The gut is exposed to a wide range of proteins, including ingested proteins and those produced by the resident microbiota. While ingested prion-like proteins can propagate across species, their implications for disease development remain largely unknown. Here, we apply a multidisciplinary approach to examine the relationship between the biophysical properties of exogenous prion-like proteins and the phenotypic consequences of ingesting them. Through computational analysis of gut bacterial proteins, we identified an enrichment of prion-like sequences in Helicobacter pylori. Based on these findings, we rationally designed a set of synthetic prion-like sequences that form amyloid fibrils, interfere with amyloid-beta-peptide aggregation, and trigger prion propagation when introduced in the yeast Sup35 model. When C. elegans were fed bacteria expressing these prion-like proteins, they lost associative memory and exhibited increased lipid oxidation. These data suggest a link between memory impairment, the conformational state of aggregates, and oxidative stress. Overall, this work supports gut microbiota as a reservoir of exogenous prion-like sequences, especially H. pylori, and the gut as an entry point for molecules capable of triggering cognitive dysfunction.

• PMID: 40425815
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Journal Article

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Seira Curto J, Dominguez Martinez A, Perez Collell G, Barniol Simon E, Romero Ruiz M, Franco Bordés B, Sotillo Sotillo P, Villegas Hernandez S, Fernandez MR, Sanchez de Groot N

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