Future IBD Therapy May Draw on Gut Protein

Future IBD Therapy May Draw on Gut Protein

Researchers at UT Southwestern Medical Center recently published the finding of a pathogen-sensing molecule that plays a key role in the maintenance of a healthy gastrointestinal (GI) system. The study is entitled “The DNA Sensor AIM2 Maintains Intestinal Homeostasis via Regulation of Epithelial Antimicrobial Host Defense” and appeared in the journal Cell Reports.

A healthy human gut is known to have trillions of microorganisms (the gut microbiota), and while some are beneficial, others can induce disease. The body’s immune system plays a crucial role in identifying and killing pathogenic species, while beneficial microorganisms are preserved.

The molecule AIM2 (an acronym for Absent in Melanoma 2) can be found in all immune and epithelial cells, which are the main type of cells present in the intestine. In the study, researchers found that AIM2 is able to detect the DNA of harmful pathogens and regulate inflammation in the gut, helping maintaining a healthy GI tract.

“We’ve shown in an animal model that AIM2 detects the cytosolic presence of microbial DNA in the gut,” explained the study’s senior author, Dr. Hasan Zaki, Assistant Professor of Pathology at UT Southwestern, in a news release. “When AIM2 detects the DNA of pathogens in immune and epithelial cells, the protein activates a molecular machine called the inflammasome … The inflammasome in turn activates the enzyme caspase-1, which then produces two proteins (IL-1β and IL-18) that play important roles in the GI tract, including activation of immune cells, induction of antimicrobial peptides, and regulation of epithelial cell proliferation.” This response helps maintain the integrity of the epithelial barrier in the intestine.

According to Dr. Zaki, the immune system is responsible for maintaining a proper microbiota balance in the gut, with AIM2 playing a vital role in this homeostasis process.

Defects in the AIM2 pathway, therefore, can lead to a microbiota imbalance in the gut, causing inflammation and disease. “Defects in AIM2-mediated inflammasome activation lead to growth of IBD-causing bacteria like E. coli, as well as dysregulated inflammation and compromised healing of intestinal injury,” Dr. Zaki said. “Our findings also suggest that defects in AIM2 may alter DNA sensing and thus contribute to intestinal inflammatory disorders such as IBD, ulcerative colitis, Crohn’s disease, and colorectal cancer.”

Dr. Zaki and his team suggested that given the important role played by AIM2, “manipulation of the AIM2 signaling pathway may be a promising treatment option for these conditions.”

The research team believes that their findings might be valuable in the treatment of gastrointestinal conditions linked to bacteria and inflammation, including IBD. “AIM2 may be a future therapeutic target to regulate altered microbiota and dysregulated inflammation in the GI system,” Dr. Zaki concluded.