Western diet may increase risk of gut inflammation, infection – Washington University School of Medicine in St. Louis

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A diet high in sugar, fat damages the immune cells in the digestive tract of mice

Ta-Chiang Liu

According to a study by researchers at Washington University School of Medicine in St. Louis and the Cleveland Clinic, eating a Western diet affects the immune system in the gut in ways that could increase the risk of infection and inflammatory bowel disease.

The study in mice and humans showed that diets high in sugar and fat damage Paneth cells, immune cells in the gut that help keep inflammation at bay. When Paneth cells do not function properly, the gut immune system becomes overly susceptible to inflammation, which puts you at risk of inflammatory bowel disease and undermines effective control of disease-causing microbes. The results, published May 18 in Cell Host & Microbe, open new approaches to regulating gut immunity by restoring normal Paneth cell function.

“Inflammatory bowel disease has historically been a major problem in western countries like the US, but it is becoming more common around the world as more people adopt western lifestyles,” said senior author Dr. med. Ta-Chiang Liu, Associate Professor of Pathology & Immunology at Washington University. “Our research has shown that long-term consumption of a high-fat, high-sugar Western-style diet interferes with the functioning of immune cells in the gut in ways that can promote inflammatory bowel disease or increase the risk of bowel infections.”

Impairment of Paneth cells is a key characteristic of inflammatory bowel disease. For example, people with Crohn’s disease, a type of inflammatory bowel disease characterized by abdominal pain, diarrhea, anemia, and fatigue, often have Paneth cells that have stopped working.

Liu and senior author Thaddeus Stappenbeck, MD, PhD – chairman of the Department of Inflammation and Immunity at the Cleveland Clinic and former co-director of the Department of Laboratory and Genomic Medicine at Washington University – set out to find the cause of Paneth -Cell dysfunction in people. They analyzed a database of demographic and clinical data on 400 people, including a Paneth cell rating for each person. The researchers found that high body mass index (BMI) was associated with Paneth cells, which looked abnormal and unhealthy under a microscope. The higher a person’s BMI, the worse their Paneth cells look. The association held out for healthy adults and people with Crohn’s disease.

To better understand this relationship, the researchers examined two strains of mice that are genetically predisposed to obesity. Such mice chronically overeat because they carry mutations that prevent them from feeling full even when fed regularly. To the researchers’ surprise, the obese mice had Paneth cells that looked normal.

In humans, obesity is often the result of a diet high in fat and sugar. Therefore, the scientists fed normal mice a diet in which 40% of the calories came from fat or sugar, similar to the typical Western diet. After two months on this diet, the mice had become obese and their Paneth cells looked extremely abnormal.

“Obesity wasn’t the problem in and of itself,” said Liu. “A diet that was too healthy had no effect on the Paneth cells. It was the high-fat, high-sugar diet that was the problem. “

Paneth cells returned to normal when the mice returned to a healthy mouse diet for four weeks. Whether people who habitually follow a Western diet can improve their gut immunity by changing their diet remains to be seen, Liu said.

“This was a short-term experiment, only eight weeks,” said Liu. “Obesity in humans doesn’t happen overnight, or even eight weeks from now. People have had sub-optimal lifestyles for 20, 30 years before they become obese. It is possible that if you’ve been on a Western diet for so long, you will cross a point of no recurrence and your Paneth cells will not recover even if you change your diet. We’d need to do more research before we can say whether this process is reversible in humans. “

Further experiments showed that a molecule known as deoxycholic acid, a secondary bile acid produced as a by-product of the metabolism of gut bacteria, is the link between Western diet and Paneth cell dysfunction. The bile acid increases the activity of two immune molecules – farnesoid X receptor and type 1 interferon – that inhibit Paneth cell function.

Liu and colleagues are now investigating whether fat or sugar play the main role in the impairment of Paneth cells. They have also begun exploring ways to restore normal Paneth cell function and improve gut immunity by targeting the bile acid or the two immune molecules.

Liu TC, Kern JT, Jain U, Sonnek NM, Xiong S., Simpson KF, VanDussen KL, Winkler ES, Haritunians T., Lu Q, Sasaki Y, Storer C., Diamond MS, Leiter RD, McGovern DPB, Stappenbeck TS . The Western diet induces Paneth cell defects through FXR and Type I interferon. Cell Host & Microbe. May 18, 2021. DOI: 10.1016 / j.chom.2021.04.004

The study was supported by the National Institutes of Health (NIH) grant numbers U01DK062413, R01 DK125296, R01 DK124274, DK109081, R01 AI143673, R01 AI127513, and R01 AI123348. the Helmsley Charitable Trust, Grant Number 2014PGIBD010; and Washington University’s Genome Technology Access Center and Core Center for Digestive Disease Research.

The 1,500 faculty physicians at Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and is consistently one of the best medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its connections with the Barnes-Jewish and St. Louis Children’s Hospitals.

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