The Role of Microbiota in Drosophila melanogaster Aging

Abstract

Intestinal microbial communities participate in essential aspects of host biology, including nutrient acquisition, development, immunity, and metabolism. During host aging, dramatic shifts occur in the composition, abundance, and function of the gut microbiota. Although such changes in the microbiota are conserved across species, most studies remain descriptive and at most suggest a correlation between age-related pathology and particular microbes. Therefore, the causal role of the microbiota in host aging has remained a challenging question, in part due to the complexity of the mammalian intestinal microbiota, most of which is not cultivable or genetically amenable. Here, we summarize recent studies in the fruit fly Drosophila melanogaster that have substantially progressed our understanding at the mechanistic level of how gut microbes can modulate host aging.

Keywords: aging; drosophila; dysbiosis; dysplasia; intestinal immunity; lifespan; microbiota.

FIGURE 1

Model depicting the impact of microbiota on intestinal homeostasis during aging in Drosophila. In a healthy, young gut (left panel), the microbiota helps to sustain intestinal homeostasis, intestinal integrity, and optimal lifespan. Commensal bacteria like L. plantarum release L-lactate in the intestine. L-lactate enters the intestinal cells via monocarboxylate transporters (MCT) and is oxidized by the host lactate dehydrogenase (LDH), thus generating NADH. NADH is used by the NADPH-oxidase Nox to generate Reactive Oxygen Species (ROS) which stimulate basal intestinal stem cell (ISC) proliferation and differentiation in EnteroBlasts (EB) and Enterocytes (EC) to ensure tissue homeostasis. L. plantarum (Lp) and other commensals such as A. pomorum (Ap) stimulate basal IMD pathway activity by triggering the receptor PGRP-LE and the Relish transcription factor which consequently induces expression of PGRP-SCs and antimicrobial peptides (AMPs)—molecules that control the proliferation of the commensal bacteria. In the aging gut (right panel), the activated FOXO transcription factor boosts Relish activity and AMPs genes expression but suppresses PGRP-SCs expression. Such an environment with an excessive amount of AMPs and reduced production of PGRP-SCs favors the emergence and selection of pathobionts in the commensal community. Such pathobionts like G. morbifer (Gm), L. brevis (Lb), or P. rettgeri (Pr) are resistant to AMPs and release uracil which promotes excessive ROS production via activation of DUOX. DUOX-dependent ROS in turn stimulates uncontrolled ISC proliferation and defective differentiation resulting in gut dysplasia, loss of tissue integrity, and reduced lifespan.