Gut Bacteria Enzymes Could Create Universal Type O Blood

Enzymes could convert red blood cells into universal type O

When a patient's life is at stake, a blood transfusion can be life-saving – provided the donated blood is compatible with their blood type.

Researchers in Denmark and Sweden have made a discovery that could assist in such emergencies and help relieve worldwide shortages of blood supplies.

In laboratory experiments, the team found that a combination of enzymes produced by a bacterium living in the human gut can convert red blood cells to universal type O with "remarkably high efficiencies". The approach advances an idea first proposed 40 years ago.

As with almost every cell in the body, red blood cells have a coating of distinctive sugar structures. These differ between individuals: some people carry type A structures, others type B, while some have both A and B. Those with neither are classed as type O.

If an immune system has not encountered A or B types before, it can immediately attack and destroy cells bearing them following a transfusion. Type O blood, by contrast, is suitable for a much broader range of recipients.

That flexibility means type O stocks can be depleted quickly, particularly during emergencies when clinicians need to act before a patient's blood type is known.

A long-standing challenge in blood conversion

The aim of converting red blood cells into universal type O is not new. In 1982, scientists pioneered the method after identifying an enzyme from coffee beans that could remove surface sugars from type B cells.

However, the enzyme reaction was highly inefficient, ruling out practical large-scale use. Although clinical trials initially appeared promising, they also prompted safety concerns. For reasons that remain unknown, donor blood could still prove incompatible with recipients even when nearly all antigens had been removed from donor cells.

Researchers therefore returned to the search for alternatives, identifying further enzymes in gut-bacteria collections as recently as 2019.

The issue is complicated by the fact that, by 2022, more than 40 blood group systems had been identified in addition to the ABO system and rhesus factor familiar to most people.

A and B blood groups also contain subtypes, whose defining molecules extend from red-cell membranes at different lengths and densities.

"Here we report the discovery of remarkably efficient enzymes, not only against A and B antigens but also against their extensions," write Mathias Jensen and Linn Stenfelt, bioengineers at the Technical University of Denmark, in their published paper with Swedish colleagues.

Gut-bacterium enzymes and clinical potential

Drawing on earlier research by other groups, the researchers chose several potential enzymes produced by the gut bacterium Akkermansia muciniphila. They applied these to red blood cells from several donors, covering a range of A and B subtypes.

Significantly for possible clinical application, the enzymes were incubated with high concentrations of red blood cells at room temperature for just 30 minutes. This improves on the longer processing times and lower efficiency associated with earlier candidates.

"These mild conditions without additives (for example, dextran) together with excellent enzyme efficacies are important feasibility parameters in clinical applications," Jensen, Stenfelt, and colleagues note.

Most importantly, the selected enzymes eliminated all four known extensions of group A and B antigens on red blood cells, as well as the shorter, standard A and B antigens found in other blood subtypes.

Removing the lengthy sugar extensions brought the incompatibility of treated type B cells with plasma samples below 9 percent, while also making any reactions that did occur less severe.

Further research is needed to establish why a small proportion of apparently sugar-free red blood cells still cross-react with group O plasma, and to improve conversion of group A blood cells.

Nevertheless, by identifying enzymes capable of removing a wider range of A and B antigens, the researchers say their work reveals "a missing link" towards producing universal blood for transfusions and potentially organs for transplantation.

In 2022, researchers used a comparable approach, using different enzymes, to change donated lungs from group A blood type to universal type O in laboratory conditions. The latest findings could enhance that work sufficiently to meet the safety requirements for human transplant trials.

Red blood cells grown in laboratories are also being tested in human trials to determine whether they survive longer than donated blood. If they do, this could lower pressure on blood supplies and help people who need repeated transfusions to avoid complications.

The study was published in Nature Microbiology.