The Predicted Metabolic Function of the Gut Microbiota ofDrosophila melanogaster

Abstract

An important goal for many nutrition-based microbiome studies is to identify the metabolic function of microbes in complex microbial communities and its impact on host physiology. This research can be confounded by poorly-understood effects of community composition and host diet on the metabolic traits of individual taxa. Here, we investigated these multi-way interactions by constructing and analyzing metabolic models comprising every combination of five bacterial members of the Drosophila gut microbiome (from single taxa to the five-member community of Acetobacter and Lactobacillus species) under three nutrient regimes. We show that the metabolic function of Drosophila gut bacteria is dynamic, influenced by community composition and responsive to dietary modulation. Furthermore, we show that ecological interactions such as competition and mutualism identified from the growth patterns of gut bacteria are underlain by a diversity of metabolic interactions, and show that the bacteria tend to compete for amino acids and B vitamins more frequently than for carbon sources. Our results reveal that in addition to fermentation products such as acetate, intermediates of the tricarboxylic acid (TCA) cycle including 2-oxoglutarate and succinate are produced at high flux and cross-fed between bacterial taxa suggesting important roles for TCA cycle intermediates in modulating Drosophila gut microbe interactions and the potential to influence host traits. These metabolic models provide specific predictions of the patterns of ecological and metabolic interactions among gut bacteria under different nutrient regimes, with potentially important consequences for overall community metabolic function and nutritional interactions with the host.IMPORTANCEDrosophila is an important model for microbiome research partly because of the low complexity of its mostly culturable gut microbiota. Our current understanding of how Drosophila interacts with its gut microbes and how these interactions influence host traits derives almost entirely from empirical studies that focus on individual microbial taxa or classes of metabolites. These studies have failed to capture fully the complexity of metabolic interactions that occur between host and microbe. To overcome this limitation, we reconstructed and analyzed 31 metabolic models for every combination of the five principal bacterial taxa in the gut microbiome of Drosophila. This revealed that metabolic interactions between between Drosophila gut bacterial taxa are highly dynamic and influenced by co-occurring bacteria and nutrient availability. Our results generate testable hypothesis about among-microbe ecological interactions in the Drosophila gut and the diversity of metabolites available to influence host traits.

Gut bacteria regulate the pathogenesis of Huntington’s disease in Drosophila model

“…Our Drosophila stocks including those with human HTT transgenes predominantly harbor several Lactobacilli strains and Acetobacter senegalensis (A. senegalensis) species. Notably, Lactobacilli and Acetobacter show temporal fluctuation in abundance independent of any transgenes, which may be related to flies’ physiology and nutritional demand (Schretter et al, 2018, Storelli et al, 2018, Henriques et al, 2020, Yamauchi et al, 2020, Ankrah et al, 2021) (Fig. 5, Supplementary fig.…”

“…Similar to mammals, gut homeostasis in Drosophila is regulated by the interaction of bacteria with the enteric neurons and intestinal epithelium including the enteroendocrine cells, which produce antimicrobial peptides (AMPs) involved in immunity against invasive pathogens and maintaining optimal abundance of commensal bacteria (Hanson and Lemaitre, 2020). Drosophila has a handful of commensal gut bacteria, which can easily be manipulated for studies on gut-brain communications (Douglas AE, 2018, Ankrah et al, 2021). Lactobacillus and Acetobacter species are the two most abundant bacterial genera, which regulate nutrients acquisition, growth, metabolism, immune development and locomotion (Schretter et al, 2018, Storelli et al, 2018, Henriques et al, 2020, Yamauchi et al, 2020, Ankrah et al, 20201).…”

Succinate: A microbial product that modulates Drosophila nutritional physiology

“…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.…”

“…To check whether the effect of succinate on fly lipid content was general to dicarboxylic acids we then analyzed flies fed on diets supplemented with fumarate, the product of succinate oxidation via the TCA enzyme succinate dehydrogenase and a metabolite that is not predicted to be released from Drosophila gut microorganisms (Ankrah et al, 2021). In contrast to flies fed on succinate, flies fed on fumarate displayed no statistically significant reductions in TAG levels compared to flies on the fumarate-free controls (Fig.…”

“…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.…”