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Polyketide synthase-derived sphingolipids determine microbiota-mediated protection against pathogens in C. elegans

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 that are derived from an iterative type I polyketide synthase (PKS), PfSgaAB, thereby revealing a non-canonical pathway for the production of bacterial sphingolipids as secondary metabolites. Sphingolipid production is common in eukaryotes but was thought to be limited to a few bacterial phyla that encode the serine palmitoyltransferase (SPT) enzyme, which catalyzes the initial step in sphingolipid synthesis. We demonstrate that PfSgaB encodes a pyridoxal 5'-phosphate-dependent alpha-oxoamine synthase, which functions as SPT, and find homologous putative PKSs present across host-associated bacteria that are so far unknown sphingolipid producers. Moreover, we provide evidence that MYb115-derived sphingolipids affect C. elegans tolerance to Bt infection by altering host sphingolipid metabolism. This work establishes sphingolipids as structural outputs of bacterial PKS and highlights the role of microbiota-derived sphingolipids in host protection against pathogens.

INSTRUMENT(S): Liquid Chromatography MS - positive

PROVIDER: MTBLS8440 | MetaboLights | 2025-05-27

REPOSITORIES: MetaboLights

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	02_QC.mzML	Mzml
	03_K10_0003.mzML	Mzml
	04_K10_0002.mzML	Mzml
	05_K10_0001.mzML	Mzml
	06_Myb_0001.mzML	Mzml

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Polyketide synthase-derived sphingolipids determine microbiota-mediated protection against pathogens inC. elegans

Project description: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 nematodeCaenorhabditis elegansand its microbiota isolatePseudomonas fluorescensMYb115 that is known to protect againstBacillus thuringiensis (Bt) infection. We find that MYb115-mediated protection depends on sphingolipids that are derived from an iterative type I polyketide synthase (PKS), thereby describing a noncanonical pathway of bacterial sphingolipid production. We provide evidence that MYb115-derived sphingolipids affectC. eleganstolerance to Bt infection by altering host sphingolipid metabolism. This work establishes sphingolipids as structural outputs of bacterial PKS and highlights the role of microbiota-derived sphingolipids in host protection against pathogens.

2023-10-14 | GSE245296 | GEO

Polyketide synthase-derived sphingolipids determine microbiota-mediated protection against pathogens in C. elegans

Project description: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 Bacillus thuringiensis (Bt) infection. We find that MYb115-mediated protection depends on sphingolipids that are encoded by the iterative type I polyketide synthase (PKS) biosynthetic gene cluster, thereby describing a noncanonical pathway of bacterial sphingolipid production. We provide evidence that MYb115-derived sphingolipids affect C. elegans tolerance to Bt infection by altering host sphingolipid metabolism. This work establishes sphingolipids as structural outputs of bacterial PKSs and highlights the role of microbiota-derived sphingolipids in host protection against pathogens.

2025-05-06 | MTBLS8694 | MetaboLights

Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans [ChIP-Seq]

Project description:Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.

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Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans [RNA-Seq]

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Polyketide synthase-derived sphingolipids determine microbiota-mediated protection against pathogens inC. elegans

Project description:Polyketide synthase-derived sphingolipids determine microbiota-mediated protection against pathogens inC. elegans

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Natural C. elegans microbiota protects against infection via production of a cyclic lipopeptide of the viscosin group

Project description:Caenorhabditis elegans is associated in nature with a species-rich, distinct microbiota, which was characterized only recently. Thus, our understanding of the relevance of the microbiota for nematode fitness is still at its infancy. One major benefit that the intestinal microbiota can provide to its host is protection against pathogen infection. However, the specific strains conferring the protection and the underlying mechanisms of microbiota-mediated protection are often unclear. Here, we identify natural C. elegans microbiota isolates that increase C. elegans resistance to pathogen infection. We show that isolates of the Pseudomonas fluorescens subgroup provide paramount protection from infection with the natural pathogen Bacillus thuringiensis through distinct mechanisms. We found that the P. lurida isolates MYb11 and MYb12 (members of the P. fluorescens subgroup) protect C. elegans against B. thuringiensis infection by directly inhibiting growth of the pathogen both in vitro and in vivo. Using genomic and biochemical analyses, we further demonstrate that MYb11 and MYb12 produce massetolide E, a cyclic lipopeptide biosurfactant of the viscosin group, which is active against pathogenic B. thuringiensis. In contrast to MYb11 and MYb12, P. fluorescens MYb115-mediated protection involves increased resistance without inhibition of pathogen growth and most likely depends on indirect, host-mediated mechanisms. This work provides new insight into the functional significance of the C. elegans natural microbiota and expands our knowledge of bacteria-derived compounds that can influence pathogen colonization in the intestine of an animal.

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RNAseq of C. elegans cultured on metformin sensitive and resistant E. coli strains with and without 50mM metformin treatment.

Project description:Metformin is the therapy of choice for treating type 2 diabetes and is currently repurposed for a wide range of diseases including aging. Recent evidence implicates the gut microbiota as a site of metformin action. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed C. elegans RNAseq to investigate the role of the metformin sensitive OP50 and metformin resistant OP50-MR E. coli microbiota in the drug effects on the host. Our data suggest an evolutionarily conserved bacterial mediation of metformin effects on host lipid metabolism and lifespan.

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