Bring in gut microbiota as a novel approach in PA/MMA

Expert Opinion on Orphan Drugs published ‘The potential role of gut microbiota and its modulators in the management of propionic and methylmalonic acidemia’ .

Propionic and methylmalonic acidemia (PA/MMA) are rare inborn errors of metabolism. In PA and MMA propionyl-CoA and/or methylmalonyl- CoA and their derived metabolites build up in the bloodstream. This in turn causes an accumulation of dangerous acids and toxins, which can cause damage to the organs.

In order to manage this accumulation, PA/MMA patients need intensive life-long management. Despite best available clinical practice1,2, long-term survivors face multiple complications, such as life-threatening episodes of hyperammonemia and metabolic acidosis3,4, intellectual disability, poor growth, movement disorders, epilepsy and autism2,5–7.

Gut contribution to total propionate burden in PA/MMA

Propionate, precursor of propionyl-CoA, derives from catabolism of amino acids and lipids but is also one of the main short chain fatty acids produced by gut microbiota8. The gut microbiota is responsible for an estimated 25% of the total propionate production. Using stable isotope techniques to measure propionate production in patients with PA/MMA, the relative contributions of amino acids, lipids and gut microbiota are estimated as 50%, 25%, and 25%.8,9

The potential role of gut microbiota as a source of propionate production provides a potentially modifiable target. In today’s healthcare practice, oral antibiotics are used to reduce the production of propionate in people with PA/MMA. However oral antibiotics have several disadvantages, such as possible perturbation of normal gut microbiota, generating drug resistant bacteria and toxicity.

Need for a novel approach

Targeting the gut microbiota could be a new approach in the management of PA/MMA. This paper explores the potential role of gut microbiota in PA/MMA and proposes factors, known to modify the gut microbiota, to be considered for new comprehensive dietary management approaches.


New approaches are required to reduce the burden of propionate and therefore improve the clinical management of PA/MMA. This paper hypothesizes that the dietary management of PA/MMA may be improved by specific prebiotics that normalize gut microbiota while stabilizing or possibly reducing PA production. However, a more in-depth knowledge of gut microbiota composition and metabolic pathways in PA/MMA patients is a prerequisite for the development of successful dietary strategies.

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