Global life expectancy is declining, partly due to Western lifestyles—high-fat diets and low activity—that are linked to obesity, diabetes, and heart disease. New research now reveals that high-fat diets, through fat accumulation and microbiota-driven inflammation, can destroy immune cells in the gut, weakening intestinal defenses.

The findings, published in Immunity, suggest that reducing dietary fat or controlling gut inflammation could help preserve immune cells and protect gut immunity, offering a strategy to prevent diet-related gut diseases. 

High-fat diets not only disrupt the gut by reducing helpful bacteria and triggering chronic inflammation, they also alter metabolism and immune responses. However, exactly how dietary fats impair immune cells is still unclear.

To address this question, Eva Torrico at Harvard Medical School in Boston, Massachusetts, and her colleagues studied how high-fat diets affect gut immune cells in mice and people.

Gut leakiness

In both people and mice, higher body weight was linked to lower levels of specific gut immune cells called ILC3, while other immune cells remained unchanged. Experiments in mice revealed that the loss of ILC3 cells was caused by the high-fat diet itself: when fat absorption was blocked, these cells were preserved.

The loss of ILC3 cells was linked to increased gut “leakiness” and inflammation. However, this damage depended on gut bacteria: mice raised without any microbiota did not lose these immune cells when fed a high-fat diet. 

The researchers also found that the harmful effects of a high-fat diet on gut health can happen within just a day. In mice, signs of gut leakiness and inflammation appeared within 24 hours of eating high-fat food. ILC3 cells began dying off almost immediately and were completely depleted within a few weeks. 

Weakened defense 

The loss of ILC3 cells weakened the gut’s ability to fight harmful bacteria, making the body more vulnerable to infections. Further experiments showed that damage to ILC3 cells occurs because fats build up inside them, causing stress and cell death. This process appears to be driven by the interaction between dietary fat and inflammatory signals from gut microbes. 

In mice, the gut’s weakened defense against bacteria could be partly reversed by reducing fat or blocking inflammatory signals. In people with obesity, intestinal ILC3 cells also accumulated fat and showed inflammatory activation, the researchers found.

“Together, our findings define a malleable mechanism whereby dietary fats and microbial cues drive ILC3 maladaptation and death, with consequences for intestinal homeostasis,” the authors say.