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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.