The human small intestine absorbs nutrients while protecting us from potentially harmful microbes. One of the cell types that plays a key role in this protection is the microfold cell, or M cell. These cells detect bacteria and other foreign particles and pass them on to immune cells. Until now, most knowledge about M cells came from studies in mice. In a new study published in Nature, researchers from the Clevers Group show that human M cells have additional immune functions. They do not only transport antigens, but they also process these antigens and present them directly to immune cells. The researchers found that M cells can also do this with gluten antigens. This suggests that M cells may contribute to celiac disease.
The small intestine absorbs nutrients with the help of tiny, finger-like projections called microvilli, which cover the surface of intestinal cells and increase the area available for absorption. The gut is also full of microbes, most of which are harmless or helpful, but some can cause disease. To protect us, the small intestine uses specialized epithelial cells called microfold cells, or M cells. These cells are found in the mucosal surfaces of the gut and play a critical role in the immune response. M cells have a smooth surface with fewer microvilli, which allows them to detect bacteria and other antigens, and transfer these from the gut lumen to immune cells deeper in the tissue. Most current knowledge about M cells comes from mouse studies, so it was unclear whether human M cells act in the same way or have additional roles.
Human M-cell organoids open new research paths
To answer this question, the researchers used human intestinal organoids: tiny lab-grown versions of the intestine. They enriched M cells in these organoids by modifying the cell culture condition. High resolution electron microscopy, performed by the Microscopy CORE Lab at Maastricht University, confirmed that the lab-grown M cells have fewer microvilli, a key feature of M cells. These organoids allowed the team to study human M cells directly and compare their function to mouse M cells.
Following the development of human M cells
The researchers found that the cell surface marker ICAM2 is a specific marker to identify M cells as they develop. By using ICAM2 together with two other well-known M cell markers (SPIB and GP2) they separated organoid M cells into early, immature, and mature stages. This allowed them to follow how human M cells grow and change over time. From this, they learned that the development of human M cells relies on certain factors that are also crucial for dendritic cells, specialized immune cells. Upon further study, the team found that human M cells closely resemble these immune cells: they share many genes, including MHC-II, and execute similar antigen-presenting function.
"The antigen-presenting function of human M cells surprised us," says co-first author Daisong Wang. "This function is typically reserved for professional antigen-presenting immune cells. Mouse M cells cannot do this, so it marks a clear difference between species." Human M cells do not only transport bacteria and antigens, as mouse M cells do, they also process antigens and present them to specific white blood cells called T helper cells.
Human M cells may help trigger celiac diseases
The team next explored whether human M cells can present gluten antigens. These antigens are resistant to digestion and can trigger an inflammatory immune response, particularly in individuals with celiac disease. With support from Chugai Pharmaceutical, they used a special antibody to recognize the presented gluten antigens. They found that human M cells can take up gluten, break it down, and present it to T cells in co-culture assays where both cell types are grown together. "Because this process resembles the first steps of celiac disease, these results suggest that M cells may play a central role in the disease," co-first author Sangho Lim explains. This finding adds to a long history of celiac disease discoveries in Utrecht. During the second world war, Dutch pediatrician W.K. Dicke observed that children with celiac disease struggled less during the Dutch famine, when wheat was scarce and bread was hardly available. When they received their first bread again after the war, their condition worsened. Dicke obtained his doctorate at Utrecht University on a case study of children with celiac disease.
Outlook: Better insight into gut immunity
The newly discovered function of M cells may help us understand conditions where the immune system is imbalanced, such as food sensitivities, inflammatory bowel disease, and microbiome-related disorders. Since the team has been able to model gluten-specific responses, the work may also support future research into celiac disease.
Future work will need to clarify how M cells behave in real intestinal tissue and how they interact with other cell types. The researchers hope that these insights will support new ideas for diagnostics or treatments. "By revealing new features of human M cells, we offer a framework for deeper studies of gut immunity," Daisong Wang says. "Our datasets are open to all researchers."
About Hans Clevers
Hans Clevers is distinguished group leader at the Hubrecht Institute ( KNAW ). He also is group leader at the Princess Máxima Center for Pediatric Oncology, distinguished professor in Molecular Genetics at Utrecht University , Investigator at Oncode Institute and ad interim director of the Institute for Human Biology (IHB) at Roche . In the past he was director of the Hubrecht Institute, president of the Royal Netherlands Academy of Arts and Sciences, director of the Princess Máxima Center for pediatric oncology and head of Pharma Research and Early Development (pRED) at Roche.
About the Hubrecht Institute
The Hubrecht Institute is a research institute focused on molecular and developmental biology. Because of the dynamic character of the research, the institute has a variable number of research groups, around 20, that do fundamental, multidisciplinary research on healthy and diseased cells, tissues and organisms. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences ( KNAW ), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht
