Researchers found that deficiencies or mutations in the gene ATG16L1 resulted in the inability of immune cells to respond to the beneficial bacterium Bacteroides fragilis, thereby causing gut inflammation and increasing risk of inflammatory bowel disease (IBD)
Inflammatory bowel disease is a family of intestine-related disorders including Crohn’s disease and ulcerative colitis. A patient with the disease presents with inflammation in the bowel (pain, discomfort, bleeding etc.) and is associated with an overactive immune response. It affects over 1.5 million people in the United States alone, and this number continues to rise with increasingly more diagnoses. Despite this, the treatment options are limited and hence understanding the mechanisms of the disease is of importance. To this end, recent studies have suggested that interactions between genetics (e.g. the genes ATG15L1 and NOD2) and the environment (gut bacteria) can dampen inflammation and restore the protective functions of the immune system in the gut. Genetic mutations in these interactions can impair the protective role of microbiota in gut inflammation and ultimately increase risk of IBD.
A report published in Science this month investigated the role that the gut bacterium Bacteroides fragilis plays in priming the immune response to a non-inflammatory state, protecting against IBD. The authors propose that Bacteroides fragilis, an abundant and beneficial bacterium in the small intestine, makes use of crucial cellular pathways involving the ATG16L1 and NOD2 genes. Outer membrane vesicles (OMVs) derived from the membrane of Bacteroides fragilis package an abundant component of the bacterium’s protective capsule – polysaccharide A (PSA). These PSA-laden OMVs are delivered to a critical immune cell known as the dendritic cells, which subsequently promote T-regulatory cells to produce interleukin-10 (IL-10). IL-10 dampens the inflammation in the gut and is known to protect against IBD. However, patients with IBD commonly have mutated ATG16L1 and/or NOD2 genes suggesting that these genes suppress pathological gut inflammation. Therefore, it is proposed that dendritic cells that are ATG16L1-deficient are inflammatory and increase the risk of inflammatory bowel disease. To test this, researchers obtained wild-type and ATG16L1-deficient dendritic cells from mice, and treated them with PSA-laden OMV, following which the cells were co-cultured with T-regulatory cells. It was observed that the wild-type dendritic cells caused an increased IL-10 release from T-regulatory cells in comparison to ATG16L1-deficient cells, in response to PSA-laden OMVs. They further conducted the experiments in mice, where they observed that wild-type dendritic cells were protective against IBD in response to PSA-laden OMVs, while the ATG16L1-deficient dendritic cells were not. In addition, they concluded that NOD2 acts by recruiting ATG16L1, and hence have a crucial role in this anti-inflammatory pathway against IBD. Furthermore, these results were confirmed using ATG16L1-mutated dendritic cells derived from IBD patients.
The results obtained in the report can be vital for the development of new therapies for IBD. For instance, the use of probiotics can favor enrichment of the Bacteroides fragilis in our guts, which in turn will play a protective role against IBD. This however, does raise the question regarding the role of other bacteria in the gut. There are some bacteria that promote inflammation, while others, like Bacteroides fragilis dampen inflammation. Overall, the report provides promising new insight into the causes of IBD, and how they can potentially be utilized for the development of new therapeutics.
Written By: Haisam Shah