A study published in Cellular and Molecular Gastroenterology and Hepatology suggests that vulnerability to peanut allergy may begin partly with problems in the lining of the small intestine, not just with an overactive immune response. To find out what might be happening before an allergic reaction ever occurs, researchers created a detailed map of individual cells in the intestinal lining of mice prone to peanut allergy and compared them with mice that were resistant. Even before the mice were exposed to peanut, the allergy-prone animals showed important differences, including stressed cells, loss of a key protective protein, and changes in immune signaling. As the authors explain, the findings “identify Paneth cell-specific barrier failure as a previously unappreciated feature of peanut allergy and reposition the intestinal epithelium as a primary determinant of allergic susceptibility rather than a passive bystander to immune activation.”
At the center of these problems are Paneth cells, specialized cells found in tiny pockets, or crypts, in the intestinal lining. These cells produce substances that help control bacteria and protect the gut. In the allergy-prone mice, researchers found that the gene responsible for producing lysozyme-1 (Lyz1), an important antibacterial protein, was missing. The researchers also found that these mice shared many of the same changes in gut bacteria previously seen in mice lacking Lyz1, including increases in groups such as Ruminococcus and Akkermansia. This suggests that the loss of lysozyme may help change the mix of bacteria living in the gut. Previous research cited by the authors has linked similar bacterial changes to the type of immune response involved in allergies.
The Paneth cells showed other signs that they were not functioning normally. Gene analysis revealed signs of cellular stress, including a process called the unfolded protein response, which cells activate when they are having trouble properly making and processing proteins. Under an electron microscope, the Paneth cells also showed visible abnormalities, including swollen internal structures and misshapen or misplaced storage granules. Together, these findings suggest that stressed and poorly functioning Paneth cells could contribute to a weaker intestinal barrier.
Researchers also discovered differences in enterocytes, the cells that make up much of the intestinal lining and absorb nutrients. In the resistant mice, they identified a group of these cells that responded strongly to interferons, signaling proteins that help cells communicate with the immune system and maintain balance in the gut. This group was significantly reduced in the allergy-prone mice. Those mice also showed signs of problems with the structures that produce energy inside cells. Although scientists are still working to understand exactly how interferon signaling affects food allergy, the findings suggest that changes in this system could influence how the intestinal lining handles food proteins and communicates with the immune system.
The changes extended to several other types of cells in the intestinal lining. Allergy-prone mice had more mucus-producing goblet cells and sensory tuft cells, both of which have been linked to allergic responses. At the same time, they had fewer enteroendocrine cells (EECs), which produce hormones and help regulate digestion and the intestinal barrier. The researchers note that “loss of EEC populations or products has been associated with increased barrier permeability.” In other words, losing these cells could make the intestinal barrier more permeable, potentially allowing food proteins to cross it more easily and come into contact with immune cells.
Importantly, the researchers looked for evidence that one of their major findings might also occur in people. They analyzed small-intestine biopsies from children with and without peanut allergy and found significantly fewer intestinal crypts producing lysozyme in the peanut-allergic group. However, this part of the study was very small, involving only eight patients, three of whom had peanut allergy. All three peanut-allergic patients also had eosinophilic esophagitis (EoE), and one had Crohn’s disease as well. The authors therefore caution that the human findings need to be confirmed in a larger group of patients.
By combining genetic analysis, detailed examination of intestinal cells, and human biopsy samples, the study provides a new way of thinking about why some individuals may be more likely to develop food allergies. The findings suggest that problems with Paneth cells, loss of antimicrobial defenses, changes in immune signaling, and a more permeable intestinal barrier may work together to make it harder for the body to tolerate normally harmless food proteins. The study does not prove that these problems cause peanut allergy in people, but it raises the possibility that strengthening or repairing the intestinal barrier could eventually become another way to treat the disease. As the researchers conclude, “Future work will further dissect intestinal epithelial cell defects in peanut allergy and focus on gut barrier targeted therapies to treat this life-threatening disease.”
