A new technology to isolate immunostimulatory members of the human gut microbiota: next-generation IgA-seq

Scientists at UMC Utrecht have developed a new technology to efficiently isolate a specific subset of gut bacteria from fecal samples that are recognized by IgA antibodies. These ‘IgA-coated’ bacteria are associated with an array of diseases and this proposed new technology has the potential to uncover the mechanisms behind these correlations and eventually lead to new treatment strategies.

The gut microbiota, the community of microorganisms living within our intestinal tract, is known to play a crucial role in teaching our immune system when and how to respond to external threats. It is therefore key in mediating how our bodies respond to certain diseases. One of the key molecules responsible for the interaction between immune cells and microbes are antibodies. The most abundant type of antibody in our intestine is immunoglobulin A (IgA) which, once released, recognizes, and binds specific gut bacteria. On average, about 35 percent of the gut bacteria are coated with IgA in healthy individuals.

Role of IgA-coated bacteria

However, in patients with an intestinal inflammatory condition, the proportion of IgA-coated bacteria is increased, and alteration in the composition of this subset of bacteria has also been observed in conditions like allergies, asthma, irritable bowel syndrome, multiple sclerosis and inflammatory bowel disease (IBD). Though links have been drawn between these microbes and the above-mentioned diseases, the exact biological role of IgA-coated bacteria in health and disease is yet to be investigated along with the underlying mechanisms. Such information would be pivotal to develop strategies against these diseases. However, the methods currently used to investigate IgA-coated bacteria are suboptimal as they are slow, inefficient, and expensive.

Capturing IgA-coated bacteria

For these reasons, the research groups of microbiologist Marcel de Zoete, PhD and gastroenterologist Prof. Bas Oldenburg, MD PhD at UMC Utrecht set out to develop a technology that allows for a faster and high-yielding isolation of IgA-coated bacteria from human fecal samples. The groups came up with an attractive solution: starting from fecal samples, they targeted the IgA antibody tethered to the bacteria by binding tiny magnetic beads to the antibodies themselves. This way, when the bacteria are put in contact with a magnet, IgA-coated bacteria are captured, whereas all other bacteria can easily be washed away.

While this approach allows for much more efficient, high-throughput identification and isolation of IgA-coated bacteria, how does this new technology fare compared to the other classically used techniques? In an extensive set of control experiments, post-doctoral researcher Merel Van Gogh, PhD (Department of Medical Microbiology) and PhD candidate Jonas Louwers, MD (Department of Gastroenterology & Center for Translational Immunology) were able to show that this new setup, called next-generation IgA-SEQ, retains qualitative similar results compared to previous methods, while offering a series of advantages such as the ability to analyze large amounts of samples rapidly and to perform high-quality sequencing of total bacterial DNA.

Valuable addition

Principal investigator Marcel de Zoete concluded: ”Next-generation IgA-SEQ is a valuable addition to our scientific toolbox that can shine light on the role that IgA-coated bacteria play in health and disease. For example, we can now identify specific immunostimulatory bacterial strains that are associated with exacerbating or relieving IBD symptoms. Implementing this technology will allow scientists to gain a better understanding of the role of the microbiota in intestinal and systemic inflammatory disorders and could open up novel avenues for future therapies.”

Publication

van Gogh M, Louwers JM, Celli A, Gräve S, Viveen MC, Bosch S, de Boer N, Verheijden R, Suijkerbuijk K, Brand E, Top J, Oldenburg B, de Zoete M. Next-generation IgA-SEQ allows for high-throughput, anaerobic, and metagenomic assessment of IgA-coated bacteria. Microbiome 2024;12:211.