Amyloid-Polyphenol Hybrid Nanofilaments Mitigate Colitis and Regulate Gut Microbial Dysbiosis

Abstract

It is a desirable and powerful strategy to precisely fabricate functional soft matter through self-assembly of molecular building blocks across a range of length scales. Proteins, nucleic acids, and polyphenols are the self-assemblers ubiquitous in nature. Assembly of proteins into flexible biocolloids, amyloid fibrils with high aspect ratio, has emerged as an unchallenged templating strategy for high-end technological materials and bio-nanotechnologies. We demonstrate the ability of these fibrils to support the deposition and self-assembly of polyphenols into hybrid nanofilaments and functional macroscopic hydrogels made thereof. The length scale of the substance that amyloid fibrils can attach with acting as the building templates was extended from nanometer down to sub-nanometer. Significantly increased loading capacities of polyphenols (up to 4.0 wt %) compared to that of other delivery systems and improved stability were realized. After oral administration, the hydrogels could transport from the stomach to the small intestine and finally to the gut (cecum, colon, rectum), with a long retention time in the colon. Oral administration of the hydrogels significantly ameliorated colitis in a mouse model, promoted intestinal barrier function, suppressed the pro-inflammatory mRNA expression, and very significantly (P < 0.01) regulated gut microbial dysbiosis. Specifically, it reduced the abundance of normally enriched operational taxonomic units related to colitis, especially targeting facultative anaerobes of the phylum Proteobacteria, such as Aestuariispira and Escherichia. The short-chain fatty acid metabolites were enriched. Combined with their nontoxic nature observed in this long-term study in mice, the obtained amyloid-polyphenol gels have high application potentials for gastrointestinal diseases by "drugging the microbiome".

Keywords: amyloid fibrils; colitis; gut microbiota; nanofilaments; polyphenols; self-assembly.