Akkermansia muciniphila Muc^T harnesses dietary polyphenols as xenosiderophores for enhanced iron uptake

Dietary proanthocyanidins (PACs) are polyphenols that promote a healthy gut microbiome. PACs are notable for their rich catechol moieties with high affinity for iron, enabling them to interfere with pathogens' iron uptake. PACs selectively increase the abundance of Akkermansia muciniphila, a symbiont known for supporting metabolic and immune health. We discovered that A. muciniphila Muc^T utilizes distinct iron-acquisition systems to take up iron sequestered by PACs, supporting its metabolic activity. Integrative proteomics and transcriptomics revealed that A. muciniphila has an active catechol-type siderophore-mediated iron uptake (Fe³⁺) system, involving membrane ATP-binding cassette transporters and lipocalins. Simultaneously, the expression of ferrous iron (Fe²⁺) transporters, zinc uptake, and iron storage proteins was upregulated. Administering iron-laden PACs in an iron-depleted medium restored the A. muciniphila growth to levels comparable to those in iron-amended conditions. This was associated with an increased expression of the A. muciniphila siderophore operon and lipocalin genes, indicating that iron-laden PACs are recognized as xenosiderophores to cope with iron depletion. Hence, we identified novel signaling mechanisms for iron acquisition and siderophore uptake regulation in A. muciniphila Muc^T upon exposure to PACs, enhancing our understanding of the role of dietary PACs in selectively promoting this gut symbiont and potentially outcompeting pathogenic bacteria.