Genetic Influences of the Microbiota on the Life Span of Drosophila melanogaster

Abstract

To better understand how associated microorganisms (“microbiota”) influence organismal aging, we focused on the model organism Drosophila melanogaster. We conducted a metagenome-wide association (MGWA) as a screen to identify bacterial genes associated with variation in the D. melanogaster life span. The results of the MGWA predicted that bacterial cysteine and methionine metabolism genes influence fruit fly longevity. A mutant analysis, in which flies were inoculated with Escherichia coli strains bearing mutations in various methionine cycle genes, confirmed a role for some methionine cycle genes in extending or shortening fruit fly life span. Initially, we predicted these genes might influence longevity by mimicking or opposing methionine restriction, an established mechanism for life span extension in fruit flies. However, follow-up transcriptome sequencing (RNA-seq) and metabolomic experiments were generally inconsistent with this conclusion and instead implicated glucose and vitamin B6 metabolism in these influences. We then tested if bacteria could influence life span through methionine restriction using a different set of bacterial strains. Flies reared with a bacterial strain that ectopically expressed bacterial transsulfuration genes and lowered the methionine content of the fly diet also extended female D. melanogaster life span. Taken together, the microbial influences shown here overlap with established host genetic mechanisms for aging and therefore suggest overlapping roles for host and microbial metabolism genes in organismal aging. IMPORTANCE Associated microorganisms (“microbiota”) are intimately connected to the behavior and physiology of their animal hosts, and defining the mechanisms of these interactions is an urgent imperative. This study focuses on how microorganisms influence the life span of a model host, the fruit fly Drosophila melanogaster. First, we performed a screen that suggested a strong influence of bacterial methionine metabolism on host life span. Follow-up analyses of gene expression and metabolite abundance identified stronger roles for vitamin B6 and glucose than methionine metabolism among the tested mutants, possibly suggesting a more limited role for bacterial methionine metabolism genes in host life span effects. In a parallel set of experiments, we created a distinct bacterial strain that expressed life span-extending methionine metabolism genes and showed that this strain can extend fly life span. Therefore, this work identifies specific bacterial genes that influence host life span, including in ways that are consistent with the expectations of methionine restriction.

The impact of the gut microbiome on memory and sleep in Drosophila

“…In addition to locomotor activity, we examined here the influence of the microbiome of circadian rhythmicity, failing to detect an effect even when flies carried the hypomorphic per L allele. Finally, and in agreement with Selkrig et al 2018 In general terms, the several among-study discrepancies in microbiome effects on locomotor activity of Drosophila can be attributed, at least partly, to the differences in host genotype and diet, both of which are known to influence microbiome effects on host traits in Drosophila (Consuegra et al, 2020;Dobson et al, 2015;Jehrke et al, 2018;Keebaugh et al, 2019;Matthews et al, 2020;Wong et al, 2014) and other animals (Ezra-Nevo et al, 2020;Leigh and Morris, 2020). Two further issues relate specifically to this study.…”

The Microbiome and Mosquito Vectorial Capacity: Rich Potential for Discovery and Translation

“…Microbiome-mediated alterations in metabolites in the host can lead to different survival outcomes. A recent study demonstrated that bacteria which lowered methionine content of food extended Drosophila host lifespan [108]. Although this was tested in flies, methionine acts as a larvicide against several mosquito species such as An.…”

Horizontal gene transfer-mediated bacterial strain variation affects host fitness

“…[15,18,52,77,78]. In particular, in D. melanogaster evidence for the importance of variation between closely related bacteria is accumulating for life history of the host [26,29,[47][48][49][50][51]79].…”

“…Techniques for the generation of gnotobiotic flies are readily available and standardized measurements of phenotypes exist. Affected phenotypes include the life history traits development time, fecundity, and life span as well as size of the adults [14,[26][27][28][29][30][31][32][33]. These traits are directly related to fitness, emphasizing the potential importance of microbes in host evolution and adaptation.…”

“…Interestingly, the metabolic potential to produce nutrients that affect fly fitness differ between closely related microbes and so do the effects on fly phenotype and fitness [26,29,32,[47][48][49][50][51].…”