Polyketide synthase-derived sphingolipids mediate microbiota protection against a bacterial pathogen in C. elegans

Lena Peters, Moritz Drechsler, Michael A. Herrera, Jing Liu, Barbara Pees, Johanna Jarstorff, Anna Czerwinski, Francesca Lubbock, Georgia Angelidou, Liesa Salzer, Karlis Arturs Moors, Nicole Paczia, Yi-Ming Shi, Hinrich Schulenburg, Christoph Kaleta, Michael Witting, Manuel Liebeke, Dominic J. Campopiano (), Helge B. Bode () and Katja Dierking ()
Additional contact information
Lena Peters: Kiel University
Moritz Drechsler: Max-Planck-Institute for Terrestrial Microbiology
Michael A. Herrera: The University of Edinburgh
Jing Liu: Max-Planck-Institute for Terrestrial Microbiology
Barbara Pees: Kiel University
Johanna Jarstorff: Kiel University
Anna Czerwinski: Kiel University
Francesca Lubbock: The University of Edinburgh
Georgia Angelidou: Max Planck Institute for Terrestrial Microbiology
Liesa Salzer: Helmholtz Zentrum München
Karlis Arturs Moors: Kiel University
Nicole Paczia: Max Planck Institute for Terrestrial Microbiology
Yi-Ming Shi: Max-Planck-Institute for Terrestrial Microbiology
Hinrich Schulenburg: Kiel University
Christoph Kaleta: Kiel University
Michael Witting: Helmholtz Zentrum München
Manuel Liebeke: Kiel University
Dominic J. Campopiano: The University of Edinburgh
Helge B. Bode: Max-Planck-Institute for Terrestrial Microbiology
Katja Dierking: Kiel University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Protection against pathogens is a major function of the gut microbiota. Although bacterial natural products have emerged as crucial components of host-microbiota interactions, their exact role in microbiota-mediated protection is largely unexplored. We addressed this knowledge gap with the nematode Caenorhabditis elegans and its microbiota isolate Pseudomonas fluorescens MYb115 that is known to protect against Bacillus thuringiensis (Bt) infection. We find that MYb115-mediated protection depends on sphingolipids (SLs) that are derived from an iterative type I polyketide synthase (PKS) cluster PfSgaAB, thereby revealing a non-canonical pathway for the production of bacterial SLs as secondary metabolites. SL production is common in eukaryotes but was thought to be limited to a few bacterial phyla that encode the serine palmitoyltransferase (SPT) enzyme, which catalyses the initial step in SL synthesis. We demonstrate that PfSgaB encodes a pyridoxal 5’-phosphate-dependent alpha-oxoamine synthase with SPT activity, and find homologous putative PKS clusters present across host-associated bacteria that are so far unknown SL producers. Moreover, we provide evidence that MYb115-derived SLs affect C. elegans defence against Bt infection by altering SL metabolism in the nematode host. This work establishes SLs as structural outputs of bacterial PKS and highlights the role of microbiota-derived SLs in host protection against pathogens.

Date: 2025
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DOI: 10.1038/s41467-025-60234-1

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