Gut Bacteria Enzyme Converts Blood to Universally Compatible Blood Group

Blood stock shortages

Blood, platelets or plasma cannot be manufactured. Patients in desperate need of blood or blood-related products rely on blood donations from strangers to, in some instances, save their life.

In September 2023, the American Red Cross announced a national blood shortage, citing a critically low blood supply level that had dropped by almost 25% since early August. Just one year previous, the UK’s NHS Blood and Transplant (NHSBT) declared an amber alert stating that there were shortages of red blood cells across multiple blood groups, and stock levels could drop even lower unless further action was taken.

Dr. Maher Abou Hachem, professor in the Department of Biotechnology and Biomedicine at the Technical University of Denmark, and Dr. Martin L Olsson, professor in the Division of Hematology and Transfusion Medicine at Lund University, have been exploring methods to convert group A and B blood to group O to address such shortage issues.

What determines our blood type?

Our blood group, or blood type, is determined by the types of antigens that are present on the surface of our red blood cells. Antigens comprise sugars and proteins that coat the surface of the cell. While there are 8 blood groups (Table 1), some are rarer than others.  

Table 1. The eight different types of blood groups and the percentage of donors with each blood type. Credit: Give Blood.

Matching blood groups is crucial during blood transfusions to prevent unwanted immune reactions, which can be fatal. Group O negative blood is therefore in high demand for such procedures, as it is universally compatible and can be received by all blood groups.

“A universal group O blood inventory would offer an attractive solution to blood shortages, reduce outdating of blood units and eliminate the risk of ABO-dependent haemolytic adverse events,” the researchers said.

Alongside international colleagues, Hachem and Olsson screened enzymes that are produced and used by Akkermansia muciniphila (A. muciniphila), a bacteria found in the gut that degrades mucins. Mucins are large glycoproteins that help form the gut’s mucus layer, which lines cells of the gastrointestinal tract and has a variety of important functions.

"Our focus on mucin-degrading gut symbionts aimed at harnessing the co-evolutionary adaptation towards ABO antigens on intestinal mucins,” the researchers explained.

Bacterial enzymes convert blood cells from one group to another

When combined, several of the structurally unique enzymes identified through the screen were capable of converting group A and B red blood cells to group O.

Enzymatic conversion of blood cell antigens is not a novel concept. First explored in the early 1980s, its clinical progress was ultimately hindered by issues such as crossmatch reactivity and poor conversion efficiency.

“Our conversion of red blood cells was uniquely performed at the highest red blood cell concentration (38% haematocrit), shortest assay time (30 min) and lowest temperature (room temperature), compared to previous work,” the researchers said. “These mild conditions without additives (for example, dextran) together with excellent enzyme efficacies are important feasibility parameters in clinical applications.”

Hachem and team estimate that ~18 and 8 mg of the limiting enzyme would be required to convert 1 unit (approx. 200 ml) of A and B red blood cells, respectively, based on the enzyme concentration used in their experiments.

The enzymes were also effective against extended versions of A and B antigens that have only recently been discovered and might explain why previous efforts using enzyme conversion were unsuccessful.

“Removing both B and extended B antigens reduced incompatible O plasmas to <9% and the remaining positive reactions were milder. Similarly, A red blood cells, where both A and extended A antigens were depleted, showed increased compatibility and decreased positive crossmatch severity as compared to removal of only the A antigen,” the research team described.

“Our work establishes the conversion of extended A and B antigens as a previously unexplored solution to ABO-universal group O blood incompatibility and highlights the potential of gut microbiota specialists for the discovery of efficient human glycoconjugate-active enzymes,” they concluded, emphasizing that further research is warranted to explore the clinical viability of this work.  

Reference: Jensen M, Stenfelt L, Hagman JR et al. Akkermansia muciniphila exoglycosidases target extended blood group antigens to generate ABO-universal blood. Nature. 2024. doi: 10.1038/s41564-024-01663-4