Phase Transition of Gastrointestinal Mucins in the Presence of Multivalent Ions

Gastrointestinal mucus is the first line of defense against bacteria, and it acts as a responsive biomaterial to multivalent ions. However, their phase behaviors and related physical mechanisms with multivalent ions are still poorly understood. Here, we reveal the order of ion binding affinity to gastrointestinal mucins, which goes against the Hofmeister series. We also provide a map of their phase diagrams with different multivalent ions, including re-entrant phase behaviors with trivalent and tetravalent ions and irreversible phase separation with divalent ions except Mg²⁺, which rather stabilizes mucin solutions. Surprisingly, our results in an extremely complex biological system can be well described by theories of simple polyelectrolytes, providing insights into the underlying physics. Combined with theory and the proof-of-concept studies, we reveal the physical mechanisms in the phase transition, including the bridging effect, the charge-reversal mechanism, and self-redissolution with trivalent ions due to the disruption of coordination complexes. Additionally, redissolution of the mucin-rich solid phase by exogenous ions is dominated by competitive ion condensation over the Debye electrostatic screening. This work could provide physical strategies to develop new methods and drugs for gastrointestinal mucus health improvement and therapeutics, such as enhancing the absorption of essential trace elements through gastrointestinal mucus by utilizing competitive ion condensation.