Peters Lena, Drechsler Moritz, Herrera Michael A, Liu Jing, Pees Barbara, Jarstorff Johanna, Czerwinski Anna, Lubbock Francesca, Angelidou Georgia, Salzer Liesa, Moors Karlis Arturs, Paczia Nicole, Shi Yi-Ming, Schulenburg Hinrich, Kaleta Christoph, Witting Michael, Liebeke Manuel, Campopiano Dominic J, Bode Helge B, Dierking Katja
Department of Evolutionary Ecology and Genetics, Zoological Institute, Kiel University, Kiel, Germany.
Department of Natural Products in Organismic Interactions, Max-Planck-Institute for Terrestrial Microbiology, Marburg, Germany.
Nat Commun. 2025 Jun 3;16(1):5151. doi: 10.1038/s41467-025-60234-1.
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.
抵御病原体是肠道微生物群的一项主要功能。尽管细菌天然产物已成为宿主与微生物群相互作用的关键组成部分，但它们在微生物群介导的保护作用中的确切作用在很大程度上仍未得到探索。我们利用线虫秀丽隐杆线虫及其微生物分离株荧光假单胞菌MYb115解决了这一知识空白，已知该分离株可抵御苏云金芽孢杆菌（Bt）感染。我们发现，MYb115介导的保护作用依赖于源自迭代型I聚酮合酶（PKS）簇PfSgaAB的鞘脂（SLs），从而揭示了一条作为次级代谢产物产生细菌鞘脂的非经典途径。鞘脂的产生在真核生物中很常见，但被认为仅限于少数编码丝氨酸棕榈酰转移酶（SPT）的细菌门，该酶催化鞘脂合成的第一步。我们证明PfSgaB编码一种具有SPT活性的依赖于磷酸吡哆醛的α-氧代胺合酶，并发现跨宿主相关细菌存在同源的假定PKS簇，这些细菌是迄今为止未知的鞘脂生产者。此外，我们提供的证据表明，MYb115衍生的鞘脂通过改变线虫宿主中的鞘脂代谢来影响秀丽隐杆线虫对Bt感染的防御。这项工作将鞘脂确立为细菌聚酮合酶的结构产物，并突出了微生物群衍生的鞘脂在宿主抵御病原体中的作用。
