High-fat diets linked to intestinal gene changes impacting immunity and metabolism

While high-fat diets are linked to several diseases, such as diabetes, obesity and fatty liver disease, US-based researchers are now revealing how these diets affect genes. In their study, they connect high-fat diets to the dysregulation of genes involved in drug metabolism, epithelial barrier function — which regulates nutrient absorption and prevents the invasion of pathogenic bacteria — inflammatory bowel disease, colon cancer, the gut microbiome and COVID-19.

The team from the University of California Riverside (UCR), US, fed mice diets with fat amounts close to the average fat consumption by US citizens at 40% of total calories.

Compared to a low-fat control diet, mice eating a high-fat diet experienced “concerning changes” in gene expression in their intestines, a process where genetic information is transformed into a functional product such as proteins. Some of these gene changes regulate susceptibility to infectious diseases.

“We saw pattern recognition genes that recognize infectious bacteria take a hit. We saw cytokine signaling genes take a hit, which helps the body control inflammation,” says senior author Frances Sladek, UCR cell biology professor.

The researchers linked long-term, high-fat diets to gene dysregulation in the gut, involved in immunity and metabolism.“It’s a double whammy. These diets impair immune system genes in the host and create an environment in which harmful gut bacteria can thrive.”

Genetic changes
The researchers analyzed RNA sequences in four different sections of the intestines, comparing a 24-week consumption of a standard low-fat diet to three distinct high-fat diets based on saturated fat from coconut oil, monounsaturated modified soybean oil (high in oleic acid) or unmodified soybean oil (high in polyunsaturated fat and linoleic acid).

One group consumed coconut oil with a small amount of unmodified soybean oil, the second group consumed almost equal parts coconut and unmodified soybean oil and the third consumed close to equal parts coconut and modified soybean oil.

The study published in Nature reveals that most dysregulated genes can be grouped into the immune system (which typically decreased) and metabolism (which generally increased). For example, they observed an increase in the pathogenic E. coli and a suppression of Bacteroides, which helps protect the body against pathogens.

According to the researchers, these changes are associated with “various pathological conditions and diseases ranging from colon cancer, inflammation and IBD to leaky gut and infectious diseases including COVID-19.”

In previous work by the research team, soybean oil was linked to obesity and diabetes, which are risk factors for COVID-19. The current research finds that all three high-fat diets increased the expression of host proteins used by COVID-19 to enter the body.

Moreover, high-fat diets dysregulated genes involved in the metabolism or transport of neurotransmitters, which could impact brain health.

In addition, the team found that high-fat food increased signs of stem cells in the colon. “You’d think that would be a good thing, but they can be precursors to cancer,” explains Sladek.

Dietary implications
The current study mirrors estimates of high-fat diets typical in the US, with 40% of calories originating from fat and a low fiber content. The authors hope its results will drive people to examine their eating habits closely.

“Word on the street is that plant-based diets are better for you, and in many cases, that’s true. However, a diet high in fat, even from a plant, is one case where it’s not true,” adds Sladek.

UCR microbiologist Poonamjot Deol, co-first author of the study, adds that some fat, perhaps 10 to 15%, is necessary in the diet. “Most people though, at least in this country, are getting at least three times the amount they need.”

“Some people think, ‘Oh, I’ll exercise more and be okay. But regularly eating this way could impact your immune system and brain functions,” she warns. “You may not be able to just exercise away these effects.”

The researchers warn that the observed changes result from long-term high-fat habits as the mice were fed these diets for 24 weeks. Deol explains: “In human terms, that is like starting from childhood and continuing until middle age. One night of indulgence is not what these mice ate. It’s more like a lifetime of food.”

The authors hope people will examine their eating habits as in the US diets with 40% of calories from fat are typical.Focus on soybean oil
Mice fed a combination of coconut and unmodified soybean oil experienced the most significant number of dysregulated genes, which the authors note suggests that excess linoleic acid has a greater impact on intestinal gene expression than oleic acid. According to the research, soybean oil is the predominant source of dietary fat in the US.

Previous work by the research team revealed that soybean oil induces obesity, diabetes, insulin resistance and fatty liver in mice. Moreover, in 2020, the team linked the oil to gene changes in the brain associated with conditions such as autism, Alzheimer’s disease, anxiety and depression.

The researchers stress that the study’s findings only apply to soybean oil and not other soy products such as tofu or soybeans.

“There are some really good things about soybeans. But too much of that oil is not good for you,” Deol explains.

Further research
At the same time, the researchers note that more research is needed. They note that the observed changes in gene expression could be due directly to the diets or to their long-term effects, such as obesity, diabetes and susceptibility to colitis.

As the three diets showed different effects in gene expression, the authors suggest that not all observed effects are due to a lack of fiber.

They conclude that the relevance to humans must be established. They anticipate that many of the effects reported will also be found in humans since many of the differentially expressed genes highlighted in the study are very similar between mice and humans.

Meanwhile, other researchers argued against limiting fat intake to 30% of daily calories, as recommended by the WHO last year. The Harvard researchers argued that low-fat diets lack benefits to reduce risk of chronic conditions, and were concerned that lowering total fat intake could increase consumption of carbohydrates, which can increase blood pressure and triglycerides.