inflammation.

Notably, moving from the Western diet to a normal diet entirely reversed the Paneth cell malfunction.

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.”

Dr Stappenbeck, Chair, Department of Inflammation & Immunity, Lerner Research Institute

Deoxycholic acid is a result of gut bacteria metabolism. Researchers discovered that eating a Western diet elevated bile acid in the ileum, which boosted the expression of two downstream molecules—type I interferon (IFN) and farnesoid X receptor (FXR).

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, Chair, Department of Inflammation & Immunity, Lerner Research Institute

Dr. Stappenbeck also stated that while the team was excited to find that modifying the eating regimen reversed the pathological changes, an additional study would be required to establish if similar changes occurred in patients as well.