Gut microbes linked to inflammatory bowel diseases worsen colitis in mice

Giorgia Guglielmi

17.03.2025

What is already known

Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are long-term conditions involving gut inflammation caused by an excessive immune response. Previous studies have shown that compared with healthy individuals, people with IBD have distinct gut microbes, which may contribute to disease flares. However, much remains unclear about the molecular mechanisms underlying IBD.

What this research adds

Researchers analyzed the gut microbiotas of more than 5,300 people to identify bacterial gene clusters linked to IBD, and found two Clostridium gene clusters that are active in people with Crohn’s disease. These clusters produce compounds called fatty acid-amines, which were detected in 61% of stool samples from people with IBD. In mice, these molecules worsened colitis by damaging gut cells and increasing intestinal permeability.

Conclusions

The findings suggest that microbiota-derived molecules contribute to IBD progression, providing new insights into disease mechanisms and potential targets for future treatments.

The findings, published in Cell Host & Microbe, suggest that microbiota-derived molecules contribute to IBD progression, providing new insights into disease mechanisms and potential targets for future treatments.

Previous studies have shown that compared to healthy individuals, people with IBD have distinct gut microbes, which may contribute to disease flares. However, much remains unclear about the molecular mechanisms underlying IBD.

Researchers led by Moamen Elmassry at Princeton University in New Jersey analyzed the gut microbiotas of more than 5,300 people to identify specific groups of genes in bacteria, called biosynthetic gene clusters, that may be linked to IBD. The genes in these clusters work together to produce specialized small molecules, such as antibiotics or metabolites, which can influence health and disease.

Gene clusters

The team identified more than 10,000 different biosynthetic gene clusters that varied between healthy people and those with IBD. Some gene clusters were enriched in people with Crohn’s disease and ulcerative colitis, suggesting they could play a role in the diseases.

Among the most notable gene clusters were those from bacteria such as Escherichia coli, which are known to contribute to inflammation, and Clostridium, another microbe commonly found in the gut.

Two gene clusters from Clostridium, ebf and ecf, were abundant and active in the gut microbiotas of people with Crohn’s disease, the researchers found. This result suggests that the molecules produced by these clusters could play a role in the disease.

Harmful molecules

The researchers identified six small molecules, known as fatty acid-amines (FAAs), produced by the ebf and ecf gene clusters. Further experiments confirmed that these molecules were being produced by Clostridia species in the gut. About 61% of people with IBD had detectable levels of these molecules in their stool.

In mouse models of colitis, FAAs led to more severe disease by increasing intestinal permeability, which is a hallmark of IBD. The researchers also found signs of damage to the gut lining, including cell damage and disruptions to proteins that help maintain the gut barrier.

“These findings suggest that microbiome-derived small molecules may play a role in the etiology of IBD and represent a generalizable approach for discovering molecular mediators of disease-relevant microbiome-host interactions,” the authors say.