Insects feeding on the nutrient-poor diet of xylem plant sap generally bear two microbial symbionts that are localized to different organs (bacteriomes) and provide complementary sets of essential amino acids (EAAs). Here, we investigate the metabolic basis for the apparent paradox that xylem-feeding insects are under intense selection for metabolic efficiency but incur the cost of maintaining two symbionts for functions mediated by one symbiont in other associations. Using stable isotope analysis of central carbon metabolism and metabolic modeling, we provide evidence that the bacteriomes of the spittlebug Clastoptera proteus display high rates of aerobic glycolysis, with syntrophic splitting of glucose oxidation. Specifically, our data suggest that one bacteriome (containing the bacterium Sulcia, which synthesizes seven EAAs) predominantly processes glucose glycolytically, producing pyruvate and lactate, and the exported pyruvate and lactate is assimilated by the second bacteriome (containing the bacterium Zinderia, which synthesizes three energetically costly EAAs) and channeled through the TCA cycle for energy generation by oxidative phosphorylation. We, furthermore, calculate that this metabolic arrangement supports the high ATP demand in Zinderia bacteriomes for Zinderia-mediated synthesis of energy-intensive EAAs. We predict that metabolite cross-feeding among host cells may be widespread in animal–microbe symbioses utilizing low-nutrient diets.

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Dear Editor,Gut microorganisms process food in animal guts and release many metabolic by-products, which are predicted to influence host physiological processes such as energy and lipid metabolism. Here, we investigate how succinate, a TCA cycle intermediate that is a major predicted release product of gut bacteria in Drosophila, influences the nutritional physiology of its Drosophila host. We administered succinate as a dietary supplement to microbefree Drosophila, and quantified key nutritional indices. Dietary succinate significantly reduced fly lipid levels by up to ∼50%. This response was not replicated in parallel experiments conducted with dietary fumarate supplement, indicating that it could not be attributed to a general effect of TCA intermediates. We hypothesize that microbe-derived succinate may contribute to the reduced lipid content of Drosophila bearing gut bacteria, relative to axenic Drosophila. More generally, this study highlights the importance of microbial-derived metabolites as regulators of host metabolism.The focus of this study, succinate, is predicted to be released at substantial rates by several of the key bacterial members of the Drosophila gut microbiota (Ankrah et al., 2021). Succinate is a TCA cycle intermediate and it has been implicated as a modulator of host metabolism in mammalian systems. Specifically, microbial-derived metabolites from the TCA cycle play important roles in regulating host glucose homeostasis (