A Cellular Signature Reveals Why Current Crohn’s Disease Therapy Does Not Work for Some People
Scientists have identified a tell-tale combination of cells in people with Crohn’s disease who do not respond to one of its most effective treatments, shedding light on the nature of the disease and revealing potential new targets for therapy. Crohn’s disease, a form of inflammatory bowel disease characterized by chronic inflammation in parts of the small intestine, can cause debilitating flares of diarrhea and abdominal pain, leading to malnutrition and weight loss. Treating Crohn’s disease is challenging because the response to therapy varies greatly from person to person, and no single treatment works for everyone. Well-tolerated anti-inflammatory medications, for example, do not work in many people with Crohn’s disease. Stronger medications that block a major component of the inflammatory response called tumor necrosis factor (TNF) have been approved to treat Crohn’s disease and are effective for many whose health did not improve with the milder anti-inflammation drugs. However, for reasons unclear, a substantial portion of people do not respond to TNF-blocking drugs and must eventually resort to more drastic approaches to control the inflammation, which usually means surgically removing the affected areas.
In a recent study, scientists applied state-of-the-art technology to determine why some people do not benefit from certain Crohn’s disease treatments. They started by isolating and identifying single cells from intestinal lesions of 11 men and women with Crohn’s disease. Comparing these cells with cells from healthy intestinal tissue from the same patients, the researchers found a specific combination of cells—including activated immune cells and cells that make up connective tissue—in the lesions from several of the study participants. When the researchers looked for this cellular “signature” in a larger, well-characterized group of male and female children with Crohn’s disease, they found it was more likely present in those whose symptoms did not respond to anti-TNF therapy. Analysis of how the cells communicate with each other showed that this particular cellular combination does not rely solely upon TNF to maintain gut inflammation, which may explain why TNF-blocking drugs are ineffective. Importantly, this analysis also identified several other molecular targets for other potential therapies that, if used in combination with TNF-blocking drugs might be able to prevent inflammation in people with Crohn’s disease who do not respond to anti-TNF medications alone.
This study builds upon recent findings showing that there are probably at least several distinct types of Crohn’s disease, which could explain why treatment responses vary so widely from person to person. The results also show that the cellular makeup of the inflammatory lesions could affect how well different Crohn’s disease medications will work. Biological signatures such as this could help caregivers predict which therapies would be most effective, and they could provide the basis for new treatments for people with this disease.
Martin JC, Chang C, Boschetti G,…Kenigsberg E. Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 178: 1493-1508.e20, 2019.