Glucomannan from Aloe vera Gel Strengthens Intestinal Barrier by Suppressing Macrophage M1 Polarization via the Lactic Acid–Piezo1–Ca2+ Axis

Abstract Modulating intestinal macrophage polarization is critical for maintaining intestinal barrier integrity. Our previous study demonstrated that glucomannan from Aloe vera gel (AGP) improved the intestinal barrier, yet its direct impact on intestinal macrophages remained undefined. Here, we demonstrated that AGP reduced M1 macrophage infiltration in colonic tissue. Integrated serum untargeted metabolomics identified lactic acid as a key AGP-induced metabolite, with 16S rRNA sequencing pointing to the gut microbiota as its potential source. Mechanistically, lactic acid suppressed M1 polarization by inhibiting the mechanosensitive cation channel Piezo1, thereby attenuating calcium influx, concurrently dampening STAT3 activation and ROS production─core drivers of M1 commitment. Critically, these effects were abrogated by a Piezo1 agonist, confirming the centrality of the lactic acid–Piezo1–Ca2+ axis. Collectively, our study defines a novel immunometabolic pathway wherein AGP fortifies the intestinal barrier through microbiota-derived lactic acid, which restrains macrophage M1 polarization via the lactic acid–Piezo1–calcium axis.