A noncanonical polyamine from bacteria antagonizes animal mitochondrial function

Canonical polyamines such as agmatine, putrescine, and spermidine are evolutionarily conserved metabolites found in nearly all forms of life ranging from bacteria to humans. Recently, interactions between polyamines produced by gut bacteria and human intestinal cells have been proposed to contribute to both Irritable Bowel Syndrome with Diarrhea (IBS-D) and inflammatory bowel diseases. However, the molecular mechanisms that underlie these effects are often unclear due in part to limitations in the methods used to manipulate and study polyamine functions in vivo. Here, we developed a Caenorhabditis elegans based screening platform and a modified LC-MS approach for profiling polyamine metabolites. We combined these methods to make the unexpected discovery that dysfunctional polyamine metabolism in both Gram-negative (E. coli) and Gram-positive (B. subtilis) bacteria can result in the accumulation of a noncanonical polyamine intermediate, N¹-Aminopropylagmatine (N¹-APA). We further find that N¹-APA is produced via spermidine synthase (SpeE) and that it is bioactive when encountered by animals. Specifically, we find that when N¹-APA is produced by bacteria in animal intestines it can be transported into intestinal cells via the polyamine transporter CATP-5 where it antagonizes both animal development and mitochondrial function across diverse animal species. Lastly, we find that N¹-APA functions analogously to the deoxyhypusine synthase inhibitor GC7. For example, like GC7, N¹-APA antagonizes eIF5A hypusination and inhibits the alternative activation of mammalian macrophages. To our knowledge, these findings are the first to demonstrate that N¹-APA is a bioactive metabolite and that bacteria can produce a small molecule that functions similarly to existing deoxyhypusine synthase inhibitors. Furthermore, these results suggest an exciting new mechanistic hypothesis for why the loss of speB in gut microbes, including E. coli, has been both linked to inflammatory bowel disease (IBD) in humans and found to drive IBD in germ free mice.