Carboxymethylcellulose ameliorates high-fat diet-associated colitis through the reduction of deoxycholic acid and restoration of mitochondrial complex I in macrophages

Ulcerative colitis is a chronic condition where the lining of the large intestine becomes inflamed, causing pain, bleeding, and frequent diarrhea. While the exact cause remains a puzzle, scientists know that what people eat plays a major role in how the disease behaves. In recent years, diets high in fat have been linked to a higher risk of developing this condition and making it worse. One of the ways a high-fat diet harms the gut is by changing the chemistry inside the intestine. Specifically, it encourages the body to produce more of a substance called deoxycholic acid. While this substance is a normal part of digestion, too much of it acts like a poison to the gut lining, triggering immune cells to attack the tissue and causing severe inflammation. Finding a way to lower this acid without causing other problems has been a difficult challenge for doctors.

Researchers at Sichuan University have discovered a surprising solution hidden in a common food additive. Carboxymethylcellulose, or CMC, is a substance found in many processed foods, used to make them smooth and keep them fresh. For a long time, scientists have been unsure if this additive helps or hurts people with gut diseases. Some studies suggested it might make inflammation worse, while others hinted it could be harmless. However, no one had looked at how it works specifically when a person is eating a high-fat diet. The team set out to test whether this everyday ingredient could calm the gut when fat levels were high. They found that CMC does more than just sit in the digestive tract; it actively changes the environment inside the gut to stop the production of the harmful acid.

To understand how this works, the researchers first looked at real people with ulcerative colitis. They asked patients about their eating habits and found that those who were currently suffering from a flare-up tended to eat more fat than those who were feeling better. This confirmed that fat intake is closely tied to how active the disease is. They then moved to mice to test the mechanics. They fed some mice a high-fat diet and gave them a chemical that causes colitis. As expected, the high-fat diet made the disease much worse. The mice lost more weight, had more severe inflammation, and their intestines were filled with high levels of deoxycholic acid.

When the researchers added CMC to the drinking water of these mice, the situation changed dramatically. The mice that received the additive stayed healthier, kept their weight, and had much less inflammation in their guts. The key to this improvement was the level of deoxycholic acid. In the mice that got CMC, the amount of this harmful acid dropped significantly. It fell from a high, damaging level down to a much lower, safer amount. The researchers wanted to know if CMC was simply soaking up the acid like a sponge or if it was stopping the acid from being made in the first place. They tested this by mixing CMC with fat in a lab dish and found that the chemical structure of the fat did not change. This meant CMC was not directly neutralizing the acid. Instead, it was working through the tiny bacteria living in the gut.

The gut is home to trillions of bacteria, and these microbes are responsible for turning normal bile acids into secondary ones like deoxycholic acid. The researchers found that the high-fat diet caused a specific type of bacteria, called Bacteroides acidifaciens, to multiply. This bacterium is a factory for the harmful acid. When the mice were given CMC, the population of this specific bacterium dropped sharply. With fewer of these bacteria around, the gut stopped making so much deoxycholic acid. The researchers confirmed this by giving the mice the bacterium directly; those that received the live bacteria got sicker, while those that got the bacteria after they had been heated and killed did not. This proved that the living bacteria were the problem, and CMC worked by keeping their numbers low.

But why does having less of this acid help the gut heal? The answer lies in the immune cells that patrol the intestine. When the gut is inflamed, a type of white blood cell called a macrophage changes its shape and behavior to become an attacker. These attackers, known as M1 macrophages, release chemicals that damage the tissue. The researchers found that in mice with high levels of deoxycholic acid, these attacker cells were everywhere. However, when the acid levels were lowered by CMC, these cells stopped acting like attackers. They returned to a calmer state.

To see how this happened, the scientists looked inside the cells themselves. They discovered that the high levels of deoxycholic acid were damaging the power plants of the immune cells, called mitochondria. These power plants are responsible for generating energy. When they are damaged, the cells switch to a less efficient way of making energy, which triggers them to become angry attackers. The researchers found that when CMC lowered the acid levels, the power plants in the immune cells were repaired. They started working efficiently again, producing energy in a way that kept the cells calm and prevented them from attacking the gut lining.

The team went a step further to prove that this energy repair was essential. They created mice that were missing a specific part of the power plant machinery in their immune cells. In these mice, even when CMC lowered the acid levels, the immune cells could not repair their power plants. As a result, the CMC did not help the mice get better; they still suffered from severe colitis. This showed that the ability to fix the cell's energy production was the critical step that allowed CMC to work.

The study also compared CMC to a standard medical drug used to bind bile acids, called cholestyramine. The researchers found that CMC worked just as well as this drug in reducing the inflammation caused by a high-fat diet. This is significant because CMC is a food additive that is generally considered safe, whereas the drug can have side effects and is not always well tolerated. The findings suggest that for people eating a high-fat diet, this common additive might actually help protect the gut by reshaping the bacterial community and lowering the levels of harmful acids.

While the study was conducted in mice and human patients, the results point to a new way of thinking about food and gut health. It shows that the effect of a food additive can depend entirely on what else is being eaten. In a normal diet, CMC might have different effects, but in a high-fat diet, it acts as a shield. By lowering the levels of a specific acid through the gut bacteria, it allows the immune system to settle down and stop attacking the body. This discovery offers a potential path for managing colitis in people who struggle with high-fat diets, turning a simple ingredient into a tool for healing.