A noncanonical polyamine from bacteria antagonizes host mitochondrial function.

Interactions between gut bacterial polyamines and intestinal cells have been proposed to contribute to inflammatory bowel diseases, but the underlying molecular mechanisms are often unclear. Here, we use a derivatization-based LC-MS approach and the model animal Caenorhabditis elegans to study microbiome-derived polyamine bioactivity. We show that aberrant polyamine metabolism in two diverse bacterial species (Escherichia coli K12 and Bacillus subtilis 168) can result in the accumulation of a noncanonical polyamine intermediate, N1-aminopropylagmatine (N1-APA). N1-APA is produced via spermidine synthase (SpeE) and is bioactive in C. elegans intestinal cells and mouse bone marrow macrophages. Specifically, bacterial N1-APA can be transported into intestinal cells via the polyamine transporter CATP-5, where it antagonizes C. elegans development and activates the mitochondrial unfolded protein response. N1-APA functions analogously to the deoxyhypusine synthase inhibitor GC7 in C. elegans and, like GC7, it antagonizes eIF5A hypusination and inhibits the alternative activation of mouse macrophages in vitro. Our results indicate that bacterial N1-APA is a bioactive metabolite that functions similarly to deoxyhypusine synthase inhibitors but has other unidentified targets that likely play roles in mitochondrial stress responses. We hypothesize that N1-APA production by the gut microbiome, caused by either high dietary agmatine or loss of agmatinase activity, might contribute to inflammatory bowel diseases.