The amyloid state of proteins occurs in many different contexts in Nature and in modern society, ranging from the pathological kind (neurodegenerative diseases and amyloidosis) via man-made forms (food processing and – to a much smaller extent - protein biologics) to functional versions (bacterial biofilm, peptide hormones and signal transmission). These classes all come together in the human body which endogenously produces amyloidogenic protein able to form pathological human amyloid (PaHA), hosts a microbiome which continuously makes functional bacterial amyloid (FuBA) and ingests food which can contain amyloid. This can have grave consequences, given that PaHA can spread throughout the body in a “hand-me-down” fashion from cell to cell through small amyloid fragments, which can kick-start growth of new amyloid wherever they encounter monomeric amyloid precursors. Amyloid proteins can also self- and cross-seed across dissimilar peptide sequences. While it is very unlikely that ingested amyloid plays a role in this crosstalk, FuBA-PaHA interactions are increasingly implicated in vivo amyloid propagation. We are now in a position to understand the structural and bioinformatic basis for this cross-talk, thanks to the very recently obtained atomic-level structures of the two major FuBAs CsgA (E. coli) and FapC (Pseudomonas). While there are many reports of homology-driven heterotypic interactions between different PaHA, the human proteome does not harbor significant homology to CsgA and FapC. Yet we and others have uncovered significant cross-stimulation (and in some cases inhibition) of FuBA and PaHA both in vitro and in vivo, which we here rationalize based on structure and sequence. These interactions have important consequences for the transmission and development of neurodegenerative diseases, not least because FuBA and PaHA can come into contact via the gut-brain interface, recurrent infections with microbes and potentially even through invasive biofilm in the brain. Whether FuBA and PaHA first interact in the gut or the brain, they can both stimulate and block each other's aggregation as well as trigger inflammatory responses. The microbiome may also affect amyloidogenesis in other ways, e.g. through their own chaperones which recognize and block growth of both PaHA and FuBA as we show both experimentally and computationally. Heterotypic interactions between and within PaHA and FuBA both in vitro and in vivo are a vital part of the amyloid phenomenon and constitute a vibrant and exciting frontier for future research.
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