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Summary The gut microbiota shapes animal growth trajectory in stressful nutritional environments, but the molecular mechanisms behind such physiological benefits remain poorly understood. The gut microbiota is mostly composed of bacteria, which construct metabolic networks among themselves and with the host. Until now, how the metabolic activities of the microbiota contribute to host juvenile growth remains unknown. Here, using Drosophila as a host model, we report that two of its major bacterial partners, Lactobacillus plantarum and Acetobacter pomorum, engage in a beneficial metabolic dialogue that boosts host juvenile growth despite nutritional stress. We pinpoint that lactate, produced by L. plantarum, is utilized by A. pomorum as an additional carbon source, and A. pomorum provides essential amino acids and vitamins to L. plantarum. Such bacterial cross-feeding provisions a set of anabolic metabolites to the host, which may foster host systemic growth despite poor nutrition., Graphical Abstract, Highlights • L. plantarum feeds lactate to A. pomorum • A. pomorum supplies essential amino acids and vitamins to L. plantarum • Microbiota metabolic dialogue boosts Drosophila's larval growth • Lactate utilization by Acetobacter releases anabolic metabolites to larvae, Biological Sciences; Microbiology; Microbiome

SUMMARYThe gut microbiota shapes animal growth trajectory in stressful nutritional environments, but the molecular mechanisms behind such physiological benefits remain poorly understood. The gut microbiota is mostly composed of bacteria, which construct metabolic networks among themselves and with the host. Until now, how the metabolic activities of the microbiota contribute to host juvenile growth remains unknown. Here, usingDrosophilaas a host model, we report that two of its major bacterial partners,Lactobacillus plantarumandAcetobacter pomorumengage in a beneficial metabolic dialogue that boosts host juvenile growth despite nutritional stress. We pinpoint that lactate, produced byL. plantarum, is utilized byA. pomorumas an additional carbon source, andA. pomorumprovides essential amino-acids and vitamins toL. plantarum. Such bacterial cross-feeding provisions a set of anabolic metabolites to the host, which may foster host systemic growth despite poor nutrition.GRAPHICAL ABSTRACTHIGHLIGHTSL. plantarumfeeds lactate toA. pomorumA. pomorumsupplies essential amino acids and vitamins toL. plantarumMicrobiota metabolic dialogue boosts Drosophila’s larval growthLactate utilization byAcetobacterreleases anabolic metabolites to larvae

The interplay between nutrition and the microbial communities colonizing the gastrointestinal tract (i.e., gut microbiota) determines juvenile growth trajectory. Nutritional deficiencies trigger developmental delays, and an immature gut microbiota is a hallmark of pathologies related to childhood undernutrition. However, how host-associated bacteria modulate the impact of nutrition on juvenile growth remains elusive. Here, using gnotobiotic Drosophila melanogaster larvae independently associated with Acetobacter pomorumWJL (ApWJL) and Lactobacillus plantarumNC8 (LpNC8), 2 model Drosophila-associated bacteria, we performed a large-scale, systematic nutritional screen based on larval growth in 40 different and precisely controlled nutritional environments. We combined these results with genome-based metabolic network reconstruction to define the biosynthetic capacities of Drosophila germ-free (GF) larvae and its 2 bacterial partners. We first established that ApWJL and LpNC8 differentially fulfill the nutritional requirements of the ex-GF larvae and parsed such difference down to individual amino acids, vitamins, other micronutrients, and trace metals. We found that Drosophila-associated bacteria not only fortify the host’s diet with essential nutrients but, in specific instances, functionally compensate for host auxotrophies by either providing a metabolic intermediate or nutrient derivative to the host or by uptaking, concentrating, and delivering contaminant traces of micronutrients. Our systematic work reveals that beyond the molecular dialogue engaged between the host and its bacterial partners, Drosophila and its associated bacteria establish an integrated nutritional network relying on nutrient provision and utilization., A study of gnotobiotic fruit flies shows that the animal is involved in an integrated nutritional network with its facultative commensal bacteria, centered around the utilization and sharing of nutrients.

The interplay between nutrition and the microbial communities colonizing the gastro-intestinal tract (i.e. gut microbiota) determines juvenile growth trajectory. Nutritional deficiencies trigger developmental delays, and an immature gut microbiota is a hallmark of pathologies related to childhood undernutrition. However, how commensal bacteria modulate the impact of nutrition on juvenile growth remains elusive. Here, using gnotobioticDrosophila melanogasterlarvae independently associated with two model commensal bacterial strains,Acetobacter pomorumWJL(ApWJL) andLactobacillus plantarumNC8(LpNC8), we performed a large-scale, systematic nutritional screen based on larval growth in 40 different and precisely controlled nutritional environments. We combined these results with genome-based metabolic network reconstruction to define the biosynthetic capacities ofDrosophilagerm-free (GF) larvae and its two commensal bacteria. We first established that ApWJLand LpNC8differentially fulfills the nutritional requirements of the ex-GF larvae and parsed such difference down to individual amino acids, vitamins, other micronutrients and trace metals. We found thatDrosophilacommensal bacteria not only fortify the host’s diet with essential nutrients but, in specific instances, functionally compensate for host auxotrophies, by either providing a metabolic intermediate or nutrient derivative to the host or by uptaking, concentrating and sparing contaminant traces of micronutrients. Our systematic work reveals that, beyond the molecular dialogue engaged between the host and its commensal partners,Drosophilaand its facultative bacterial partners establish an integrated nutritional network relying on nutrients sparing and utilization.

SummaryThe microbial environment influence animal physiology. However, the underlying molecular mechanisms of such functional interactions are largely undefined. Previously, we showed that upon chronic undernutrition, strains of Lactobacillus plantarum, a dominant commensal partner of Drosophila, promote host juvenile growth and maturation partly via enhanced expression of intestinal peptidases. By screening a transposon insertion library of Lactobacillus plantarum in gnotobiotic Drosophila larvae, we identify a bacterial cell wall modifying machinery encoded by the pbpX2-dltXABCD operon that is critical to enhance host digestive capabilities and promote growth and maturation. Deletion of this operon leads to bacterial cell wall alteration with a complete loss of teichoic acids D-alanylation. We thus conclude that teichoic acids modifications participate in commensal-host interactions and specifically, D-alanine esterification of teichoic acids contributes to optimal L. plantarum mediated intestinal peptidase expression and Drosophila juvenile growth upon chronic undernutrition.Highlights- LpNC8 mutant library screening identifies genes affecting Drosophila growth promotion.- pbpX2-dlt operon is required for D-alanylation of teichoic acids and Drosophila growth.- Deleting the pbpX2-dlt operon alters host intestinal peptidase expression.- Peptidoglycan and pbpX2-dlt dependent signals are required for LpNC8 mediated growth promotion.eTOC blurbAnimals establish interactions with their microbial communities that shape many aspects of their physiology including juvenile growth. However, the underlying molecular mechanisms are largely undefined. Matos et al. reveal that bacterial teichoic acids modifications contribute to host juvenile growth promotion.

The microbial environment influences animal physiology. However, the underlying molecular mechanisms of such functional interactions are largely undefined. Previously, we showed that during chronic undernutrition, strains of Lactobacillus plantarum, a major commensal partner of Drosophila, promote host juvenile growth and maturation partly through enhanced expression of intestinal peptidases. By screening a transposon insertion library of Lactobacillus plantarum in gnotobiotic Drosophila larvae, we identify a bacterial cell-wall-modifying machinery encoded by the pbpX2-dlt operon that is critical to enhance host digestive capabilities and promote animal growth and maturation. Deletion of this operon leads to bacterial cell wall alteration with a complete loss of d-alanylation of teichoic acids. We show that L. plantarum cell walls bearing d-alanylated teichoic acids are directly sensed by Drosophila enterocytes to ensure optimal intestinal peptidase expression and activity, juvenile growth and maturation during chronic undernutrition. We thus conclude that besides peptidoglycan, teichoic acid modifications participate in the host–commensal bacteria molecular dialogue occurring in the intestine. Under nutritional limitation, modification of the Lactobacillus plantarum cell wall by d-alanylation of teichoic acids is important for host intestinal peptidase expression and consequently growth of the Drosophila host, providing further insights into host–commensal interactions.